Biosensors and Nanotheranostics

1.  Introduction

Tuberculosis remains the deadliest infection attributable to a single pathogen, the intracellular bacterium Mycobacterium tuberculosis (M. tb) (Onnainty & Granero, 2025; World Health Organization [WHO], 2024). Current estimates place the global toll at roughly 10.7 million new active cases in 2024 and approximately 1.23 million deaths (Tiwari et al., 2026). That burden is magnified by the steady emergence of drug-resistant strains, chief among them multidrug-resistant TB (MDR-TB), defined by resistance to the two cornerstone first-line agents isoniazid (INH) and rifampicin (RIF), and the still more intractable extensively drug-resistant TB (XDR-TB) (Makled et al., 2021; Omoteso et al., 2025). MDR-TB alone accounts for close to 450,000 new cases each year, yet global treatment success hovers near a modest 60%, a figure that lays bare the inadequacy of standard chemotherapy (Omoteso et al., 2025).

Conventional management of both drug-susceptible and drug-resistant disease rests on systemic oral or parenteral administration of multi-drug combinations sustained for 6 to 24 months (Bourguignon et al., 2023; Ramachandran et al., 2023). This approach carries three recurring liabilities. High systemic doses are required to drive antibiotic concentrations to therapeutic thresholds in the lung, which frequently provokes hepatotoxicity, nephrotoxicity, ototoxicity, and gastrointestinal distress (Kaur & Singh, 2014; Zhu et al., 2026). Rapid hepatic metabolism, extensive plasma-protein binding, and non-specific distribution leave too little active drug within infected pulmonary tissue (Baranyai et al., 2021; Kia et al., 2023). And the combination of prolonged timelines with severe adverse effects erodes adherence, which in turn selects for increasingly resistant mutant sub-populations (Muthukrishnan, 2021; Tiwari et al., 2026).

The difficulty of curing MDR-TB is written into the biology of the infection (Bourguignon et al., 2023; Ranjith Singh et al., 2025). After inhalation, M. tb droplet nuclei descend into the deep alveolar spaces and are taken up by alveolar macrophages, the pathogen's principal host niche (Ramachandran et al., 2023). Rather than being destroyed, the bacillus arrests phagolysosomal maturation, blocks endosomal acidification, and replicates within the macrophage (Cung et al., 2025; Tiwari et al., 2026). As the immune response matures, infected macrophages recruit monocytes, lymphocytes, and neutrophils, and the lesion organizes into a tuberculous granuloma (Lyu et al., 2024; Ranjith Singh et al., 2025). A mature granuloma presents a central necrotic, caseous core of dormant bacilli ringed by lipid-laden foamy macrophages, epithelioid and multinucleated giant cells, and an outer fibrotic capsule (Tiwari et al., 2026).

These structures are, in effect, pharmacological fortresses. High lipid density, hypoxia, acidic pH, and poor vascularization throttle the passive diffusion of systemic antibiotics into the caseous core (Prideaux et al., 2015; Tiwari et al., 2026). Free drug molecules often cannot cross the thick, hydrophobic mycobacterial cell wall or the host macrophage membrane at bactericidal concentrations (Luz et al., 2020; Rudolph et al., 2023). And any inhaled agent must first survive mucociliary clearance, mucosal gel layers, and surfactant interactions before it ever reaches the alveoli (Gao et al., 2025; Makled et al., 2021).

Direct pulmonary delivery sidesteps much of the pharmacokinetic penalty of systemic dosing (Makled et al., 2021; Onnainty & Granero, 2025). Depositing drug at the site of infection raises local bioavailability, bypasses hepatic first-pass metabolism, and allows the total systemic dose, and its attendant toxicity, to fall (Kia et al., 2023; Ramachandran et al., 2023). To accumulate inside infected cells, nanoparticle drug delivery systems in the 10–500 nm range are formulated so that their aerodynamic behavior, often as nano-in-micro dry-powder aggregates of 1–5 µm, carries them past upper-airway clearance into the deep lung (Baranyai et al., 2021; Garg et al., 2016).

Surface engineering then turns passive deposition into active targeting (Baranyai et al., 2021; Cung et al., 2025). Decorating nanoparticles with ligands that engage receptors overexpressed on infected macrophages triggers receptor-mediated endocytosis: mannose, mannosamine, or hyaluronic acid for CD206-mediated uptake (Bera et al., 2024; Omoteso et al., 2025); 1,3-β-glucan or curdlan for Dectin-1, which simultaneously stimulates innate signaling (Kutscher et al., 2026; Omoteso et al., 2025); and maleylated albumin, transferrin, or aptamers for scavenger and transferrin pathways (Cung et al., 2025; Tiwari et al., 2026).

