International Journal of Nanomedicine Dovepress

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REVIEW

Innovative Therapeutic Approaches Based on

Nanotechnology for the Treatment and
Management of Tuberculosis
International Journal of Nanomedicine downloaded from https://www.dovepress.com/ on 25-Sep-2023

1 2
Pooneh Kia , Umme Ruman , Ariyati Retno Pratiwi 3 , Mohd Zobir Hussein 2

1
Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia; 2Nanomaterials Synthesis and Characterization Laboratory (NSCL),
Institute of Nanoscience and Nanotechnology (ION2), Universiti Putra Malaysia, UPM Serdang, Selangor, Malaysia; 3Department of Oral Biology,
Faculty of Dentistry, Universitas Brawijaya, Malang, Indonesia

Correspondence: Mohd Zobir Hussein, Email [email protected]

Abstract: Tuberculosis (TB), derived from bacterium named Mycobacterium tuberculosis, has become one of the worst infectious
For personal use only.

and contagious illnesses in the world after HIV/AIDS. Long-term therapy, a high pill burden, lack of compliance, and strict
management regimens are disadvantages which resulted in the extensively drug-resistant (XDR) along with multidrug-resistant
(MDR) in the treatment of TB. One of the main thrust areas for the current scenario is the development of innovative intervention
tools for early diagnosis and therapeutics towards Mycobacterium tuberculosis (MTB). This review discusses various nanotherapeutic
agents that have been developed for MTB diagnostics, anti-TB drugs and vaccine. Undoubtedly, the concept of employing
nanoparticles (NPs) has strong potential in this therapy and offers impressive outcomes to conquer the disease. Nanocarriers with
different types were designed for drug delivery applications via various administration methods. Controlling and maintaining the drug
release might be an example of the benefits of utilizing a drug-loaded NP in TB therapy over conventional drug therapy. Furthermore,
the drug-encapsulated NP is able to lessen dosage regimen and can resolve the problems of insufficient compliance. Over the past
decade, NPs were developed in both diagnostic and therapeutic methods, while on the other hand, the therapeutic system has
increased. These “theranostic” NPs were designed for nuclear imaging, optical imaging, ultrasound, imaging with magnetic resonance
and the computed tomography, which includes both single-photon computed tomography and positron emission tomography. More
specifically, the current manuscript focuses on the status of therapeutic and diagnostic approaches in the treatment of TB.
Keywords: tuberculosis, nanomedicine, theranostic, diagnostic, therapeutic

Introduction
Tuberculosis (TB) is possibly a contagious fatal illness that has a destructive effect on the human lungs. Mycobacterium
tuberculosis, the TB-causing bacteria, can be spread through airborne droplets from one person to another by sneezes or
coughs. In 1882, Robert Koch was awarded the Nobel Prize for this significant discovery. Mycobacterium tuberculosis
(MTB) known as an intracellular pathogen and an acid-fast bacillus that has evolved a variety of survival mechanisms to
resist of being destroyed by macrophages.1 MTB is one of the most effective pathogens, able to living for decades in the
host without creating any signs or symptoms of TB.2 According to the latest evaluation, MTB has infected around 25%
of the world’s population. The World Health Organization (WHO) estimated the TB global outbreak peaked between
2003 and 2019, and to be declining slowly and that 1.6 million people being killed of tuberculosis in 2019,3,4 whilst TB
was labelled a worldwide health emergency by the World Health Organization in 1993. M. leprae, M. avium and
M. kansasii are among species of the pathogenic Mycobacterium. M. kansasii and M. avium do not result in tuberculosis
or leprosy but do cause pulmonary infection and are hence known as non-TB mycobacterium.
TB can persist as a latent or active infection, whilst the former is symptomless and does not cause for disease
transmission and the latter one is severe and contagious. Some studies have shown that persons with latent tuberculosis
have a 10% probability of developing active tuberculosis if they have a weak immune system. Hence, it is also necessary

International Journal of Nanomedicine 2023:18 1159–1191 1159

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for diagnosing latent tuberculosis and preventing it from becoming active.5 Primarily Mycobacterium mostly affects the
respiratory system; however, it has the ability to attack any part of the body, such as bones, bloodstream (miliary
tuberculosis), lymphatic system, kidney, joints, genitourinary system and central nervous system (meningitis).6 Success
or failure rate in the treatment of TB depends on various factors such as (a) smoking, (b) malnutrition, (c) patient
adherence to treatment, (d) insufficient monitoring by clinical staff, and (e) and coexisting diseases like HIV.
The main issue with the current TB chemotherapy is the longer period for the medication to be administered orally or
given intravenously, the systemic blood circulation distributes it throughout the body, and most of the molecules fail to
reach to the target destinations; therefore most of it remains in the body, creating toxicities and destructive impacts.
Drugs have low plasma life with a high clearance rate, which can limit their efficacy.7 To overcome the problems of the
anti-tuberculosis medications and reestablish a better efficacy of TB therapy, a new generation of TB treatments must be
developed, especially to overcome the tuberculosis clinical management.8
Some major challenges to the current TB therapies include (a) extended treatment duration and (b) continual and
common varied drug doses, which often leads to patients’ poor or noncompliance with existing therapy. The patient’s
poor complying is the predominant related cause in the re-emergence of the illness, as well as the multidrug resistance
(MDR) TB and further serious condition known as extensively drug-resistant (XDR) TB.9 Furthermore, MDR-TB and
XDR-TB are on the rise in emergent nations, placing medical researchers to the challenge as well as becoming a serious
threat globally.
AIDS, which provides a favorable ground for MTB development in an immunocompromised host, is another key
factor in the rising prevalence of tuberculosis.10 Spreading strains of MDR and XDR, as well as a lack of effective
treatment strategies, emphasize the need for novel and efficacious anti-TB drugs to conquer issues of shorter treatment
durations, drug resistance, and greater compliance.11 Nanotechnology-based treatment, or nanomedicine, has been
studied in recent decades as a means of substituting the conventional practice of delivery of antibiotics or other
pharmaceuticals using drug-encapsulated nanoparticles (NPs). Drug delivery via nanomedicine technology provides
the advantages of a controlled-, slow-, and sustained-release from biodegradable nanoparticles.12 Nanoparticles with
sizes defined as nanometers (<100 nm) are commonly employed as nanocarriers in drug delivery techniques. Drugs can
be embedded onto the nanoparticles or loaded in a matrix of the nanocarriers for therapeutic reasons.12 Nanocarriers can
be any biocompatible and biodegradable nanomaterials like polymers, which can be either solid, lipids, natural, or
synthetic, etc.13 They penetrate cells more efficiently and successfully than the larger-sized molecules, making them
a potential route for the target delivery system. The nanocarriers are engineered to allow for persistent, controlled- and
slow-release of drugs from the matrix. In addition, nanomedicine has advantages over conventional tuberculosis therapy
approaches owing to the targeted treatment of anti-tubercular drug-loaded nanocarriers, particularly into the lungs, where
primary TB is grown. This innovation could well circumvent anti-TB drug metabolism by escaping the first-pass
metabolism system, with fast permeation and therapeutic results owing to the alveolar large surface area, avoid non-
targeted distribution by using theranostic and diagnostic capabilities, reducing cytotoxic activity (liver and renal toxicity),
and promoting patients’ compliance towards the therapy.14 Despite the high deposition efficiency and consistency of drug
delivery to targeted tissues, this delivery system may penetrate straight into the deep tissues of the lungs and alveolar
macrophages and provide its therapeutic impact.15 Despite the targeted delivery, controlled and site-specific aerosolized
target delivery in nanomedicine, which exhibits greater absorption into the alveoli as well as better macrophage uptake,
the absence of medication persistence inside the lung’s alveoli inhibits clinical translation of this therapeutic
alternative. As a result, delivery of intracellular nanomedicine that particularly targets medication release or distribution
in infected cells can conquer all the therapeutic hurdles linked to conventional TB therapy.
Nanomedicine has received a lot of attention in the past few years as a viable replacement for conventional
therapeutic applications for tuberculosis treatment due to its greater efficacy, the capability to deliver multiple therapeutic
payloads at the same time, improve selectivity, the strategies to endure multiple drug resistance and thus increased drug
strength. Nanomedicine eliminates side effects and toxicity of the drugs by delivering the medication to the target tissue
in a particular way that avoids off-target release, whereas its nano-sized diameters increase the permeability and
solubility of the drug loaded in the nanocarrier. Furthermore, this enhances the stability of drug by isolating it from

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other external factors, and it enhances the drug residence by preventing the drug from passing away, which results in
greater therapeutic effects.16
This review will discuss different types of Mycobacterium tuberculosis infections, conventional diagnostics and
treatments. In addition, research, development and innovation using nanotechnology approaches for the treatment of TB
will also be discussed.

Genus of Mycobacterium
The famous scientist Robert Koch, a Nobel Laureate in Medicine in 1905 discovered and in 1882 isolated this microbe.
Discovery and diagnosis of the cause factor of (MTB), on March 24, 1882, paved the way both for a preventive plan
based on laboratory germ attenuation and an effective searching for something like a pharmaceutical therapy.17
Mycobacterium is the main genus in the Mycobacteriaceae family and belongs to the Actinomycetales order, which
now contains about 100 identified genus or proposed species, as well as variety of saprophytic microorganisms and
pathogenic of the warm-blooded animals. The presence of mycolic acids and acid-fastness are defining features of this
genus. Mycobacteria are aerobic, slow-growing, rod-shaped, slender and free-living in soil and water and non-spore-
forming microorganisms. The generation time of these bacteria is about 20 h, but identification and isolation may take up
to 6 weeks. Moreover, they are acid-alcohol-fast microorganisms that resist decolorization when stained with strong
mineral acids and acidified alcohol. This acid-fastness feature, caused by waxy cell walls, is critical for detecting
mycobacteria.18 Since the rest of bacteria with Gram-positive features (such as Rhodococcus, Corynebacterium, or
Nocardia) are frequently acid-fast; therefore, the staining process must be done carefully.
The MTB complex includes Mycobacterium tuberculosis, Mycobacterium bovis BCG, Mycobacterium pinnipedii,
Mycobacterium africanum, Mycobacterium bovis, Mycobacterium caprae and Mycobacterium microti. These bacteria
cause tuberculosis, which is defined by tubercles development as well as the caseous necrosis in tissues. The tubercle
bacilli are derived from tuberculous individuals. M. tuberculosis is perpetuated by humans, while M. bovis is perpetuated
by cattle, bison, and deer; and M. avium is perpetuated by chickens. M. tuberculosis, M. bovis, and M. avium can infect
and transmit to wild mammals and birds, and these animals can be potential infection sources for the domestic animals.19
The MTB cell wall’s structural details and its interactions with anti-TB drugs are shown in Figure 1. Rifampin (RIF)
and isoniazid (INH) are the two major anti-TB drugs with recognized mechanisms of resistance. Rifampin is used as the
first-line drug in the treatment regimens. Rifampin functions by limiting synthesis of the RNA, commonly known as

Figure 1 Cell wall structure of MTB and its interaction with the anti-TB drugs.
Notes: Adapted from Tuberculosis drugs and mechanisms of action. National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/tbdrugs.
Accessed March 1, 2023.21

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transcription, and eventually induce cell death. Since Rifampin resistance is usually coupled with Isoniazid resistance,
resistance to this antibiotic is used to predict and estimate the multidrug-resistance TB.20
Mycobacteria are gram-positive bacteria that are immobile, slow-growing, and have a high genomic G+C content
(61–71%). Mycobacteria is called acid-fast because of their staining properties under a microscope, that are mediated
with mycolic acid inside the cell wall, and this is one of the reasons for mycobacteria’s hardiness.
There are three types of Mycobacteria complex,19 and this will be discussed below.