Targeted delivery improves potency, but conventional formulations remain blind, unable to report where the drug went or whether it worked (Bueno, 2025; Onnainty & Granero, 2025). Nanotheranostics address this by folding therapy and non-invasive diagnostics into one construct (Akinnawo & Dube, 2025; Onnainty & Granero, 2025). Near-infrared (NIR-I/NIR-II) luminogens, including aggregation-induced emission dyes, allow deep-tissue tracking of drug deposition and bacterial clearance (Liao et al., 2020). Superparamagnetic iron oxide nanoparticles and iron-based metal–organic frameworks serve as MRI contrast agents while releasing antibiotics in a pH-responsive manner (Onnainty & Granero, 2025; Wyszogrodzka et al., 2018). Biomimetic, membrane-camouflaged particles combine lesion homing with photothermal or photodynamic killing (Li et al., 2024). And host-directed payloads, from autophagy inducers to agents that repolarize macrophages toward the bactericidal M1 state, attack the infection through the host rather than the pathogen (Bahlool et al., 2022; Bekale et al., 2025).

Despite two decades of encouraging preclinical data, few inhalable targeted formulations have reached human trials, held back by nanotoxicology, aerodynamic formulation complexity, GMP scalability, and regulatory uncertainty (Erothi et al., 2026; Ramachandran et al., 2023). Prior reviews have tended to treat nanomedicine platforms or systemic chemotherapy in general terms, without drawing together the specific advances in actively targeted inhalable nanotheranostics that combine delivery, imaging, and immunomodulation against MDR-TB (Cung et al., 2025; Onnainty & Granero, 2025; Ranjith Singh et al., 2025). This review was undertaken to fill that gap. Its objectives are: (i) to evaluate inhalable nanocarrier platforms for anti-TB delivery; (ii) to examine active receptor-mediated macrophage targeting; (iii) to assess integrated diagnostic and imaging modalities; (iv) to investigate host-directed and resistance-agnostic strategies; and (v) to identify translational bottlenecks and outline a clinical roadmap (Erothi et al., 2026; Tiwari et al., 2026).

2.  Targeted Pulmonary Nanomedicine Reaches Dormant Mycobacteria and Reprograms Host Immunity in Tuberculosis

2.1  The Epidemiological Imperative and the Therapeutic Shift

Epidemiological assessments converge on a sobering picture: roughly 10.7–10.8 million people developed active TB in 2024, with 1.23–1.25 million deaths, the burden concentrated across South-East Asia, the Western Pacific, and sub-Saharan Africa (Afreen et al., 2026; Carnero et al., 2026; Gautam & Venugopal, 2026). Resistance compounds the problem. MDR-TB contributes more than 400,000 new cases annually and is a major driver of antimicrobial-resistance mortality (Carnero et al., 2026; Tiwari et al., 2026). Against drug-susceptible disease, success rates sit near 60% for MDR-TB and fall to roughly 39% for XDR-TB (Baranyai et al., 2021). The conceptual response, traced in Figure 1, is a shift away from viewing nanoparticles as passive drug vectors and toward treating them as active platforms that overcome anatomical, microenvironmental, and mycobacterial barriers at once (Baranyai et al., 2021; Onnainty & Granero, 2025).

2.2  Pathophysiological, Anatomical, and Cellular Barriers

The failure of systemic chemotherapy is bound up with the niches M. tb establishes in the host (Baranyai et al., 2021; Ranjith Singh et al., 2025). Within alveolar macrophages the bacillus arrests phagosome–lysosome fusion, blocks vacuolar acidification, and suppresses apoptosis and autophagy, converting the phagosome into a permissive compartment and drawing on host lipids to enter a slow-growing, dormant state (Afreen et al., 2026; Omoteso et al., 2025). As infection progresses, the granuloma takes on its characteristic layered architecture, shown in Figure 2: a caseous necrotic core, a foamy-macrophage layer, a cellular rim of epithelioid and giant cells, and a peripheral fibrotic cuff (Lyu et al., 2024; Tiwari et al., 2026). Each layer raises the barrier to drug penetration. The core is hypoxic, acidic, lipid-rich, and avascular (Prideaux et al., 2015; Ranjith Singh et al., 2025). Inhaled agents must additionally survive mucociliary clearance and sequestration by non-infected phagocytes (Gao et al., 2025; Onnainty & Granero, 2025), and at the alveolar air–liquid interface they acquire a surfactant corona of lipids and proteins (SP-A, SP-D) that reshapes aggregation, uptake, and residence time (Gao et al., 2025; Uskoković, 2023). The physicochemical and formulation strategies that answer these barriers are catalogued in Table 1.