Nontuberculous Mycobacteria (NTM)

Biochemical differentiation of mycobacteria from the rest of similar genera was carried out by analysis of the mycolic
acids or fatty acids. Mycobacteria have mycolic acid with chemo-type IV within their wall.22 Nelson staining is one of
the most prevalent approaches and at the same time the easiest technique for the primary detection of mycobacteria.
Runyon in the 1950s divided mycobacteria into four categories based on pigment production and growth rate. To some
extent, the Runyon classification of nontuberculous mycobacteria is based on the rate of growth: photo-chromogen, non-
chromogen, scoto-chromogen and fast-growing. Fast-growing mycobacteria formed in solid media grow in less than 7
days, while most non-tuberculosis (NTM) generations belong in this category. Other generations in the Runyon category
were considered slow-growing kinds. It takes more than 7 days for these species to grow in solid media, and the bacilli of
Mycobacterium tuberculosis complex and several non-tuberculosis species are classified in this group. It is reported that
many slow-growing species were closely associated with disease in humans and animals. Unlike slow-growing species,
most fast-growing species were less pathogenic to humans and were considered opportunistic pathogens.23

Mycobacterium tuberculosis
These nine species are the main group of the Mycobacterium which causes tuberculosis: Tuberculosis sensu stricto,
M. africanum, M. canetti, M. bovis, M. caprae, M. microti, M. pinnipedii, M. mungi and M. orygis. Slow-growing
Mycobacterium tuberculosis should be incubated in culture media for almost 3 to 8 weeks. It takes about 10 to 20 days
for the Bacillus colonies to appear in a small, dry, scaly solid medium. Mycobacteria generation time is 14 to 15 hours
and in some sources up to 18 hours. Owing to the existence of wax and fat in the bacterial wall, the transfer of nutrients
into the cell is slow; therefore, the growth of this bacterium is slow.24

Mycobacterium leprae
Mycobacterium leprae is the pathogen that causes leprosy, an infectious disease which affects skin and nerves. Despite
effective therapies in previous decades, the spread of the disease continues unabated, and the transmission channels are
still unknown. Despite the widespread opinion which incurable M. leprae-infected individuals are the primary transmis­
sion source, little evidence suggests that environmental sources might serve as a reservoir. It was also looked at if
M. leprae DNA may be found in soil in leprosy-endemic areas or places with potential animal reservoirs like armadillos
and red squirrels.25

Pathogenesis of Tuberculosis
Tuberculosis is disseminated by MTB complex-containing droplet nuclei in the air and is 1–5 μm in diameter. Once
people cough, sneeze, talk or sing while suffering from pulmonary or laryngeal TB, these droplet nuclei develop. Aerosol
therapies, bronchoscopy aerosolization and lesions or tissue manipulation and sputum induction, or secretion processing
in the hospital or laboratory might all result in them.26 Droplet nuclei contain two to three MTB organisms and are so
tiny that they may be kept airborne for a long time by air currents found in any indoor area.27 They are tiny enough to go
into the lungs’ alveoli, where the germs replicate.28 Although TB patients create bigger particles holding more bacilli,
these particles are not recognized to be efficient transmitters for contagious infection since they are unable to remain in
airborne and cannot penetrate the alveoli if inhaled. Organisms deposited on healthy mucosa or skin do not affect tissue.
Once particles of a larger size are inhaled, these collide with the airway or upper respiratory tract wall, are caught in the
mucous blanket and transported into the oropharynx, where they are digested or expectorated.29 The chance of MTB
transmission is determined by the four parameters listed below.

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(a) The quantity of organisms released into the air.

(b) Organism concentration in the air, which is defined by the space’s volume and ventilation.
(c) Time the exposed person is exposed to contaminated air.
(d) Immunological condition of the person who was exposed.

The droplet nucleus is transferred via the bronchial tubes and implanted in a bronchiole or respiratory alveolus
immediately after inhalation. There is no question that an inhaled tubercle bacillus causes an infection in the lungs;
nevertheless, the virulence of the bacterium as well as the ability of the microbicides alveolar macrophage that ingests it
plays a significant role. The bacillus has a chance to multiply inside the alveolar macrophage if it survives the initial
barrier. The tubercle bacillus replicates gradually in the macrophage, dividing every 25 to 32 hours. There are no known
endotoxins or exotoxins in Mycobacterium TB; hence, there is no immediate host response to infection. The micro­
organisms develop for 2 to 12 weeks till they exceed a population of 103 to 104, that triggers a cellular immune
response,30 It can be recognized by a TB skin test response.31 Before developing the cellular immunity, tubercle bacilli
transmit from the lymphatics to the hilar lymph nodes and subsequently via the circulation to more distant regions.
Many tissues and organs are resistant to the bacilli’s subsequent multiplication. Mycobacteria are frequently found in
the bone marrow, liver, and spleen, however uncontrolled growth of the bacteria in these places seems to be an exception.
Sediment of organisms inside the upper lungs, brain, bones, and kidneys could find a suitable environment to grow, and
numerous bacterial divisions may arise before particular cellular immunity develops and limits duplication. In individuals
with flawless cell-mediated immunity, accumulations of activated T-cells and macrophages from granulomas restrict the
multiplication and spread of the organism. Antibodies towards M. tuberculosis are shaped; however, they do not appear
protective.32 The organisms are often concentrated in the centre of the granuloma, which commonly turns necrotic.33
Duplication of M. tuberculosis is stopped in most people with normal immune systems as soon as cell-mediated
immunity forms, however, if a few numbers of live bacilli remain in the granuloma. Although a main complex could
often be seen on a chest radiograph, the majority of pulmonary TB infections are clinically and radiographically
undetectable.34 The most frequent sign that an infection with M. tuberculosis has occurred is indeed a positive tuberculin
skin test result.
People who have latent TB infection but not the active ones, are not contagious, making it impossible to spread the
organism. According to the studies, approximately 10% of those with TB infections who do not receive preventative
treatment can spread active tuberculosis and the risk of infection is still significantly high during 2 years of infection, this
is the time that half of cases will occur.35 Additionally, diseases like silicosis, diabetes mellitus, and illnesses related to
immunosuppression, such HIV infection, along with corticosteroids and other immunosuppressive drugs, are likely to
reduce the host’s capabilities to respond to the organism. In these conditions, the risk for developing and spreading TB is
risen, particularly during the first 2 years of life.36 Figure 2 indicates the stages of bacteria that enter the lung tissue,
which are generally digested by alveolar macrophages; however, several bacteria grow inside macrophages and once the
macrophages die, they are eventually released. Living macrophages (carrying M. tuberculosis) can transfer the bacteria
into tissues and organs via the lymphatic system or even the blood, resulting in extra pulmonary TB. Extra pulmonary TB
infects the lymph nodes, meninges, kidneys, spine, and bones about 15–20%. Extra-pulmonary TB has an atypical
clinical appearance, which is frequently stimulated by inflammation or neoplasia.37

Types of TB Infections
Tuberculosis infections and tuberculosis illness are two different things. Whenever a person is exposed to someone who
has tuberculosis and breathes in the TB germs, this person is recognized as having TB infection. The majority of people
with strong immune systems are able to stop the infection at that time and avoid developing TB. Some people with
tuberculosis infection (positive TB skin test but normal chest X-ray) are not ill and is not infectious to others.
Medication therapy Tuberculosis can effectively destroy bacteria and stop future TB infections. Nevertheless, if
a person with tuberculosis does not take preventative medication, the bacteria can develop and cause active tuberculosis.
A persistent cough that lasts 2 or more weeks, pain in the chest, fatigue, and lack of appetite are all symptoms of
tuberculosis.38 When a person has active TB disease, the individual may be contagious and cause infection in other

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Figure 2 Pathogenesis of tuberculosis.

people, specifically those with whom they spent the most contact. Anyone with active tuberculosis will need to take
various TB drugs for several months to recover and not infect others. Although, after a few weeks of medication, they
may no longer be contagious and will be allowed to return to work and normal activities while finishing their TB
treatment. People can have active tuberculosis in any organ of the body, but this is only infectious to others when it is in
the lungs or larynx.39
Table 1 shows some of the most common signs of active tuberculosis in the lungs: cough with sputum and blood at
times, chest pains, weakness, weight loss, fever and night sweats.40 Latent TB occurs when a person is infected with
tuberculosis but does not develop an overt disease. They have no symptoms, and their chest X-ray may even be clear.
A reaction to a tuberculin skin test (TST) or an interferon-gamma release assay (IGRA) may be the only symptom of this

Table 1 Symptoms Difference Between Latent and Active TB

Features Latent TB Active TB Ref.

Infectivity Latent TB patients are unable to People with active TB can spread [42]
transmit the infection the disease

Symptoms No Five major symptoms; cough [43]

lasting three or more weeks,
coughing up blood, losing weight,
night sweats, shortness of breath,
and fever

Skin test Positive Positive [44,45]

Interferon gamma release assay Positive Positive [45]

Sputum acid-fast bacillus smear Negative Negative or positive [47]

Chest radiography Normal or stable calcified Abnormal findings with active TB [48]
granulomas infections

Treatment Conceder treatment to prevent Isolation and drug regimen [49]

progression to active TB

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interaction. Yet, there is a continuing possibility that the latent TB infection could escalate to the active TB. Other
diseases, such as HIV, or medications that weaken the immune system, enhance the risk of infection as well.
Furthermore, miliary tuberculosis is a rare type of active tuberculosis that arises when TB bacteria enter the bloodstream.
In this condition, the bacteria rapidly spread throughout the body in tiny nodules and affect numerous organs at the same
time. This kind of tuberculosis can be rapidly fatal.41

Classification of Mycobacterium
While TB affects the respiratory system, it may also infect other cells and tissues, for instance the spine, brain, and
kidney. TB can be fatal if adequate medical treatment is not taken. The medical community classifies TB into two
categories, pulmonary and extrapulmonary, which result in 11 different forms of tuberculosis (Table 2). Four of these are

Table 2 Classification of TB and Their Main Symptoms

Type of TB Specific TB Devastating Effect Symptoms Ref.
Pulmonary Laryngeal Bacterium attacks the throat’s vocal cords. Frequently confused with other throat diseases [50]
like chronic laryngitis and laryngeal carcinoma

Cavitary Bacterium creates gradual destruction Coughing up blood, excessive sweating, fever, losing [51]
to the lung by developing cavities or weight and fatigue. TB empyema occurs when the
expanded air spaces, in the lungs. illness progresses into the pleural space (pleural pus).

Miliary Lymphatic and hematogenous spreading Night sweating, fever and losing weight are all [52]
and it’s possible that happen soon after the symptoms of this condition. Since the initial chest
primary infection. X-ray is often clear, it might be difficult to diagnose.

Pleurisy The pleural space, which is placed The mass of fluid in the lungs rises quickly, [53]
between the lungs and the chest wall is compressing the lungs and causing breathing
ruptured at the edge of the lung by problems (dyspnea) and severe chest discomfort that
a granuloma. gets worse when patients take a big breath (pleurisy).

Extrapulmonary Adrenal The bacterium affects the adrenal gland Inadequate adrenal gland production causes [54]
and the production of adrenal hormone. weakness or faintness.

Lymph node The bacterium impacts the lymph nodes Lymph nodes become so large, they rupture [55]
and causes them to become enlarged. through the skin if not diagnosed in time

Osteal The bacterium infects the bones and Bone tissue weakening and even bone fractures [56]
spines. depending on where the disease has spread in the
body and back deformity.

Peritonitis The bacterium can attack the intestines’ Increased fluid production, similar to that of [57]
outer linings as well as the linings of the tuberculosis pleuritis. Abdominal distention and
abdominal wall. pain are caused by an increase in fluid. Patients are
fatigued to moderate sick with a fever.

Renal Pyuria, or the white blood cell presence in In men, renal TB can lead to swelling of the tube that [58]
the urine, is caused by the bacterium and connects the testicles with the vas deferens,
can harm reproductive organs. a condition known as Renal tuberculosis in males can
cause inflammation of the tube that links the testicles
to the vas deferens, a disease named epididymitis.

Meningitis The bacterium causes stroke or a brain This highly deadly type of extra pulmonary TB, [59]
tumor. attacks the brain.

Pericarditis Pericarditis happens by excessing builds The heart’s ability to pump blood and function [60]
fluid around the heart. normally might be affected when TB damages this
tissue.

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Figure 3 TB infection risk factors.

caused by pulmonary TB, whereas the remaining seven are caused by extrapulmonary tuberculosis. Extrapulmonary TB
is the most common in those with a weakened immune system.

The Factor That Influences TB

There are two stages in the possibility of developing active TB after exposure to tuberculosis bacilli, and each stage is
impacted by both internal and external risk factors. Furthermore, exogenous factors including bacillary concentration in
sputum and contact with an active TB case play an essential role in speeding the development from exposure to infection.
The progression of infection to active TB illness is also influenced by endogenous factors. Comorbidities like diabetes,
indoor air pollution, alcohol, immunosuppressive medication use, and cigarette smoke, illicit drug use, in addition to
well-established risk factors (such as HIV, malnutrition, and young age) have a massive effect on both populations and
individuals.61 Socioeconomic status and behavioral aspects have also been shown to enhance infection susceptibility.
Certain groups, including health care professionals and indigenous peoples, are also at a greater risk of catching TB.
Figure 3 highlights the major risk variables that affect an individual’s risk of getting TB infection. It illustrates the
primary features that influence an individual’s risk of contracting infection and disease.62

Tuberculosis Current Situation and Challenges

Tuberculosis (TB) is among the most deadly and oldest infectious diseases that harmed human skeletons for thousands of
years.63 Until 1882, the major cause of TB was unclear. Dr Robert Koch reported the discovery of bacillus
Mycobacterium tuberculosis as the major cause of the disease, during the second final decade of the nineteenth century.
Every year since then, the 24th of March has been observed as “World Tuberculosis Day”.64 TB is a contagious illness
that spreads readily from person to person. The main cause of tuberculosis is coughing, which occurs when a person
afflicted with tuberculosis, expel the bacteria into the air. Data from the National vital registration systems indicate that in
the late eighteenth century, tuberculosis was known as the leading cause of mortality in various European countries,
North America, and other parts of the world. However, throughout the twentieth century, with rapid improvements in
nutrition, income, and housing, the rate of TB cases began to decline, and the majority of TB casualties also started to
drop, albeit slowly (1–2% each year).65 Since the early 1940s, the number of tuberculosis cases has been declining at
a pace of 10% each year. Similarly, the rate of TB mortality has been dropping. One of the primary reasons for the
decrease in the cash rate and the fatality rate was the innovation, progress, and administration of effective drug
treatments. In several countries, tuberculosis is known as a disease of the past, owing to the low disease prevalence.

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These countries have less than one mortality per 100,000 people and fewer than 10 fatalities per year. Even though the
prevalence of tuberculosis is declining, in some parts of the globe, tuberculosis remains a persistent and never-ending
public health problem. With prompt diagnosis and appropriate medication therapy, tuberculosis (TB) can be cured.
In 1993, many international health agencies, including the World Health Organization (WHO) announced
a worldwide health emergency. TB fatalities also increased in 2021, rising to 1.7 million from 1.6 million in 2020
(Including 187,000 people with HIV). TB is the second most common infectious cause of death, after COVID-19 (over
HIV/AIDS), and the 13th largest cause of death overall. The COVID-19 pandemic had a negative impact on the fight
against tuberculosis, undoing years of work in providing critical TB care and reducing disease burden. A (4.5%) rise in
2021 from 2020 is due to the wide range of misdiagnosed and untreated cases that contributed to the first spike in TB
mortality in more than a decade.66,67 In addition, 450,000 instances of multidrug- or rifampicin-resistant (MDR/RR)-TB
were recorded in 2021, representing a 3% rise in the incidence of drug-resistant tuberculosis from 2020. The excessive
number of infections and death are related to a decline in crucial TB care since the pandemic starts in 2020.68
MDR-TB or multidrug-resistant tuberculosis is still a common health concern and a health security risk. The number
of people with multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) who were discovered and notified in 2019
was 206,030, which was an increase of 10% from 186,883 in 2018. Globally, from 2015 to 2019, the incidence of the
TB disease fell by roughly 2% every year, the cumulative reduction was 9%. This was less than halfway to the End TB
Strategy milestone of a 20% reduction between 2015 and 2020. TB diagnosis and treatment saved up approximately
60 million lives between 2000 and 2019. Ending the tuberculosis pandemic by 2030 is one of the United Nations
Sustainable Development Goals’ health goals (SDGs).69–71
This disease is more frequent in males than in women, and in adults rather than in youngsters. According to some
researchers, tuberculosis is one of the top 10 deadliest diseases on the planet. In terms of mortality, this disease ranks
higher than HIV/AIDS. In 2014–2015, all UN and WHO members agreed to put an end to this pandemic disease. In
May 2014, at the World Health Assembly, these states overwhelmingly approved and adopted the UN Sustainable
Development Goals (SDGs) and WHO’s End Tuberculosis Strategy. The End TB Strategy’s and tuberculosis-related
fatalities chief goal is to eradicate TB endemic by 2030–2035.72
The primary purpose for combining anti-tuberculosis drugs (ATDs) with diverse mechanisms of action is to prevent
the growth of drug-resistant strains. However, inconsistencies in medication production, noncompliance with therapy,
unsuitable regimens, and poor management all led to the formation of resistant strains. Multidrug-resistant (MDR) Mtb
strains are those that are resistant to the essential antibiotics INH and RIF, whilst extensively drug-resistant (XDR) Mtb
strains are those that are also resistant to a second-line injectable antibiotic (amikacin (AMK), capreomycin, or
kanamycin) and fluoroquinolone (such levofloxacin or moxifloxacin (MXF)).73 Furthermore, multiple examples of strains
resistant to all first- and second-line TB treatments have been documented in recent years. MDR-TB and XDR-TB
treatments duration are almost between 18 and 20 months and need to be taken with second-line drugs, that costs more
with higher toxicity effects than in compared to the first line. Injectable drugs additionally make it increasingly
challenging to follow treatment plans. Furthermore, TB therapy in HIV patients is worsened by considerable drug–
drug interactions between ATDs and antiretroviral treatments.74 The only three ATDs include pretomanid (2019),
bedaquiline (BDQ, 2012) and delamanid (2014) authorized towards MDR-/XDR-TB treatment in the past four decades.
Different therapies for MDR-/XDR-TB are being tested in clinical trials, such as the NiX-TB experiment. This 6-month
all-oral regimen, which the Food and Drug Administration (FDA) lately authorised, combines linezolid, BDQ and pre­
tomanid for the treatment of XDR-TB and other MDR-TB cases.66 It had a successful outcome; however, side effects
were recorded. The majority of RR-/MDR-TB cases may be cured with completely oral regimens, according to the most
recent WHO recommendations for the treatment of drug-resistant TB, with injectable drugs (particularly AMK) only
being used in cases when other treatments are not possible. These reflect a significant requirement for shorter treatment
times and more potent medicines with less toxicity side effects. To overcome the limits of existing TB treatment,
nanotechnology provides various advantages.75–77

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Table 3 Comprehensive Overview of the Various Conventional Technologies Used in Tuberculosis Diagnosis
Method Use Detection Duration and Ref.
Sensitivity

Culture The gold standard (Agar-based and egg-based Sputum samples can be cultured in one of two ways: Results within 3 or 4 [79,80]
media incorporating green malachite and 1. Solid media (observed by visualizing the colonies), weeks with 79–82%
Middlebrook broths or solid media) dug susceptibility testing and mycobacterial growth sensitivity
2. Liquid media (detected by microscopic
observation), drug susceptibility testing and
tuberculosis detection

Löwenstein–Jensen media Malachite green dye added to glycerated egg- Prevent MTB from growing while also providing Results within 2 to 3 [81]
(LJ) potato medium a contrast color that makes Mycobacterium colonies weeks or several months.
easier to observe. (92.7%) sensitivity
Susceptibility test for antibiotic.

Microscopic Diagnosis Ziehl Neelsen technique; bacteriological stain The detection of acid-fast bacilli (AFB) in stained and Results within 1–2 days, [82]
(smear microscopy) used to identify acid-fast organisms, mainly acid-washed smears examined microscopically may with (78–92.9%)
Mycobacteria. provide the primary bacteriologic diagnosis of sensitivity
mycobacteria among a clinical specimen. This is
a quick and effortless technique.

Skin test Mantoux test, performed by injection of Transverse induration at the TB skin tests (TST) Results within 48–72 [83,84]
0.1 mL of fluid containing 5 TU (tuberculin spot is measured in millimeters after 48–72 hours, hours. Sensitivity in
units) PPD (purified protein derivative) into and the optimum cut point ranges from 2 mm to younger patients is 70%,
the forearm’s top layers of skin. 16 mm, depending on prevalence and testing in elderly patients is 27%
purpose.

Interferon-gamma release QuantiFERON – TB Gold and T-Spot TB assay. The cytokine INF, which is produced by the T cells Results within 24 hours [85,86]
assays (IGRA) A blood test determines whether or not during the infection by MTB, is measured via with 93% sensitivity
a person has been exposed to the (TB) a serological test. Unable differentiate between
bacterium. latent and active infections.

Chest radiography CXR chest X-ray identification of lung Cavitation caused by TB bacteria in lung tissue and Results within a few [87]
abnormalities. acute TB pulmonary could be detected easily by minutes, sensitivity is
using CXR imaging, however, in the extra-pulmonary 93%
TB area not able to be recognized using chest
radiography.

Molecular assays Detect mycobacterial gene mutations 1. LPA: Rapid technique based on polymerase chain 1. Results within 1–2 days [88–91]
associated with anti-TB drug resistance: reaction (PCR) that is used to detect MTB complex as sensitivity 81.3–100%
1. Line probe assay (LPA) well as drug sensitivity to rifampicin (RPM) and isoniazid 2. Results within 24 hours
2. Nucleic acid amplification technology (INH) and sensitivity 98.2%
(NAAT) 2. NAAT: Rapid molecular method for detecting tiny
quantities of an organism’s genetic material in
a particular specimen (genetic material nucleic acids).
NAAT method entails amplification inhibition screening.

Volatile organic compounds VOCs in the head space of cultured MTBs VOCs in exhale breath serve as tuberculosis (TB) Results within few [92, 93]
test (VOCs) were collected on sorbent traps and analyzed biomarkers since MTB produces VOC metabolites minutes, an hour, 8
using gas chromatography/mass spectrometry as being detected in the exhale of infected people. hours, or 24 hours,
(GC/MS). sensitivity 89.4%

Current Conventional Methodology for the Diagnosis of Tuberculosis

To identify Mycobacteria, methods ranging from the most basic laboratory tests to the most complicated molecular and
non-molecular approaches have been developed. Sputum smear and culture techniques are the most conventional
techniques for identifying MTB. These methods are time-consuming, requiring experienced employees to conduct the
test and requiring several days or weeks to obtain a result. Most conventional methods are so insensitive that they can
only identify 50% of the active MTB. This was found that sensitivity is much lower in HIV co-infected patients or
youngsters with a small active colony-forming unit. Diagnosing TB and its drug resistance in the early stages of the
infection increases the chances of surviving, and by diagnosing contagious patients at an early stage, we can manage and
treat them and try to decrease the number of fatalities.78 Table 3 provides a detailed overview of the many conventional
methods utilized in tuberculosis diagnosis.