2.3  Formulation Engineering of Inhalable Nanocarriers

Pulmonary administration concentrates drug in the alveoli while sparing systemic tissues (Makled et al., 2021; Ramachandran et al., 2023). Where a particle lands is governed by its mass median aerodynamic diameter (MMAD), as summarized in the upper panel of Figure 3: particles above 5 µm impact in the upper airways and are cleared, those below 1 µm are largely exhaled, and the 1–5 µm window, achievable directly or through nano-in-micro aggregates, deposits efficiently in the deep alveoli (Ramachandran et al., 2023; Uskoković, 2023). The principal carrier classes and their aerodynamic performance are compared in Table 1.

Lipid-based nanocarriers

Liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) encapsulate both hydrophilic and lipophilic antibiotics (Bourguignon et al., 2023; Ramachandran et al., 2023). Liposomes, while versatile, are prone to instability during nebulization and to lipid oxidation and leakage, whereas SLNs and NLCs offer better physical stability, high encapsulation efficiency, and sustained release of lipophilic second-line drugs such as linezolid or clofazimine (Makled et al., 2021; Ramachandran et al., 2023).

Table 1.  Physicochemical properties, formulation engineering, and aerodynamic performance of inhalable nanocarrier platforms for anti-TB delivery. Comparison of the major inhalable nanocarrier classes evaluated for anti-tuberculosis delivery, aligning each platform's composition and particle size with its aerodynamic performance (mass median aerodynamic diameter, MMAD; fine particle fraction, FPF), drug payload and encapsulation efficiency (EE), and principal advantages and limitations. Across classes, formulation into spray-dried nano-in-micro aggregates brings the MMAD into the 1–5 µm window required for deep-alveolar deposition. Lipid and polymeric carriers favor sustained release and biocompatibility, whereas inorganic frameworks offer the highest loading and stimulus-responsive gating at the cost of slower biodegradation. Abbreviations: DPI, dry-powder inhaler; RIF, rifampicin; INH, isoniazid; P-gp, P-glycoprotein; ζ, zeta potential.

Table 2.  Active receptor-mediated macrophage and granuloma targeting ligands in nanomedicine-based TB management. Receptor-targeting strategies that convert non-specific phagocytic capture into active, ligand-directed internalization of nanocarriers by infected macrophages. For each overexpressed receptor the table lists the matched surface ligand, the target cell or microenvironmental niche, the endocytic pathway engaged, a representative carrier–payload pairing, and the reported biological outcome. Mannose (CD206) and β-glucan (Dectin-1) systems dominate the evidence base, the latter coupling delivery to innate immune activation, while hyaluronic acid (CD44) and biomimetic membrane coatings extend reach into the dense fibrotic cuff and hypoxic lesion core. Abbreviations: RIF, rifampicin; INH, isoniazid; ROS/RNS, reactive oxygen/nitrogen species; TNF-α, tumor necrosis factor-α.

Polymeric nanoparticles

Carriers built from poly(lactic-co-glycolic acid) (PLGA) or from natural biopolymers such as chitosan and alginate combine high loading capacity with sustained intracellular release (Bourguignon et al., 2023; Zhu et al., 2026). Chitosan adds mucoadhesion and transient tight-junction opening to prolong retention (Garg et al., 2016), and cationic polymers promote endosomal escape through the proton-sponge effect (Zhu et al., 2026).

Inorganic and hybrid constructs

Mesoporous silica nanoparticles, SPIONs, gold nanoparticles, quantum dots, and metal–organic frameworks provide rigid, high-surface-area scaffolds that can carry drug and diagnostic function simultaneously (Onnainty & Granero, 2025; Uskoković, 2023).