Current Tuberculosis Drugs

WHO, in 2021, updated the most recent guidance for treating patients with drug-susceptible TB. Based on this guidance,
a 6-month treatment plan consisting of four first-line TB medicines, namely isoniazid, rifampicin, ethambutol, and
pyrazinamide, is suggested. All four medications are used during the first 2 months of therapy, and two medications are

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utilized throughout the remaining 4 months of treatment until the treatment is finished. This is a strong recommendation
based on data with intermediate certainty.94 This treatment regimen has been extensively accepted across the world, and
about 85% who use this procedure will have a satisfactory treatment outcome. The present four-drug treatment program
has been in effect over almost three decade and is based on foundational TB therapy research done in the 1980s
according to the British Medical Research Council.
Research into shortening the duration of TB treatment has increased during the past several years. As a result, several
trials and other research have been conducted to determine whether therapy may be reduced while remaining highly
effective. While this research has mostly concentrated on drug-resistant TB (owing to the fact that the typical duration of
treatment was 18–24 months until recent years). A recent trial evaluated the effectiveness and safety of two 4-month
regimens for the TB drug-susceptible treatment. One of these regimens, which included a fluoroquinolone and a high
dosage of rifapentine, passed the non-inferiority test. This trial represents the recommended body of evidence for the
forthcoming Guideline Development Group to evaluate (GDG).70 Table 4 illustrates the first and second-line TB drugs’

Table 4 The First- and Second-Line Drugs for TB Treatment

First-Line Drugs Main Characteristics Adverse Reactions Dose Amount FDA-Approved
Year

Isoniazid Inhabits the synthesis of mycolic acid Cell wall hepatitis, medication (5 mg/kg up to 300 mg) 1952
complications, peripheral
neuropathy, lupus syndrome.

Pyrazinamide Bactericidal slow metabolizing organism within the Hyperuricemia, gouty arthritis, (15–30 mg/kg up to 2 g) 1952
acidic area of gaseous granuloma or phagocyte rarely nephritis
interruption of electron transport across the
membrane

Ethambutol Cell wall synthesis inhibitor bacteriostatic Optic neuritis, exfoliate rash (15–25 mg/kg) 1961
prohibition transference of arabinosyl

Rifampin Block the synthesis of RNA, by blocking the DNA Drug interactions, body fluids (10 mg/kg upto 600 mg) 1966
dependent the RNA polymerase becoming orange, GI, hepatitis,
fever, severe renal failure,
hemolytic anemia

Second-Line Drugs Main Characteristics Adverse Reactions Dose Amount FDA-Approved

Year

Streptomycin Prohibition of the synthesis of protein by an Cochlear and vestibular toxicity (15 mg/kg) 1944
interruption in ribosomal function nephrotoxicity

PAS Blocks the synthesis of folic acid GI toxicity, rash, or fever (15–20 mg/kg) 1946

Cycloserine Blocks the synthesis of peptidoglycan synthesis Dizziness, CNS, or depression (15–20 mg/kg) 1952

Clofazimine Mycobacterial DNA and mRNA binding GI toxicity, ocular discoloration (100–300 mg/day) 1954
and cutaneous

Capreomycin Blocks synthesis of the protein Cochlear and vestibular toxicity, (15–30 mg/kg) 1956
nephrotoxicity

Ethionamide Blocks the synthesis of mycolic acid GI nausea, toxicity, or hepatitis (15–20 mg/kg) 1956
(cell wall)

Kanamycin Blocks synthesis of the protein Cochlear and vestibular toxicity, (15–30 mg/kg) 1957
nephrotoxicity

Amikacin Blocks synthesis of the protein Cochlear and vestibular toxicity, (15–30 mg/kg) 1974
nephrotoxicity

Ciprofloxacin Blocks the DNA gyrase synthesis Toxicity, CNS or tendon rupture (750–1550 mg/d GI) 1987

Ofloxacin Blocks the DNA gyrase synthesis Toxicity, CNS or tendon rupture (600–800 mg/day) 1995

Levofloxacin Blocks the DNA gyrase synthesis Toxicity, CNS or tendon rupture (500 mg/day) 1996

Moxifloxacin Blocks the DNA gyrase synthesis Toxicity, CNS or tendon rupture (400 mg/day) 1999

Gatifloxacin Blocks the DNA gyrase synthesis GI toxicity, hypoglycemia, CNS (400 mg/day) 1999

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discovery year, primary features, and most often reported adverse effects.95 Table 4 includes the first- and second-line
drugs for TB treatment.
Anti-TB therapy is typically used for a period of 6 months. For the first 2 months, only four drugs, namely
pyrazinamide, isoniazid, rifampin, and in some cases, ethambutol are used. The use of rifampin and isoniazid is
continued for the next 4 months (Table 4). Sometimes, the six-month regimen is termed as “short-course” anti-TB
therapy. These drugs are administered daily. Now the questions remain that why does it take so long to TB disease in
patients while the cultures of M. tuberculosis may be destroyed in a matter of mere hours to days? The existing model
shows that numerous populations of bacilli must be dealt with in infected individuals: those that are growing rapidly,
those growing slowly, and those that sporadically replicate. The cells of these separate populations are killed in two
phases. At the first bactericidal phase, rapid multipliers are cleared. During the second sterilizing phase, the remaining
multiplying organisms are being killed slowly and sporadically. Streptomycin and isoniazid are two types of drugs that
had bactericidal activity when tested in animals. These drugs reduce the infection burden by a magnitude of four to five
orders. However, these drugs failed to kill the infections. Thus, despite the fact that these drugs killed the inflections, the
multiplying populations of M. tuberculosis remain persistent. These slowly and sporadically multiplying populations of
M. tuberculosis can only be cleared with antibiotics possessing “sterilizing” activity. Sometimes, these persisted cells
become more phenotypically resistant to anti-TB therapy and therefore can take longer to be cleared. Rifampin is
sterilizing antibiotic that can decrease the bacillary counts to zero during the second stage of treatment in human beings.
With the use of pyrazinamide during the first 2 months of therapy, the length of therapy is reduced. However, it shows
minimal bacterial activity when used alone. Ethambutol is an effective drug for drug-susceptible M. tuberculosis and is
normally included in the regimen when it is suspected that a certain population has drug-resistant TB.96
Sometimes treatment of TB diseases takes 6 to 9 months by taking several drugs. Only 10 drugs have been
recommended by the United States Food and Drug Administration (FDA). Pyrazinamide (PZA), ethambutol (EMB),
rifampin (RIF), and isoniazid (INH) are the first line of the approved drugs. These drugs form the core of treatment
regimens.97 TB bacteria that is resistant to at least one of the first-line anti-TB drug, is a kind of TB drug-resistant. TB
bacteria that are resistant to more than one anti-TB drug are called multidrug-resistant TB (MDR-TB). This bacteria is at
least resistant to both rifampin (RIF) and isoniazid (INH). While another uncommon kind of MDR-TB is resistant to
rifampin and isoniazid, fluoroquinolone is also one of at least three injectable intravenous second-line drugs – capreo­
mycin, kanamycin, or amikacin – and is called extensively drug-resistant TB (XDR-TB). The treatment and cure of drug-
resistant TB are very complicated. In order to treat this drug-resistant TB, a comprehensive consultation with a TB
specialist is required.98

Clinically Approved ATD’s for Therapy and Diagnostic

To treat MTB, first-line drugs INH, PYR, EMB, and RIF have been given orally in combination in recent years. Second-
line drugs are also combined with the first-line drugs in this treatment.
A combination of second-line drugs is also used to treat MDR-TB. Some of the medications on this list are
polypeptides – enviomycin, viomycin and capreomycin; aminoglycosides – kanamycin and amikacin; thioamides –
ethionamide, cycloserine and prothionamide viomycin; fluoroquinolones – moxifloxacin, levofloxacin and ciprofloxacin.
Generally, first-line drugs are cheaper than second-line ones. Drugs that are now widely known as the third-line TB
therapy are thioridazine, rifabutin, vitamin D, thioacetazone, macrolides, linezolid, arginine, and clarithromycin.99 Third-
line drugs may not be as successful as first- and second-lines, though, as their effectiveness has not yet been shown and is
still being researched.6
For the treatment of MDR, several medications have been proven in clinical research, while others still require further
study. Bedaquiline, rifapentine, linezolid, and pretomanid are a few examples. A brand-new ATD called Bedaquiline (Phase 2
trial) has been approved for use in the management of drug-resistant TB. Due to its core heterocyclic quinolinic nucleus
containing amine and alcohol side chains, bedaquiline (BDQ), a member of the diarylquinoline class of compounds, plays an
important role in antituberculosis therapy. In addition to inhibiting synthesising mycobacterial ATP, it binds to and disrupts the
interface of the a-c subunit, impairing the proton cycle and killing the Mycobacterium.100 A nitroimidazo-oxazine known as
pretomanid has anti-replicating and anti-dormant mycobacterial activity by inhibiting the formation of mycolic acid

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Figure 4 Authorized nanomedicines available on the global markets: (a) Current status of development, (b) indications, and (c) formulation.

and preventing the formation of cell walls. Furthermore, in anaerobic or hypoxic situation, pretomanid effects on non-
replicating bacilli.101 Linezolid (LNZ), an oxazolidinone that has been modified and is currently in phase 2, prevents the
production of proteins in mycobacteria. The creation of a 70S initiation complex is prevented by LNZ when it binds to the 50S
ribosomal subunit’s 23S rRNA domain V.102 These medications’ efficacy is constrained by their fast release and shorter
plasma half-life. Therefore, in order to increase the success rate of TB therapy, pharmacological treatments are required.102
Figure 4 includes the nanomedicines that are available on the global markets.
The Cortellis Drug Discovery Intelligence (CDDI) database was used to find nanomedicines that have been
authorized for use on the market or in clinical studies. In June 2021 recent data was examined and evaluated,
which indicated that there are now 563 nanomedicines in various phases of drug clinical trials and 100 nanomedicines
on the market (663 totally). The majority of these are in clinical phases I and II in which (33%) for former and (21%) for
later. They mostly target the treatment of cancer (53%) and infections (14%) respectively (Figure 4a). Recent advances in
nanomedicine have enabled the treatment of more diseases affecting the nervous, immunological and metabolic systems,
blood, brain, endocrine inflammatory, ophthalmic, cardiovascular and dermatitis problems among other diseases
(Figure 4b). Additionally, they are used in the imaging diagnostics and vaccinations development. Liposomes, or lipid-
based nanoparticles, account for the vast majority of nanomedicines on the market or in different phases of clinical devel­
opment are (33%), next by antibody-drug conjugates (15%), polymer-drug/protein conjugates (10%), and polymers
(10%). Viral vectors (8%), inorganic nanoparticles (3%), cell-derived vehicles (4%), emulsions, protein-based nanopar­
ticles (3%), nanocrystals, micelles, and dendrimers are more forms of nanomedicines (Figure 4c).103,104

Current Tuberculosis Vaccine

The Bacillus Calmette–Guérin (BCG) vaccine was utilized to combat tuberculosis (TB) since 1921 and is regarded as the
most extensively used vaccination in the world.105 However, it is recognized that the BCG protective effectiveness
depends on the geographic region in which it is given.106

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How BCG’S Response to Mycobacterium tuberculosis

BCG, a live-attenuated Mycobacterium-based immune complex vaccine, promotes immune activation and the local
infection at the injection area, where existing dendritic cells (DCs), macrophages and monocytes react to the
bacterium.107 BCG vaccine may survive inside dendritic cells for up to 2 weeks,108 producing the immune-polarizing
cytokines, in the meantime causing the activation of costimulatory molecules, which are characterized by enhanced
expression of the differentiation clusters including CD40, CD80, CD83, and CD86.109 BCG cell wall skeleton immuno­
genic parts, such as covalently linked mycolic acid, arabinogalactan, and peptidoglycan, are phagocytosed and destroyed
by macrophages,107 which may also significantly stimulate an inflammatory response by activating several pattern
recognition receptors (PRRs).110,111 While toll-like receptors constitute the first line of defense system against microbes
(TLR) 2, signaling is activated by lipids and mycobacterial cell wall lipoglycans like lipomannan (LM). Other
mycobacterial proteins, including as heat-shock proteins and glycoproteins, trigger by TLR4 signals.112,113 BCG CpG-
DNA has been shown to induce TLR9 intracellular in macrophages and DCs, leading to activation of the cell and the
generation of interleukin-12 (IL-12), tumor necrosis factor α (TNF-α), and monocyte chemoattractant protein-1 (MCP-1),
a key mediator of the T helper type 1 (Th1) immunological responses.114,115 Similarly, the complement receptors CR3
and CR4, as well as nucleotide-binding oligomerization domain (NOD)-like receptors or even C-type lectins, have all
been demonstrated to react with the cell wall components of bacteria and have a crucial role in BCG recognition and
internalization.116 Similarly, research on BCG-immunized adults has shown that monocyte progenitors are reprogrammed
with stronger PRR expression and enhanced responsiveness to stimuli like TLR agonists. Antigen-presenting cells,
including DCs, macrophages, and B lymphocytes white blood cells (B cells), deliver BCG-derived antigen peptides to
primary T-cells and major histocompatibility complex (MHC) molecules in the surrounding secondary spleen or
lymphoid tissue in order to initiate an adaptive immune response (Figure 5).117,118
After the BCG vaccine is given intravenously, macrophages, monocytes and dendritic cells (DCs) detect the BCG and
create a powerful immunological response. DCs or macrophages detect and internalize BCG. BCG’s cell wall and other
components operate as PRRs, binding to various ligands, upregulating costimulatory molecules in activated cells, and

Figure 5 BCG vaccination induces an immune response, with MTB-specific effects. (A) BCG is absorbed by DCs or macrophages and could activate the anti-TB immune
response when their cell walls perform as PRRs and are connected to a co-stimulatory receptor-ligand. (B) The formation of plasma cells, memory cells, and antigens with
particular antibodies is triggered by B cell activation.Memory T and B cells remain in lymph nodes after activation.