2.4  Active Receptor-Mediated Macrophage and Granuloma Targeting

Passive accumulation in inflamed tissue yields only modest benefit; active surface targeting markedly increases uptake into infected macrophages (Baranyai et al., 2021; Cung et al., 2025). Infection upregulates specific pattern-recognition and endocytic receptors, each of which can be addressed with a matched ligand, as laid out in the lower panel of Figure 3 and catalogued in Table 2 (Baranyai et al., 2021; Cung et al., 2025).

Mannose receptor (CD206)

CD206 internalizes terminal mannose, fucose, and N-acetylglucosamine residues (Baranyai et al., 2021; Bera et al., 2024). Functionalizing PLGA, chitosan, or SLNs with mannose, mannosamine, or methyl α-D-mannopyranoside raises intracellular accumulation by up to 15-fold and delivers payloads straight to the phagolysosome (Bera et al., 2024; Luan et al., 2025).

Dectin-1 receptor

Dectin-1 recognizes 1,3-β-glucan, and coating nanoparticles with curdlan triggers Dectin-1-mediated phagocytosis while activating SYK–CARD9 signaling, pro-inflammatory cytokine release (TNF-α, IL-12), and ROS production, uniting delivery with immune stimulation (Bekale et al., 2025; Omoteso et al., 2025).

Hyaluronic acid receptor (CD44)

CD44, upregulated on inflamed macrophages and epithelioid cells, binds low-molecular-weight hyaluronic acid with high affinity, improving penetration across the dense fibrotic cuff of mature granulomas (Baranyai et al., 2021; Carnero et al., 2026).

Scavenger, transferrin, and peptide receptors

Scavenger receptors (SR-A, MARCO) take up maleylated albumin and anionic lipids, while transferrin-binding peptides, camelid antibodies, and tuftsin enhance internalization and deep accumulation in avascular caseous centers (Baranyai et al., 2021; Tiwari et al., 2026).

2.5  Integrated Diagnostic Imaging and Biomimetic Phototherapeutics

The defining move of nanotheranostics is to make therapy visible, pairing drug delivery with non-invasive imaging and, increasingly, light-activated killing within one construct, as mapped in Figure 4 and detailed in Table 3 (Bueno, 2025; Onnainty & Granero, 2025).

NIR imaging and AIE luminogens

Conventional dyes photobleach and quench in aqueous media; aggregation-induced emission (AIE) luminogens instead brighten upon aggregation (Liao et al., 2020). RIF-loaded AIE nanocarriers emit strong NIR-II fluorescence inside granulomas, enabling high-resolution, background-free tracking in live animals (Liao et al., 2020; Onnainty & Granero, 2025).

MRI contrast

SPIONs and iron-based frameworks such as Fe-MIL-101-NH2 act as T2 contrast agents for pulmonary lesions and, when ligand-decorated, combine anatomical imaging with sustained antibiotic release (Onnainty & Granero, 2025; Wyszogrodzka et al., 2018).

Cell-membrane camouflage and resistance-agnostic phototherapy

Nanoparticles cloaked in membranes from pre-activated, M. tb-stimulated macrophages home to infected tissue while evading clearance (Li et al., 2024; Ranjith Singh et al., 2025). Under 1064 nm irradiation they generate localized heat and ROS, destroying drug-resistant bacilli independently of antibiotic susceptibility while permitting simultaneous NIR-II imaging (Li et al., 2024; Onnainty & Granero, 2025).

Figure 1.  Global MDR-TB burden and the rationale for inhalable nanotheranostics. Schematic overview linking the epidemiological burden of tuberculosis to the design logic of inhalable nanotheranostic platforms. The persistent global case and death toll, together with the high annual incidence of multidrug-resistant disease, exposes two convergent problems: the pharmacological failures of conventional systemic therapy (prolonged, toxic regimens with low pulmonary bioavailability) and the pathophysiological barriers that shelter the pathogen (macrophage sequestration, granuloma hypoxia, mucociliary clearance, and the surfactant corona). These define an unmet need that inhalable nanotheranostics address through four coordinated capabilities, deep-lung deposition, active macrophage targeting, integrated bioimaging, and resistance-agnostic action, yielding high local exposure, reduced toxicity, real-time monitoring, and resistance bypass.

Figure 2.  Architecture of the tuberculous granuloma and its drug-penetration barriers. Concentric structure of the mature tuberculous granuloma and the gradient of drug accessibility it imposes. Moving inward from the vascularized periphery, the peripheral fibrotic cuff (T/B lymphocytes, fibroblasts, collagen), the cellular rim (epithelioid and multinucleated giant cells), the lipid-laden foamy-macrophage layer, and the hypoxic intermediate zone surround a central caseous necrotic core harboring dormant, non-replicating bacilli. Progressive hypoxia, acidification, and loss of vascularization toward the core, depicted by the lower gradient bar, steadily raise the barrier to antibiotic penetration, explaining why systemically delivered drugs reach the caseum at sub-therapeutic concentrations and why lesion-penetrating nanocarriers are needed.

2.6  Nanocarrier-Enabled Host-Directed Therapies

Because M. tb so readily evolves resistance to direct-acting drugs, host-directed therapy (HDT) offers a resistance-agnostic paradigm, modulating host pathways rather than bacterial targets and thereby removing the selective pressure that breeds resistance (Bekale et al., 2025; Omoteso et al., 2025; Tiwari et al., 2026). The principal mechanisms, with representative nanomaterials and outcomes, are compiled in Table 4 and summarized in Figure 4.

• Autophagy stimulation. Curcumin-loaded and curdlan-coated PLGA nanoparticles engage Dectin-1 and drive the LC3-II autophagic cascade, overriding M. tb-induced phagolysosomal arrest and cutting intracellular burden (Bekale et al., 2025; Omoteso et al., 2025).

• Macrophage repolarization. Iron-tropic iron oxide nanoparticles deliver intracellular iron that repolarizes permissive M2 macrophages toward the bactericidal M1 phenotype, with release of TNF-α and IL-12 (Onnainty & Granero, 2025; Tiwari et al., 2026).

• Vascular normalization and matrix remodeling. Carriers delivering anti-VEGF or matrix-metalloproteinase inhibitors normalize aberrant granuloma vasculature and loosen the surrounding matrix, improving penetration of co-administered antibiotics (Datta et al., 2024; Onnainty & Granero, 2025).

2.7  Translational Challenges, Safety, and a Clinical Roadmap

The preclinical case is strong, but translation is constrained on several fronts (Erothi et al., 2026; Tiwari et al., 2026). Non-biodegradable carriers can provoke pulmonary inflammation, oxidative damage, and fibrosis on repeated dosing (Poojary & Dash, 2025; Uskoković, 2023). Interaction with native surfactant can disturb alveolar surface tension and mask targeting ligands through corona formation (Poojary & Dash, 2025; Tiwari et al., 2026). Nanoparticles aggregate during nebulization or spray-drying, degrading aerosol performance (Erothi et al., 2026; Ramachandran et al., 2023). And GMP-scale synthesis with batch-to-batch consistency in size, loading, ligand density, and sterility remains a formidable industrial hurdle (Poojary & Dash, 2025; Tiwari et al., 2026). Addressing these will require standardized nanotoxicology panels, microfluidic manufacturing, and long-term, multi-dose toxicity studies in non-human primates (Erothi et al., 2026; Poojary & Dash, 2025).

3.  Methods

3.1  Study Design and Reporting Framework

This work was conducted as a structured narrative review of actively targeted inhalable nanotheranostics for MDR-TB. Because the aim was integrative synthesis across heterogeneous formulation, imaging, and immunological studies rather than a pooled quantitative estimate, a narrative design was chosen over a meta-analysis. To keep the process transparent and reproducible, screening and selection were documented.

3.2 Information Sources and Search Strategy

Four electronic databases, PubMed/MEDLINE, Scopus, Web of Science Core Collection, and Google Scholar, were searched from database inception to June 2026. The search combined controlled vocabulary (MeSH) and free-text terms across three concept blocks joined with the Boolean operator AND, with synonyms within each block joined by OR. Block 1 (disease): "tuberculosis" OR "Mycobacterium tuberculosis" OR "multidrug-resistant tuberculosis" OR "MDR-TB" OR "XDR-TB". Block 2 (platform): "nanoparticle" OR "nanomedicine" OR "nanocarrier" OR "liposome" OR "solid lipid nanoparticle" OR "PLGA" OR "metal-organic framework" OR "mesoporous silica" OR "theranostic". Block 3 (route/function): "inhalable" OR "pulmonary delivery" OR "dry powder" OR "alveolar macrophage" OR "targeted" OR "imaging" OR "host-directed". Reference lists of included articles and relevant reviews were hand-searched to capture records the database queries missed.