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Figure 6 BCG vaccination results in the formation of trained immunity.

activating the anti-TB innate immunity. When B-activated DC cells move to lymph nodes, they trigger Th1-type, CD4+
and CD8+ T cells that are specific for mycobacteria and then secrete large quantities of cytokines like IFN-gamma and
granzyme. Memory cells, plasma cells, and antigen-specific antibodies are produced all at once by B cells that react to
BCG antigens.118
Activated DCs at the BCG vaccination spot move towards the draining lymph nodes, where they release tumor
necrosis factor-alpha (TNF-α), Interleukin 6(IL-6), and Interleukin 12 (IL-12), which trigger both of the CD4+ and CD8+
T-cells.119,120 Activated CD4+ and CD8+ T cells produced IFN-γ, which boosts macrophage antimycobacterial
activity.121 This demonstrates how people with IFN–γ mutations are more susceptible to TB.122 Neutrophils and activated
DCs both works together to boost antigen-specific T-cell responses. According to some researchers, 10 weeks after BCG
vaccination, newborns’ peripheral blood may contain a substantial amount of BCG-specific CD4+ and CD8+ T cells.
Furthermore, the serum contains higher concentrations of IFN-γ, granzyme, TNF-α, and IL-2.123,124 Figure 6 indicates
the BCG vaccination results in the formation of trained immunity.
BCG vaccination causes monocytes/macrophages to develop trained immunity, resulting in greater epigenetic
reprogramming and host defensive abilities. When monocytes are exposed to non-specific infections (respiratory
syncytial virus or yellow fever virus), chromatin rearrangement causes them to become “trained”, increasing the
efficiency of their innate immune response and triggering the release of proinflammatory cytokines like IL-6, IL-1,
and TNF-alpha (Figure 6). However, further research is needed to determine if this “training process” will try and stop
SARS or other respiratory syndrome-like coronaviruses.

Conventional TB Drug Therapy Disadvantages

Clinical management in TB therapy is presently seen as one of the most difficult challenges. Drugs are transported all
over the body by systemic blood circulation after being taken orally or intravenously, and many molecules aggregate in
other parts of the body rather than targeting the right site, triggering disadvantages including nephrotoxicity, hepato­
toxicity, ocular toxicity, and ototoxicity. Most TB drugs are administered orally, which leads to pharmacokinetic issues
like limited bioavailability and a low therapeutic index. Drug therapy in a conventional route necessitates a lengthy
therapy regimen that includes frequent and continuous administration of multiple drugs, leading to lower patient

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adherence to existing treatments. This is a critical indicator sign of infection recurrence, as well as formation of
multidrug-resistant MDR-TB and the more severe extensively drug-resistant XDR-TB.9
In undeveloped countries, the outbreak of MDR-TB is steadily growing. This is a source of a big problem and
concern for the health care services.125 Although present anti-TB medications are successful, there seems to be a critical
need to find effective and sustainable solutions with producing new short-term regimens that combine novel drugs to
tackle the challenges of treatment length, drug resistance and adhere to the treatment.11 As a result, a method will be
developed to overcome the therapeutic limitations associated with conventional treatment. Higher bioavailability,
effective drug loading, longer retention time, and improved drug encapsulation capacity in body cells, and gradual and
consistent drug release might lead to reduced frequency and multiple-drug dosage. Moreover, it was mentioned that when
a drug is delivered to the targeted tissue, localised drug exposure is preferable over systemic exposure in order to reduce
or indeed prevent systemic side effects. Hence, targeted drug therapies have gained a lot of attention as a way to reduce
such systemic adverse effects.126

Advantages and Disadvantages of Nano Drug Delivery System

To overcome the challenges and the side effect of conventional treatment, researchers have brought new novel
formulation of nanomedicine which can provide effective therapeutics index. Inhalable nanoparticles are biodegradable
and biocompatible, which contain high drug loading capacity this made them to enhanced mucosal cell adhesion, and
improved drug delivery to the respiratory system for the treatment of (TB).127 Although nanocarriers based drug delivery
agents are achieved high drug loading, high stability, effective drug tolerability, reduce multidrug and extra drug
resistance, controlled release, and site-specific delivery, the clinical phases are slow for the benefit of human. Physical
and biological factors like pH, protein, phagocytic sequestration, enzyme, shear forces, renal clearance, and aggregation
create hostile environments for nanocarriers. The nanocarrier-based medicines have marketed in the pharmaceutical
industry at a slow phase.128
For TB drug delivery, the nanocarriers cannot often reach to the deep lung since majority of the drug doses are
exhaled. The nanocarriers administer in different routes in TB treatment such oral, topical, intravenous, and pulmonary
delivery. These routes have different various limitations, barriers of biological environment, interaction of biological
components such as protein corona, loose of nanocarriers before reaching the disease sites, clearance by phagocyte
system and so on. The nanocarriers with low water solubility, low bioavailability and low biodistribution exhibit
biological and anatomical barriers in the respiratory tract as well as gastrointestinal tract and liver. Beside these barriers,
the inhaled therapeutics agents in lung airways exhibit some obstacles in reaching the target TB cells. As a result, the
deposition of nanocarriers’ physicochemical properties, particle size, size distribution, density, shape, and electrostatic
charge play an important role to reach in deep lung deposition. The composition of the nanocarriers’ inhaled particles
should be very small enough to reach the lung TB cells and avoid the deposition in the airways by sedimentation or loss
by exhalation. The size and composition become challenging nowadays for the researchers to deliver nanocarriers. To
overcome these limitations and achieve the highest efficiency, the nanocarrier characteristics could be tailor-made to
target and function effectively for the desired delivery routes.129,130 Nanocarrier based delivery has shown potentially
remarkable feature such as biodegradable particle, slow, sustained, controlled release. Although different animal models
have been studied to develop the anti-TB therapy based on nanotechnology against M. tuberculosis , unfortunately the
clinical management of tuberculosis remains a difficult task and many models do not stand up to the expectations of
human TB treatment. Several studies have been conducted by researcher for nanocarrier-based TB therapy. Bhardwaj
et al used spray-dried lipid–polymer hybrid nanoparticles for the delivery of isoniazid to TB cells. The formulation was
found to be proven to have more uptake by TB cells.131 Recently, Ahmed et al has developed dendrimer-based
nanocarrier system to load rifampicin and delivered to TB cells and has found that the drug carrier has high drug
loading, negligible toxicity, and extended-release pattern for rifampicin. Although nanocarrier-based systems are more
effective than conventional treatments, many studies need to be conducted due to the high necessity of TB effective
treatment as well as reduction of the limitations of nanocarrier-based treatment.132

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Barriers to Nanoparticle Drug Delivery to the Lung Anatomy

The airway defense system, tight epithelial cell layer, as well as the mucus hypersecretion are the key barriers to NP
delivery for chronic lung diseases. However, this will vary depending upon the type of delivery system, respiratory
system disease area and the development of the disease. Intranasal, inhaled, or intravenous delivery all were employed
to treat pulmonary (TB), even though each brings its own set of challenges. The appropriate route will be determined by
the kind of NP, the required bioavailability, as well as the airway target tissue. Targeted nanoparticles towards the lungs
must contend with not just the particular structure of the lung but also intravascular, specialized pulmonary, and
intracellular barriers.133 In terms of drug delivery, the respiratory tract in lung anatomy is divided into two sections:
the top, which includes the nasal cavity, pharynx, whilst the bottom includes the larynx, trachea, bronchi, and alveolar.
There are two principal bronchi in this trachea, which branch into the tinier bronchioles inside the lungs, creating air
pathways toward the alveoli terminal. The tubes become smaller and split into even more tubes as they pass down from
the trachea to the respiratory tract.
There were also reported to be 20 to 23 divisions, all of which led to the alveolus. Although each bronchus or
bronchiole has a lower cross-sectional size, the total surface area is bigger due to the huge number of them. As a result,
resistance in the terminal bronchioles was reduced. Because of the turbulence, the majority of the resistance is positioned
three to four divisions from the trachea. Despite their small size, alveoli contain a significant overall surface area that
allows for effective and sufficient gas exchange. Moreover, alveoli contain a single epithelial (400 nm) cell layer that
separates the air from the capillaries.134 Rather than being a barrier, this wide surface area offers a great capacity for drug
absorption, and thus escape the first-pass metabolism helps to make the pulmonary route desirable for theranostic NP
drug delivery.135

Pulmonary Barriers
Many barriers related to pulmonary are formed in healthy lungs, and many more are formed in diseased lungs for
exogenous nanoparticles, the airway’s mucociliary system is the primary defensive mechanism for removing dust and
eliminating microorganisms. The first barrier goes to submucosal glands, and goblet cells create mucous that coats the
whole respiratory system and increases the mucus thickness of the airways in disease from 2–30 to >260 m. Mucous is
pushed forward as the periciliary liquid layer beneath helps the cilia’s consonant rhythmic beating repetitively into the
proximal airways, where it is either ingested or expelled.
The second barrier is, pulmonary surfactants lower the surface tension and prevent collapse at the alveolar air-liquid
interface; however, surfactant proteins SP-A and SP-D also play a significant role in pulmonary immune defense.134
Surfactant proteins SP-A and SP-D are key components in pulmonary immunology because by opsonizing and binding
the invading microbes from the lung allowing them to be cleared by alveolar macrophages (AM).136 Alveolar macro­
phages are prominent in inhaled particles or fiber removal from the lung. AM size variations across species may alter the
amount and size range of particles/fibers which can then be phagocytized and removed by AM.137 Because both SP-A
and SP-D may attach to NPs and induce clearance from the lungs, this characteristic of these molecules offers the most
serious challenge for NP administration. Both molecules were found to increase the AM uptake of NPs in recent
research; however, the effect was maximum with SP-D for hydrophilic NPs and most pronounced with SP-A for
hydrophobic NPs. However, despite the different NP surfaces, both different kinds of NPs interact with AM to
a roughly equal extent in the existence of native surfactants in this research, implying that SP-A and SP-D activities
with NPs need to be studied further to completely comprehend this complex of the lung clearance process.138
The third barrier is, respiratory illnesses including cystic fibrosis, COPD, and asthma alter lung bifurcation angles,
causing turbulent flow and obstructing airways. This decreases particle deposition to around 2% in the most obstructed
parts, which are in most need of treatment. Applying NPs to solve these issues will provide significant benefits when
using the pulmonary route. Nanoparticles can easily enter the systemic circulation due to the great level of vasculariza­
tion, the enormous surface area of the respiratory tract, as well as the super-thin barrier in between the pulmonary lumen
and the capillaries.135

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Intravascular Barriers
The high ionic strength of the blood may result in particle agglomeration and sequestration after intravenous injection of
NPs loaded with drug given via systemic circulation.96 Extracellular proteins or opsonins as part of plasma proteins may
also adsorb with NPs, causing phagocytic identification and removal of the NPs from the circulation shortly after
delivery. Since NPs need to extravasate through the blood circulation and lymphatic vessels to reach target area, size
restrictions imposed by various endothelium layers all across the body may have still another obstacle.139 These
intravascular barriers can sometimes help with targeted delivery, and even in the situation of “leaky” tumor vasculature,
which allows NPs to extravasate more easily in tumor tissues than in healthy parts. Due to inadequate lymphatic drainage
and defective vasculature, NPs can easily accumulate in the tumor interstitium, causing increased penetration and
persistence.140

Intracellular Barriers
To have a therapeutic effect, it is necessary that NPs can pass through cell membranes and penetrate the cytoplasm,
nucleus as well as other organelles of the target cells after reaching the diseased tissue. As lipophilic cell membrane
would be the first barrier that intracellularly targeted NPs encounter, larger charged molecules like DNA, drugs, and
proteins cannot enter cells through the lipophilic cell membrane; however, endocytosis is expected.141 A useful technique
for receptor-targeted NP absorption is clathrin-mediated endocytosis; however, NPs that enter the cell by this mechanism
may get trapped by late endosomes, where they combine with lysosomes.142

The Application of Nanotechnology to Overcome Delivery Barriers in the

Respiratory System
The design and fabrication of materials at the atomic and molecular nanoscales is known as nanotechnology. The term
“nanomedicine” refers to the use of nanotechnology in medicine. Nanomedicine is capable to overcome several
limitations in diagnosis, treatment, and bring a drastic change in healthcare, and human illness management. For the
last many decades, a lot of efforts have been made to introduce nanotechnology-based platforms in order to enhance the
treatment and diagnosis of different kinds of diseases including disease-related to lungs. However, there are certain
barriers that limit the application of nanotechnology against acute and chronic respiratory diseases. Nanotechnology’s
utilization in medical applications is quickly expanding, and it has tremendous potential in a wide range of applied
scientific domains.143
To address the barriers posed by lung biology and anatomy, NPs with particular alteration in their shape, hydro­
dynamic dimension, and surface charge/hydrophobicity have been emerged. In order to evade the mucus barrier, the
electrostatic, hydrophobic and steric characteristics of NPs should be adjusted. To improve NP’s stability, it is preferable
to coat the NP’s surface by surfactants, proteins, lipids, dendrimers, polymers, copolymers, and inorganic molecules.
Dextran or polyethylene glycol polymer coatings provide biocompatibility onto NPs and provide significantly longer
blood circulation durations. NP surfaces’ most prevalent functional groups are amines and carboxyls, which allow
antibodies, fluorescent dyes, peptides, radionuclides, therapeutic agents aptamers, quantum dots and other small mole­
cules to bind. The NPs may be directed to a certain location or kind of cell using antibodies and peptides, and they can be
imaged using quantum dots and fluorescent dyes.144
Nanotechnology is rapidly being used in medical application for therapeutic and diagnostic purposes, and it has great
promise in various applications. Nanoparticles have been used as drug delivery systems and diagnostic imaging agents,
paving the way for tissue target delivery that can significantly enhance therapeutic efficiency while reducing drug side
effects.145 By designing and preparing dual-purpose nanomaterials that can serve as both diagnostic medical devices and
drug delivery systems, it is also conceivable to integrate these two functionalities in one particle.
Theranostic is a term that was used to describe the idea of combining diagnostics and therapy.146 Researchers define
a theranostic agent as a system that simultaneously allows and monitors drug delivery and outcomes, consequently
allowing a proper therapy–patient match.147 Figure 7 illustrates the theranostic NPs and their uses.

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Figure 7 Theranostic NPs and their functions.

Nanotheranostic Agents for the Treatment of TB Synthesized Using the

Host–Guest Supramolecular Chemistry
Host–guest supramolecular chemistry is the chemistry of non-covalent intermolecular molecular assemblies of the host
and the guest species. For the synthesis of TB nano-theranostics, usually, the hosts are selected from nanomaterials with
a high specific surface area so that they can host one or more active agents to simultaneously serve as the TB diagnostic
and therapeutic purposes. Otherwise, diagnostic and therapeutic active agents can be loaded separately onto the host,
resulting in the nano delivery system for diagnostic and therapeutic, respectively. Nanomaterials such as layered
hydroxides,148–150 carbon nanomaterials such as CNTs, graphene and their derivatives,151–153 chitosan154 polymeric155
and inorganic156 nanoparticles are subjected to intense research for these purposes.
Generally, any nanomaterials – 0-, 1-, 2- or 3-dimensional – can be used to host the guests; any active agents for anti-
TB drugs such that the final product of the host–guest complex can be formed through various non-covalent bonding
between them. Under a suitable microenvironment, due to the presence of external forces such as the higher affinity of
the incoming ions or the disintegration of the host, the breaking of the bonds between the host and the guest will be taken
place, resulting in the guest will be released gradually (due to the reversible, non-covalent bond between the host and the
guest) and therefore resulting in the slow or controlled release of the drug, which later taken by the adsorbed on the target
cell. This will reduce the over-dosage and under-dosage drug concentration, and maintain the drug concentration in the
therapeutic window, therefore enhancing the drug availability, improving efficacy and therefore better compliancy of the
patients.
Theranostics successfully combines therapy and diagnostics to create more specific and individualized treatment
methods for various pathologies, as well as to combine diagnostic and therapeutic agents together in a one agent,
resulting in an effective therapeutic approach that includes diagnosis and drug target delivery, and finally monitoring the
treatment responses. Theranostics is indeed a revolution from examination and development of drugs to prediction,
prevention, and drug customization that leads to enhanced the quality of the treatment.157 Theranostic agents are
classified as integrated nontherapeutic systems that able to diagnose, provide targeted therapy along with monitor the
treatment response. This integrated strategy provides several prospects for the advancement of customized medicines. It
provides the monitoring of the release of drugs, biodistribution and accumulation at the targeted area, dosage

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modification to individual patients, and consequently, tracking of disease progression.158 Recent therapies for the
treatment and diagnosis of TB mostly relied on complicated and lengthy multidrug treatments. Although these therapies
are effective in the early stage of infection, they lose effectiveness on latent infection and in the later stage of the
treatment. Besides this, the development of drug resistance has negatively affected the effectiveness of the current
treatments of TB. The same situation exists in antibiotic drug market.
However, recently, the TB infection awareness and understanding have inspired researchers to develop host-directed
approaches and inhaled TB therapies.159 Lung anatomy and biology have posed several obstacles, while multifunctional
NPs with specific modifications in size, surface charge and structure have been produced and these properties should be
adjusted in order to pass these NPs into the mucus barrier and reach the target site. Furthermore, covering the NP with
copolymers, dendrimers, polymers, inorganic compounds, proteins, surfactants, and lipids can increase its surface
stability. To some extent, polymer coatings based on polyethylene glycol or dextran maintain NPs biocompatible and
allow for longer blood circulation durations.
Multi-functional NPs can play multiple purposes simultaneously, for example, treatment and imaging of the target
disease with theranostic NPs. Therapists can diagnose diseases at earlier phases, monitor treatment noninvasively,
facilitate site-specific drug delivery to reduce side effects, and enhance preoperative staging only with the help of
therapeutic molecule combination with effective and safe contrast agents. Table 5 lists the various forms of NP contrast
agents as well as certain theranostic NPs that incorporate with them.
Medical imaging is used to diagnose and monitor many diseases by using techniques like positron emission
tomography (PET), X-ray computed tomography (CT) and magnetic resonance imaging (MRI). They are simple to
use, have a low level of invasiveness, and may provide clear images with details. PET scans are frequently combined
with MRI or CT images for therapy since the combination provides metabolic and anatomic details related to a tumor. In
addition, in vivo imaging from metabolic, physiological, and molecular activity may be accomplished via near-infrared
fluorescence optical imaging. A wide range of organic dyes such as radioisotopes as well as chelated metal ions
conjugated to targeting ligands was designed to provide contrast and improve the effectiveness of medical imaging,
and though due to their advantages, plenty of innovative NPs including fullerenes, carbon nanotubes, transition metal
oxides, semiconductor quantum dots, and noble metals have obtained considerable interest to be used as contrast agents.
Organic materials including liposomes, micelles, and polymers are employed to create NPs which also are encapsulated
and delivered the new contrast agents. Theranostic NPs, with their imaging and therapeutic capabilities, have the
opportunity to prognosis, diagnosis and treat the diseases. For the treatment of any kind of disease, swift treatment,
early and accurate detection are the most vital steps.
For the last few decades, several nanotechnology-based platforms have been created and employed to enhance the
diagnosis and treatment of diseases.96 Contrast agents imaging has been created to enhance the quality and quantity of
the information collected through MRI procedures. Metals are used in most of these agents to produce contrast; however,
those including gadolinium, may be quite toxic. The weak or poor signal intensity of MRI imaging of the lungs is a key
obstacle to diagnosing lung diseases; however, emerging nanotechnology is overcoming this
constraint. Nanoparticles loaded with metals with shorter relaxation time and entrapment of potentially toxic metal
ions offer opportunities as effective and safe MRI contrast agents in biomedicine. Recently, Branca et al employed
superparamagnetic iron oxide NPs (SPIONs) worked with luteinizing hormone-releasing hormone to use high-resolution
hyperpolarized 3He MRI to specifically target and observe pulmonary micrometastases.160 From another aspect, barium
and iodinated substances used as clinical X-ray CT contrast agents have large densities that seem to cause them to appear
radiopaque through the CT scan.
Even though there are not any NPs contrast agents that have been approved by the medical community for scanning,
initial CT surveys have been conducted to look into utilizing the gold having high atomic numbers and densities, which
gives a significant improvement in contrast compared to conventional iodine contrast agents. Recently, a study was
published by Wang et al on the use of embedded gold NPs in modified dendrimers with folic acid for the targeted
CT scanning of a patient with lung cancer.161 Most NP contrast agents are currently in the early phase of research or
preclinical testing, despite their helpful features and prospective applications. Although the importance of inflammatory
signaling and oxidative stress in chronic obstructive pulmonary disease COPD and cystic fibrosis CF has been proven, the

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Table 5 The Benefits and Drawbacks of Various Contrast Agents for Nanotheranostic Applications
Nano Application Advantages Disadvantages Ref.
Theranostic
Agents

Metal oxide To construct a theranostic NP, Super paramagnetic iron ● FDA approval for clinical ● Not biocompatible [164,
oxide NPs (SPIONs) must be used and the ability to deliver use, ie, Combidex, ● Toxic (release of metal ions) 165]
therapeutic agents at the same time must be incorporated Ferridex, Gadodiamide, ● Indicated inflammatory symptoms in
into the NP. Lumenhance. respiratory systems
● SPIONs exhibit magnetic
properties.
● The flexible surface is mod­
ified with different coatings,
therapeutic molecules and
dyes.

Gold NP Gold NP formulated as NPs, nano-shells, nanorods, and ● The size of the NPs deter­ ● Toxic. (Peroxidation of lipid, antioxidants [166,167]
nanocages with the capability of use in theranostic mines by the magnitude of upregulation, expressions of protein and
applications like lung and chronic respiratory disease the light that is scattered gene of stress response in respiratory
diagnosis and absorbed. systems)
● Flexible surface modification
with different ligands, dyes,
coatings and therapeutic
molecules.

Quantum dots QD is co-encapsulated in polymeric micellar, or liposomal ● Narrow wavelength emis­ ● Low biocompatibility. [168–
NPs for theranostic applications. sions that are size- ● Toxic due to heavy metals (lung injury and 170]
dependent. inflammation.
● Ultra-high photostability Lessen cell viability, genetically damages,
with high fluorescent immune cell disordered)
efficiency.

Carbon nanotubes Carbon allotrope and fullerenes-like carbon nanotubes ● Intrinsic features, providing ● Low [96,171]
(CNTs), graphene, nano-diamonds, and carbon dots are imaging modalities like NIR biocompatibility.
used to diagnose and treat lung and chronic respiratory and Raman ● Toxic; Produce free radicals and caused
disorders. ● High surface area and inside oxidative stress. Produce reactive oxygen
space for loading drug and species (ROS) caused chronic granuloma­
bioconjugation. tous disease.