3.3  Eligibility Criteria

Records were eligible if they were peer-reviewed, written in English, and reported original experimental data or authoritative synthesis on inhalable or macrophage-targeted nanocarriers for TB, including physicochemical characterization, aerodynamic performance, in vitro or in vivo efficacy, imaging function, or host-directed activity. Studies of systemic-only formulations with no pulmonary or macrophage-targeting relevance, conference abstracts without full text, and non-English records were excluded. Global epidemiological figures were drawn from the World Health Organization's Global Tuberculosis Report.

3.4  Study Selection and Data Extraction

Titles and abstracts were screened against the eligibility criteria, and the full texts of potentially relevant records were assessed. From each included study, the following were extracted into a standardized matrix: nanocarrier class and composition; particle size, surface charge, and encapsulation efficiency; aerodynamic descriptors (MMAD, fine particle fraction); targeting ligand and receptor; imaging modality; therapeutic or host-directed mechanism; experimental model; and principal outcomes. Extracted data were organized into four thematic tables corresponding to formulation engineering (Table 1), receptor-mediated targeting (Table 2), diagnostic imaging and phototherapy (Table 3), and host-directed therapy (Table 4).

3.5  Synthesis Approach

Evidence was synthesized thematically rather than statistically. Findings were grouped under the four domains above, and recurring quantitative signals, such as fold-changes in macrophage uptake or reductions in colony-forming units, were compared across studies where measurement conditions were broadly comparable. Four schematic figures were constructed to integrate the extracted concepts. Given the preclinical heterogeneity of the evidence base and the absence of standardized outcome reporting, no formal risk-of-bias scoring or quantitative pooling was attempted; this limitation is weighed explicitly in the Discussion.

4.  Converging Evidence Across Four Functional Domains

Read together, the included studies tell a reasonably coherent story, though not an evenly developed one. Engineered nanocarriers no longer behave as passive vehicles; across formulation, targeting, imaging, and immunomodulation they actively negotiate the barriers that defeat systemic drugs (Figure 1). The strength of the evidence varies by domain, and it is worth being candid about where the signal is robust and where it rests on a handful of landmark reports.

4.1  Aerosol Mechanics and Aerodynamic Deposition

The first requirement is almost mechanical: a particle has to land where the macrophages are (Figure 3). Here the data are consistent. Formulating nanoparticles into spray-dried microparticulate aggregates with inert sugar carriers reliably lands the MMAD between 1.0 and 3.8 µm, with fine particle fractions above 62–93% (Table 1). Linezolid-loaded NLCs, for instance, reached an MMAD of 2.0 µm and an FPF near 93%, with 73% of payload crossing synthetic airway mucus within an hour (Makled et al., 2021). Spray-dried PLGA microparticles carrying clofazimine behaved similarly, holding an MMAD of about 2.57 µm while sustaining release over 48–120 hours (Bourguignon et al., 2023).

One result stands somewhat apart. High-dose, surfactant-stabilized amorphous drug nanoparticles, prepared by solvent–antisolvent precipitation, produced ultra-small structures of 60–62 nm with remarkable loading, roughly 69% for bedaquiline and more than 99% for BTZ-043 by mass (Rudolph et al., 2023). In C3HeB/FeJ mice these carrier-free particles crossed epithelial barriers, reached necrotic granulomas, and showed up to 50% greater bactericidal effect than oral or systemic solutions (Rudolph et al., 2023). It is a striking figure, and one worth treating as promising rather than settled until it is reproduced more widely.

4.2  Active Receptor-Mediated Targeting

Surface functionalization turns indiscriminate phagocytosis into something closer to address-based delivery (Table 2). The clearest numbers come from CD206. Conjugating mannose or mannosamine to SLNs, PLGA, or chitosan raised intracellular uptake by roughly 8- to 15-fold over plain carriers, and in one latent/active model mannose-decorated SLNs achieved 97.2% macrophage uptake against 42.4% for the unmodified controls (Bera et al., 2024; Luan et al., 2025). Dectin-1 targeting with curdlan did more than speed entry; it engaged SYK–CARD9 signaling and prompted the host cell to release TNF-α and IL-12 and to generate ROS, so that delivery and immune activation ran together (Bekale et al., 2025; Kutscher et al., 2026). Low-molecular-weight hyaluronic acid, meanwhile, helped carriers diffuse across the fibrotic cuff and deposit antimicrobial peptides such as LLKKK18 into the lesion core, a region that is otherwise notoriously hard to reach (Baranyai et al., 2021; Carnero et al., 2026).