Radioisotopes and Positron emission tomography (PET) scans have long used ● Flexible incorporation with ● Targeting deficiency [172]
fluorescents radioisotopes like 11C, 13N, 5O, 18F, and 64Cu) attached different nanodrug delivery ● Short half-life
molecules to specific biomolecules in order to track their distribution systems. ● Low biocompatibility.
and metabolism throughout the body. ● Early diagnosing. ● Toxic; Due to radiation exposure had side
● Monitoring non-invasive effect on the function of granulocyte and
real-time treatment. lymphocyte.

absence of real-time diagnosis of inflammatory/oxidative states may also lead to incorrect therapy, which can result in
chronic and deadly pulmonary pathophysiology. Cho et al synthesized chemiluminescent micelles capable of peroxalate
interactions in order to detect hydrogen peroxide (H2O2) concentrations as low as 100 nm and imaging of H2O2 delivered
in mice in a recent work.162
Mycobacterium DNA detection for clinical samples via NPs has now been discovered, and it has a bright future
ahead. A practical and inexpensive biosensor technology for detecting mycobacteria from the Mycobacterium TB
complex was recently presented, consisting of a photodetector nanocrystalline silicon with appropriate application to
reduce human errors and failures. To identify gold NPs in clinical sputum samples, ultrasensitive approaches based on
scan-based, fluorometric, colorimetric, surface-enhanced Raman scattering, and electrochemical procedures have been
developed. The detection of gold NPs generated by thiol-modified oligonucleotides has been established to be accurate,
simple, and inexpensive. With the use of these NPs, Mycobacterium TB may be identified from other Mycobacterium
species. In addition, quantum dots, fluorescent semiconductor and magnetic beads have been employed to identify
Mycobacterium species DNA, without the PCR requirement. A probe consisting of superparamagnetic iron oxide NPs
was developed for detecting extrapulmonary TB.163
Table 5 indicates the benefits and drawbacks of various contrast agents for nanotheranostic applications.

Nanocarrier-Based Therapeutic Agents for the Treatment of Tuberculosis

Nanoparticles are particle structures with a diameter of fewer than 100 nanometers. The bioactive is trapped in the
polymatrix structures as solid solutions or entangled particulates, and it could be physically or chemically bonded to the
particle surface. There are approximately 2300 kilometers of airways and 300 million alveoli in the human lungs for gas

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exchange. In adults, lungs’ surface area ranges from 75 to 140 m2. In comparison to the airways, the alveoli have an
extremely large surface size and intimate air-blood contact, making them less well-defended towards inhaled NPs.41 The
nanocarrier system of antibiotics was created with the goal of eliminating the issue of drug resistance, shortening
treatment duration, and reducing drug side effects with antiretroviral treatment. However, the first generations of ATDs
still are effective. The main goals of pharmaceutical technology are to eliminate the therapeutic agents’ major
technological disadvantages, for example, reduced aqueous solubility and stability, and bioavailability, in order to
improve adherence and compliance, and to achieve better drug’s effectiveness by concentrating on infection reservoirs
(for example, alveolar macrophages). Hence, nanocarriers appear to be one of the most promising technologies in this
context.
Nanocarrier technologies have rekindled interest in targeted drug delivery in pulmonary tuberculosis. Lungs are
a desirable target for drug delivery because of their noninvasive structure, which allows them to possibly have high
systemic bioavailability, avoid initial metabolism, have faster therapeutic activity, and also have a large specific surface
area. There are several advantages of using nanocarrier drug delivery in pulmonary; to obtain relatively uniform drug
dose distribution amongst alveoli, enhanced drug solubility beyond its own aqueous solubility, sustained drug release,
that lessen dosing frequency, suitability for macromolecule delivery, lower chance of side effects, better patient
adherence and its possibility for drug internalization by cells.173,174 Carriers enable us to construct multiple delivery
agents but also give flexibility for designing the delivery route. Consequently, according to the formulations, ATDs may
be delivered via implants/injections, or by respiratory or oral.175,176
Carriers can be broadly classified into natural or synthetic. Poly(DL-lactide-co-glycolide) (PLG), polylactic acid
(PLA), polyglycolic acid (PGA), poly-anhydrides, polymethyl acrylates, carbomer, etc, are illustrations of the synthetic
drug delivery carriers. Natural carriers, on the contrary, include alginic acid, lipids (solid lipid NPs and liposomes),
dextrins, gelatine, chitosan and many others. Carriers assist in the construction of various delivery systems and facilities
the pathway of this system. As a result, based on the formulation type, ATDs may be delivered as implants/injections, or
by the oral and respiratory systems. In experimental TB models, all delivery methods have undergone a thorough
evaluation. The nanocarriers that are currently under the stage of research and clinical trial for TB delivery include
chitosan NPs, micelles, silica NPs, dendrimers, liposomes, gold NPs, carbon nanotubes, etc.41

Polymeric Nanoparticles
Natural biodegradable polymers indeed are prominent application for managing the drug release. Langer and
Folkman generated the drug-delivery method with polymer-based for macromolecule delivery in 1976. The first
polymeric NPs had limited therapeutic effects due to their fast release through the reticuloendothelial system (RES)
following intravenous injection. This issue was resolved in 1994 with the development of long-circulating stealth
polymeric NPs.176,177 Polymeric NPs have various significant properties that make them ideal to deliver the
antimicrobial drugs. To some extent, polymeric NPs are sustainable, and may be produced with a narrower size
dispersion. Additionally, nanoparticle parameters such as size, zeta potential, and drug-release pattern may be
precisely regulated during synthesis using different polymer lengths, surfactants, and organic solvents.
Furthermore, the functional groups on the surfaces of polymeric NPs can be changed chemically with targeting
ligands and drug moieties. For antimicrobial drug delivery, polymeric NPs now come in two varieties. First is
created by the spontaneous self-assembly of diblock copolymers with hydrophilic and hydrophobic regions. This
hydrophobic part creates a polymer core that holds the drugs, whilst the hydrophilic part protects the core against
opsonization and destruction. The hydrophobic chain length can be modified to control the rate of drug release.
A number of biopolymers, including polycaprolactone (PCL) and poly(cyanoacrylate) (PCA), have been employed
to produce the hydrophobic polymeric core, while polyethylene glycol (PEG) was utilized as a hydrophilic part.
Hence, due to the general hydrophobic properties of the NP core, polymeric NPs are frequently employed to deliver
drugs that are less water-soluble.46

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Solid Lipid Nanoparticles

Since 1990, solid lipid nanoparticles (SLNs) are subjected to intense interest as an antibacterial drug delivery system. For
several drug-delivery purposes, SLNs are generally particulate systems with average sizes ranging from 50 to 1000 nm.
Solid-phase lipids make up the vast majority of SLNs, which could prepare at room temperature and surfactants for
emulsifying agents.178 Stearic acid, cetyl palmitate, etc, are solid lipids used in the formulation of SLN. Surfactants
including phosphatidylcholine, soybean lecithin, sodium cholate, poloxamer 188, and sodium glycocholate are often
employed as emulsifying agents to sustain lipid dispersion. Ultrasonication, high-shear mixing, spray drying and high-
pressure homogenization (HPH) are standard techniques for producing SLNs.179 TB infection can move from the lungs to
the lymphatic system in certain severe forms. ATDs like INH, RIF and PZA can be delivered to the lymphatic systems as
well as the lungs via SLNs. These SLNs after phagocytosed by AMs, delivered to lymphoid organs after they reach the
lungs. Radio-labeled aerosolized SLNs were used to evaluate the SLN delivery process and biodistribution via
pulmonary delivery in mice. Effective uptake of radio-labeled SLNs by the lungs was observed and indicated
a sustained release of the antibiotic payloads carried by the SLNs, that can efficiently clear the viruses and bacteria
hosted at these lymphatic zones.41

Liposomes
Liposomes are defined as multilayer carriers with a membranous lipid bilayer enclosing an aqueous volume. They
are the most extensively researched approaches for controlled drug delivery to the lungs as they are capable to
entrap both hydrophobic and hydrophilic drugs since they may be created by phospholipids endogenous to the lungs
as surfactants.180 Drugs encapsulated in liposomes have higher bactericidal efficacy than free drugs, notably in
the monocytes and macrophages treatment.41 The release of the drug from the liposome may help the drug to
maintain its position inside the lungs while inhibiting its release to other tissues. Liposomes-based drug delivery is
superior; low toxicity, a wide range of sizes (20 nm–1 mm), ability to solubilize drugs with poor water-solubility,
facilitating their nebulization, represent as a biobased pulmonary reservoir with prolonged residence period,
minimize mucociliary clearance of drugs owing to their surface viscosity, used as a targeting agent within the
lung, particularly to infected or impaired AMs and the lung epithelial tissue. This unique delivery method along with
the presence of the nanocarriers can be delivered to the lungs in a variety of methods: insufflations, nebulization,
instillation, etc.181

Microspheres
Microspheres are tiny spheres with sizes in micrometers sizes, usually 1 to 1000 μm. This drug carrier can be made in
a variety of particle sizes, which is important for nanocarrier’s in vivo deposition. Also, drugs may be readily integrated
with great loading and efficiency, and variable drug-release ratios may be obtained by manipulating the synthetic
synthesis technique. In vitro and in vivo, microspheres have greater chemical and physical stability. Entrapped drugs
represent longer duration of action with a slower rate of release. The increased stability facilitates the formulation.41

Chitosan Nanoparticles
The applications of natural polymers for anti-tubercular drug delivery for therapeutic or theranostic purposes are
enormously grown in past decades. Chitosan (CS) is among the drug delivery methods that play a vital application in
anti-TB drug delivery field. It is a cationic polysaccharide with unique properties that makes CS a potential delivery
vehicle.182 CS has been utilized as a matrix or coating material to protect drugs from chemical or enzymatic degradation.
As a result, CS-based nanocarrier systems have been significantly used for targeted drug administration for TB
treatment.16

Gold Nanoparticles
Gold NPs have recently received substantial attention for drug delivery purposes. Gold NPs (AuNPs) recently are utilized
for the drug delivery system for TB therapy and successfully and significantly suppress the TB cell growth.183

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Silica Nanoparticles
Silica NPs exhibited various unique advantages such as biocompatibility, biodegradability, hydrophobicity, stability,
resistance to pH difference, and capability to incorporate with a therapeutic agent.