4.3  Diagnostic Bioimaging and Phototheranostic Performance

The imaging results are perhaps the most visually persuasive, and here a few constructs carry much of the weight (Table 3; Figure 4). NIR-II AIE luminogens built into PLGA cores (TPE-BT-BBTD) lit up granulomatous tissue on aggregation, and when camouflaged with pre-activated macrophage membranes (BBTD@PM) they circulated long enough to home to lesions

(Li et al., 2024; Wang et al., 2024). Under transthoracic 1064 nm irradiation at 0.2 W/cm², localized heating near 55 °C eliminated intracellular mycobacteria, reportedly to 0 CFU/mL, without surrounding necrosis (Li et al., 2024). Iron-based frameworks (Fe-MIL-101-NH2) and SPIONs did double duty, supplying T2-weighted contrast while releasing isoniazid in a pH-responsive manner within acidic endosomes (Onnainty & Granero, 2025; Wyszogrodzka et al., 2018). Mannose-functionalized mesoporous polydopamine carrying rifampicin reached 51.3 °C under 808 nm light and cut bacterial loads in cutaneous and pulmonary models (Fan et al., 2024). These are impressive demonstrations; whether a single platform can hold all of these functions together at scale is a separate question.

4.4  Host-Directed Immunomodulation and Microenvironmental Remodeling

The host-directed results point in a consistent direction, even if the mechanisms are varied (Table 4). Curcumin-loaded PLGA nanoparticles restored autophagic flux, converting LC3-I to LC3-II and degrading p62, and in combination with isoniazid produced greater than 99% reductions in intracellular M. tb in RAW 264.7 cells and murine lungs (Bekale et al., 2025; Gupta et al., 2023). Mannose-PEG-coated iron oxide nanoparticles localized to acidic lysosomes, released iron, and pushed macrophages from the permissive M2 state toward bactericidal M1, with TNF-α secretion rising accordingly (Shen et al., 2023). And adjunctive vascular agents such as losartan and bevacizumab reduced excess matrix and normalized granuloma microvasculature, which in turn improved the deep penetration of second-line antibiotics in rabbit models (Datta et al., 2024). The through-line is that acting on the host, rather than the bacillus, sidesteps the resistance problem altogether, at least in principle.

5.  Promise, Caveats, and the Path to the Clinic

What the assembled evidence suggests is not that any one nanomaterial has solved MDR-TB, but that a particular combination of capabilities is beginning to look coherent. Localized deposition, receptor-level targeting, embedded imaging, and resistance-agnostic action each address a different failure of conventional therapy, and the more interesting reports are the ones that manage two or three of these at once (Onnainty & Granero, 2025). That said, it would be a mistake to read the preclinical numbers too literally.

5.1  Interpreting the Efficacy Signal

Some of the headline figures, 0 CFU/mL after photothermal treatment, greater than 99% intracellular killing, 15-fold gains in uptake, are genuinely arresting (Li et al., 2024; Bera et al., 2024). They are also, for the most part, drawn from tightly controlled in vitro systems or small-animal models that do not fully recapitulate the human granuloma (Table 3; Table 4). The caseous core that makes human disease so difficult is imperfectly reproduced in most murine models, and a particle that clears bacilli in a macrophage monolayer may behave quite differently against a mature, hypoxic lesion (Prideaux et al., 2015; Ranjith Singh et al., 2025). The amorphous-nanoparticle result, with its 50% bactericidal advantage in a necrosis-prone mouse strain, is encouraging precisely because it was tested in a more realistic model (Rudolph et al., 2023), and it is the kind of validation the field needs more of.

5.2  The Barrier Within the Barrier: Surfactant and Corona Effects

One recurring theme deserves more attention than it usually gets. The same surfactant layer that the lung depends on can quietly undo a carefully engineered particle (Figure 2). Adsorption of SP-A, SP-D, and lipids forms a biomolecular corona that can mask targeting ligands and alter biodistribution, so that a nanoparticle optimized in buffer may lose much of its selectivity at the air–liquid interface (Gao et al., 2025; Uskoković, 2023). This is not a peripheral detail; it sits directly between a promising formulation and its performance in vivo, and the studies that engineered around it, with zwitterionic or PEGylated coatings, tended to be the ones with more durable targeting (Poojary & Dash, 2025).