Graphene and Graphene Oxide

Graphene and graphene oxide are becoming popular nanocarrier systems for TB drug delivery. Its high specific surface
area enables them to host single or multiple active agents to be transported to the target location.184

Carbon Nanotubes
Carbon nanotubes (CNTs) recently are developed as nanocarriers to explore their potential function as nanocarriers.
Owing to chemical and physical unique features, CNTs have also been utilised as a nano-drug delivery structure for anti-
TB drugs.184

Niosomes
The self-assembly of non-ionic amphiphiles inside an aqueous phase generates non-ionic surfactant-based vesicles
(niosomes), which are closed bilayer nanostructures. The assembly is seldom spontaneous, and it often needs some
form of energy input, like mechanical agitation or temperature. Thus, the hydrophobic sections of the compound are
protected from the aqueous solvent, while the hydrophilic head sections have the most interaction with it. These
structures, which are similar to liposomes, can encapsulate aqueous solutes and perform as drug delivery nanocar­
riers. Non-ionic surfactants have been used as a substitute for phospholipids due to their low cost and higher
stability.185

Dendrimer
A dendrimer is a new form of polymer material. They are receiving increasing attention due to their distinct structure, the
maximum level of control over molecular weight, and morphology, that is resulted in the production of unimolecular
micelles. Poly(propylene imine) (PPI) dendrimers are among the many potential dendrimers that have just recently been
formed on a large scale and analyzed either experimentally or by molecular modeling. The PPI dendrimers’ potential
applications are based on their following characteristics; standard morphology and sizes, the greater amount of freely
available end groups, nitrile or amino groups, the capability of end group adjustment to control solubility properties,
stability, toxicity, reactivity, polyelectrolyte property, glass transition temperature, and the capability to encapsulate guest
molecules are all important factors to consider. Dendrimers must be non-toxic and biocompatible if they are to be used as
drug carriers.41,186

Dry Powder
Pulmonary drug delivery with the method of dry powder inhalers (DPIs) has accelerated progress in recent decades to
realize the full potential for lung disease therapy, both local and systemic, due to its propellant-free nature, great patient
adherence, higher drug dosage loading and drug stability. However, DPIs’ effectiveness is dependent on several factors,
including the inhaler’s design, the powder formula, and the patient’s airflow. DPI performance has increased dramatically
over the last decade due to the use of engineered nanoparticles and improved dosage formulations.187

Cyclodextrins
Cyclodextrins contain oligo-saccharides made up of six to eight glucose molecules connected by β-1,4-glucosidic
linkages. These cyclical compounds have an inner hydrophobic cavity as well as a hydrophilic external surface, making
them susceptible to forming complexes with other hydrophobic compounds. They have been utilized in order to deliver
a large amount of drugs and maintain their stability and solubility.188

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Nanoemulsions
Nanoemulsions are oil-in-water (o/w) colloidal carriers and the particle sizes ranging from 10 to 100 nm that are
thermodynamically stable. The fundamental benefit of these methods is that they are self-generated and can be mass-
produced without requiring high energy for homogenization. Filtration can also be used to sterilize them. The increased
absorption of nanoemulsions by phagocytic cells explained the nanocarrier’s passive targeting features. After oral
administration, these are also absorbed by lipoprotein receptors, which are mostly found in the liver.189

Nanosuspensions
Nanosuspensions are defined as colloidal dispersions from the pure drugs that are sustained by surfactants and exist
in sub-micron sizes. The reduction of particles to nanoscale which is called “nanonization” is a beneficial platform
helping to enhance and boost the drug solubility with a high melting point and great solute–solute interactions, along with
low lipid and water solubility. The pure drug particles’ solid and dense states offer a maximum mass per volume ratio,

Table 6 Nanocarriers That Have Been Used for the Treatment of TB

Nanoparticles Therapeutic Agents Cell Line (MTT Assay) Cell Lines (Antimycobacterial Assays) Ref.

AgZnO Rifampicin (THP-1): Human monocytic cell line Escherichia coli [190,191]
(MCF-7): Breast cancer cell line.

ZnO Ciprofloxacin and MRC-5: Lung normal cell line E. coli bacteria, Staphylococcus aureus [192,
ceftazidime THP-1: Human monocytic cell line. 193]

Graphene oxide (GO) Ethambutol (3T3): Eukaryotic cells Mycobacterium smegmatis cells [194]

Chitosan nanoparticles Bedaquiline (BDQ). (J774): Macrophage cell lines Staphylococcus aureus [195,196]
(CSNP)and lipid Rifampicin

Poly(lactic-co-glycolic acid) Clarithromycin N/A Staphylococcus aureus, Listeria monocytogenes, [197]

(PLGA) Klebsiella pneumonia

Solid lipid nanoparticle Ethambutol hydrochloride A549: Adenocarcinomic human alveolar basal N/A [198]
(SLN) epithelial cells

Gold nanorods (AuNRs) Rifampicin (RAW 264.7): Macrophage cells N/A [199]

Polymeric nanoparticle Pyrazinamide Animal study on Charles Foster strain rats N/A [200]

liposomes Rifampicin (A549): Adenocarcinomic human alveolar basal N/A [201]

epithelial cells

Microspheres poly(lactic-co Moxifloxacin Animal study on Male Swiss albino mice Microplate Alamar Blue Assay on M. tuberculosis [202]
-glycolic acid) Hydrochloride

Silica nanoparticles (SiNPs) Pretomanid (pa-824) and (Raw 264.7): Monocyte/macrophage-like cells Monocyte cells infected with M. tuberculosis [203]
Moxifloxacin strain no: H37Rv-GFP

Carbon nanotube Isoniazid N/A Monocyte cells infected with M. tuberculosis [204]
strain no: H37Rv

Niosomes Ethambutol Animal study on Swiss Albino mice lungs Livers and Löwenstein–Jensen medium used for culture of [205]
spleens of guinea pigs Mycobacterium species

Dendrimer Rifampicin (RAW 264.7): Monocyte/macrophage-like cells. N/A [206]

Dry powder Nitroimidazo-oxazine PA- Animal study on guinea pigs lung TB-infected animals [207]
824

Cyclodextrins Rifampicin and (RAW 264.7): Monocyte/macrophage-like cells Mycobacterium smegmatis cells [208]
Levofloxacin (L929) mouse fibroblast cells

Nanoemulsions Rifampicin N/A Mycobacterium tuberculosis (strain ATCC 25,618 / [209]

H37Rv)

Nanosuspensions Clofazimine Animal study on C57BL/6 mice Monocyte cells infected with M. tuberculosis [210]
strain no: H37Rv

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which is extremely important in methods that need heavy loadings of the drug. Considering its potential features, several
researches aimed at improving TB medication have been published.189
The aforementioned nanocarriers are examples of carriers that can overcome drug resistance and facilitate
ATD delivery to MTB infection. As a consequence, medicines that are well known for their beneficial effects can
be safely used for effective TB treatment in the form of nanocarriers. The novel negative effects caused by the usage
of these carriers, on the other hand, must be investigated. Tables 6 indicates the list of nanocarriers used for the
treatment of TB.

Ligand Anchored Nanocarrier Systems for Pulmonary Tuberculosis

To improve the targetability, the nanocarriers are conjugated with ligand, which targets the receptors present on the desire
sites or the macrophage surface as the nanocarriers are excreted from the body by the process of opsonization and
phagocytosis. Various ligands have been used as a ligand to target the TB sites such as mannose, mycolic acid, ;ectin,
pH-sensitive liposomes, aptamers, etc, are being used for targeting antitubercular drugs.

Lectin
Mycobacterium tuberculosis (Mtb) is recognized by various pathogen recognition receptors (PRRs) which are expressed
on the surface of innate and adaptive immune cells. The category of pathogen recognition receptors (PRRs), which
include C-type lectin receptors, may identify a wide range of exogenous and endogenous ligands.211 C-type lectins have
been identified as determinant players in the early recognition of invading pathogen.212 Lectin can be employed as
a mucosal ligand to promote the absorption of TB drugs and enhance the target and binding of nanocarrier to the
surface.213

Mycolic Acid
Numerous substances found in the mycobacterial cell wall can act as receptors for ligand targeting. Since mycolic acids
(MA) are the predominant lipids in the outer cell wall of Mycobacterium species, they are among the potential ligands.214
Lemmer et al conducted a study on Mycolic acid as a ligand using PLGA nanoparticles (NPs) for targeting the TB cells.
They found that MA can be a promising mycobacterial ligand of nano-encapsulated drugs carrier for targeting the
tuberculosis mannose.196
Another ligand that can be used as to target the Mtb is mannose. In situ gel-based nanocarrier system with mannose-
conjugated rifampicin-loaded chitosan nanocarrier has been developed by Prabhu et al. This approach ensures localiza­
tion in the intra-articular cavity, prolonged release, and conjugation of nanocarrier with mannose as ligand to increase
high uptake and deliver the rifampicin drug.215 In order to target and improve the therapeutic index of rifampicin, Vieira
et al created solid lipid nanoparticles (SLNs) employing mannose as a lectin receptor ligand. The research indicate that
the mannosylated models are an effective and safe approach to treating tuberculosis.216 Mannosylated chitosan nano­
particles conjugated hyaluronic acid (HA) that loaded with isoniazid were synthesized by Mukhtar et al in 2022 and
successfully used as an inhalation powder for the treatment of TB.217

Ligand-Anchored pH-Sensitive Liposomes

Drug delivery for TB can be accomplished using ligand-anchored pH-sensitive liposomes. A dry powder inhaler with
a ligand-anchored pH-sensitive liposome was designed and described by Bhardwaj et al for the specific delivery of TB
drugs to the lungs. The sustained drug release and efficient in vitro cellular absorption were reported. They concluded
that ligand-anchored pH-sensitive liposomes are one of the most successful delivery systems for targeted drug delivery in
pulmonary TB.218 Bhardwaj et al 217 by using macrophage-specific ligands also created ligand-appended liposomes
encapsulated with ATDs in the surface of liposome and delivered in the respiratory system to enhance the impact of
chemotherapy over the pulmonary TB.219

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Nanoembedded Microparticles
For the purpose of TB drug delivery, nanoembedded microparticles also were formulated. Goyal et al encapsulated RIF
and INH into nanoembedded microparticles for pulmonary delivery and discovered that the drugs’ effectiveness was
improved while systemic toxicity was significantly reduced. Thus, it may be a potential carrier for ATD’s delivery. In
a mouse model of TB infection, Grenha et al synthesized nanoembedded microparticles that were loaded with isoniazid
and rifabutin which was significantly successful.219

Future Research and Development

Nanotechnology’s application in medicine has already yielded several achievements and is on its way to becoming an
important part of the medical sector. The ever-increasing number of research articles and patents awarded in the subject
of nanocarrier systems for drug delivery attests to this reality. Multidrug resistance (MDTB) with toxic side effects that
lead to diagnosis and treatment failure is still a major concern in the treatment of tuberculosis. The target for the future is
to develop or manufacture efficient and effective nano theranostic treatments that reduce treatment time, eliminate drug
toxicity, and also have better bioavailability, as well as to discover a method to eliminate the transmission of causative
organisms, however this is challenging, multifaceted, and difficult cause of limitations in diagnosis, multidrug resistance,
and poor patients’ adherence to therapy. A range of novel anti-TB potential nano-medications are in the pipeline;
however, key concerns are included: lack of systematic research effort, massive costs, difficulties in targeting MDR and
latent bacilli, along with toxicities of drugs. These are the motivations that drive the future research for novel and unique
alternative nano-therapeutic drugs. It was discovered that nanoparticle-based therapies and nanotheranostic as
a combination of diagnostic and therapeutic features through one platform might provide a possible benefit over
conventional TB therapy, with the future goal of decreasing TB drug dosage and enhance patient compliance.

Conclusion
Tuberculosis is among the most serious health issues worldwide with an annual rise in the number of patients. Nowadays,
the conventional anti-tubercular therapeutic method needs high dosages of numerous drugs over a longer duration. This
tends to result in drug-related detrimental effects or the development of MDR. Furthermore, the drugs currently in use
have practical limits of solubility, stability, and penetration. Also, it may lead to resistance over time, resulting in relapse,
and extend to peripheral body parts, which caused secondary TB.
In this review, current developments in methodologies and concepts for pulmonary drug delivery systems have been
briefly outlined. New drug delivery techniques based on nanocarriers and ligands were explored, and various nano
delivery systems were summarized. The use of pulmonary nanodrug delivery systems as a therapeutic agent for the
treatment of TB has become extremely useful. Targeted drug delivery, enhanced drug solubility, decreased toxicity,
reduced side effects compared to conventional drug regimens that cause MDR and XDR, and synergistic therapeutic
effects are among the benefits of using nanomaterials to deliver drugs for the treatment of infectious lung diseases. It
might be challenging to determine if a certain drug delivery system feature is advantageous or disadvantageous since it
depends on the treatment procedures and targets that have been defined. Although nanomedicines have great potential,
they are currently in the middle of their development. Research is still being done on concerns including physicochemical
analysis, pharmacological activity, and pharmacodynamic applications. It is anticipated that new drugs will be available
as a nanomedicine therapy, particularly the respiratory system, during the next several years based on current trends in
clinical trial stages. Consequently, the overall future for nanoparticle drug delivery systems is promising, since they are
being developed not just for diagnosing and treating respiratory diseases but also for a wide range of other diseases.

Acknowledgments
This work was supported by Gran Putra Berimpak, Grant No. UPM/800-3/3/1/GPB/2019/9678800.

Disclosure
The authors declare no conflicts of interest in this work.

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