5.3  Host-Directed Therapy as a Hedge Against Resistance

If there is a strategic reason for optimism, it is probably the host-directed arm (Table 4). Targeting autophagy, macrophage polarization, or the granuloma microenvironment removes the selective pressure that generates resistance in the first place, which makes these approaches attractive regardless of a strain's drug-susceptibility profile (Bekale et al., 2025; Datta et al., 2024). The appeal is conceptual as much as empirical: an agent that works through the host does not care whether the bacillus is INH-resistant. The catch is that host

​​​​​Figure 3.  Aerodynamic deposition and active receptor-mediated macrophage targeting. Two determinants of effective inhaled anti-TB nanotherapy. (A) Aerodynamic size governs regional deposition: particles with a mass median aerodynamic diameter (MMAD) above 5 µm impact in the oropharynx and are cleared, those below 1 µm are largely exhaled, and the 1–5 µm window sediments optimally into the deep alveolar sacs where infected macrophages reside. (B) Once deposited, ligand-decorated nanocarriers engage receptors overexpressed on infected alveolar macrophages, CD206 (mannose), Dectin-1 (β-glucan), CD44 (hyaluronan), and scavenger/transferrin receptors, each driving receptor-mediated internalization toward the intracellular mycobacterial niche, with Dectin-1 additionally triggering SYK–CARD9 signaling and autophagy.

Figure 4.  Integrated diagnostic imaging and host-directed therapeutic modalities. Dual-function design of multifunctional inhalable nanotheranostic constructs, which simultaneously diagnose and treat. The diagnostic arm combines near-infrared (NIR-I/NIR-II) fluorescence from AIE luminogens and quantum dots, T2-weighted magnetic resonance from SPIONs and iron-based frameworks, and photoacoustic/CT imaging from gold and membrane-camouflaged cores for deep lesion tracking and localization. The therapeutic arm delivers resistance-agnostic action through autophagy induction, M2-to-M1 macrophage repolarization, and photothermal/photodynamic killing. Together these arms establish a theranostic feedback loop enabling image-guided dosing and real-time response monitoring, achieving simultaneous lesion visualization and multi-pathway bacterial eradication within one construct.

pathways are shared pathways, and modulating immunity carries its own risks that the current preclinical literature has only begun to probe (Omoteso et al., 2025).

5.4  Translational Bottlenecks

The obstacles to translation are, by now, familiar, which does not make them smaller (Erothi et al., 2026; Tiwari et al., 2026). Multifunctional constructs are harder to manufacture reproducibly than single-function ones, and every added feature, a ligand, a contrast agent, a membrane coat, multiplies the parameters that must stay within specification at GMP scale (Poojary & Dash, 2025). Long-term pulmonary safety is still underexplored, particularly for inorganic and non-biodegradable cores on repeated dosing (Uskoković, 2023). And aerosol stability, so easily lost during nebulization or spray-drying, can erode the very deposition profile that justified the inhaled route (Ramachandran et al., 2023). None of these is insurmountable, but together they explain why so little of this work has reached human trials.

5.5  Limitations of This study

This review has its own constraints. It is narrative rather than systematic in its synthesis, and the underlying evidence is preclinical, heterogeneous, and reported without standardized outcomes, which makes quantitative pooling inappropriate and cross-study comparison approximate. Positive results are also more likely to be published than negative ones, so the balance of the literature may be more encouraging than the underlying reality. These caveats temper, without erasing, the central observation that the convergence of targeted delivery, imaging, and host-directed action represents a meaningful departure from conventional chemotherapy.

6.  Conclusion

Inhalable nanoparticle theranostics bring together, in a single construct, the capabilities that conventional MDR-TB therapy lacks: deep-lung deposition, receptor-level targeting of infected macrophages, non-invasive imaging of where the drug goes and whether it works, and resistance-agnostic action through host-directed and light-activated mechanisms. The preclinical evidence synthesized here is consistent and at times remarkable, from marked gains in intracellular uptake to near-complete bacterial clearance in model systems. Yet the gap between benchtop performance and clinical reality remains wide, defined by nanotoxicity, surfactant-corona effects, aerosol instability, and manufacturing scale. Progress will depend less on discovering new nanomaterials than on validating existing ones in granuloma-faithful models and carrying them through standardized, GMP-compatible development toward the high-burden settings that need them most.

References