Breaking barriers: The potential of nanosystems in antituberculosis therapy

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, continues to pose a significant threat to global health. The resilience of TB is amplified by a myriad of physical, biological, and biopharmaceutical barriers that challenge conventional therapeutic approaches. This review navigates the intricate landscape of TB treatment, from the stealth of latent infections and the strength of granuloma formations to the daunting specters of drug resistance and altered gene expression. Amidst these challenges, traditional therapies often fail, contending with inconsistent bioavailability, prolonged treatment regimens, and socioeconomic burdens. Nanoscale Drug Delivery Systems (NDDSs) emerge as a promising beacon, ready to overcome these barriers, offering better drug targeting and improved patient adherence. Through a critical approach, we evaluate a spectrum of nanosystems and their efficacy against MTB both in vitro and in vivo. This review advocates for the intensification of research in NDDSs, heralding their potential to reshape the contours of global TB treatment strategies.

Keywords: Barriers; Drug resistance; Mycobacterium tuberculosis; Nanoscale drug delivery systems; Tuberculosis.

Graphical abstract

Fig. 1

Structure of the mycobacterium cell wall. The innermost layer is the plasma membrane that acts as an impermeable barrier. Above it, the mAGP's peptidoglycan layer maintains cell integrity and increases pathogenicity. The mAGP's surface contains glycolipids linked by mycolic acids, which can function as virulence factors. This complex multilayered structure enables mycobacteria to resist antibiotic treatments and adapt to fluctuating environments. Created in biorender.com.

Fig. 2

The dynamic, complex structure of TB granuloma encompasses cellular interconnections and distinct microenvironments. Created in biorender.com.

Fig. 3

Mechanism of action of the main drugs used in TB therapy. Created in biorender.com.

Fig. 4

The potential of NDDS for anti-TB therapy.

Fig. 5

The NDDS employ various drug administration routes to specifically treat areas affected by TB. Created in biorender.com.

Fig. 6

A) Profile of the cumulative percentage of RIF release B) Mean concentration-time curves for RIF in plasma, C) Concentrations of RIF in lung tissue homogenates, D) Confocal laser scanning microscopy (CLSM) image demonstrating nanoemulsion endocytosis [276]. Reprint published from open access article by Taylor & Francis Copyright 2017.

Fig. 7

A) Wet organ weights of animals infected with tb based on the treatment, B) Number of viable bacteria in the lung and spleen tissues of the animals at necropsy after 10 days of treatment. RIF-loaded microparticles (RM); RIF-loaded liposomes (RL); RM-RL association; control for microparticles and liposomes (BL-BM) [285]. Reprint published from open access article by MDPI Copyright 2021.

Fig. 8

A) Physicochemical stability over time under room temperature conditions and at 4 °C, and how these parameters can affect the hydrodynamic diameter and zeta potential. The influence of the THP culture medium on these parameters was also evaluated by varying incubation intervals. B) Release pattern of RIF over 24 h, C) Enhanced intracellular killing of mycobacteria by RIF-loaded liposomes without any cytotoxic effects and D) Analysis of liposome internalization within macrophages [286]. Reprint published from open access article by MDPI Copyright 2021.

Fig. 9

A) The release profiles of RIF-loaded formulations were meticulously analyzed in vitro, considering the progression of time and the simulation of different environments including the lung fluid, the phagosome, and the phagolysosome. B) The mannosylated NDDS conjugated with fluorescein isothiocyanate showcased enhanced efficiency in terms of internalization within primary macrophages. Reprinted/adapted with permission from Ref. [300]. Copyright 2017, Future Medicine Ltd.

Fig. 10

A) Temporal plasma concentration profile of Scar2-loaded NLS following a single oral administration via gavage at a dose of 300 mg/kg body weight, B) Intramacrophage activity of Scar-loaded nanosystems [303]. Reprint published from open access article by Frontiers Media S.A. Copyright 2018.

Fig. 11

A) Depiction of the MIC through broth microdilution assay for the ZnO NPs and RIF combination against WT M. smegmatis at 37 °C over a period of 48 h. B) Kill kinetics of WT M. smegmatis when subjected to treatment with ZnO NPs and RIF. C) Examination of the WT M. smegmatis cells' morphology utilizing Cryo-SEM images following 4 and 12 h of ZnO NPs and RIF treatment. D) Impact of ZnO NPs and RIF on the membrane integrity of WT M. smegmatis cells. Reprinted/adapted with permission from Ref. [318]. Copyright 2020 American Chemical Society.

Fig. 12

A) SEM image of bare MSN B) Absorption isotherm C) Release analysis of NZX-loaded MSN (PBS and SLF) D) CLSM of NZX@MSNs in macrophages E) Intracellular assay of NZX, MSN and NZX@MSN F) In vivo anti-MTB activity assay. Reprinted/adapted with permission from Ref. [338]. Copyright PLOS 2019.

Fig. 13

A) Kinetics of the bactericidal efficacy of the treatment applied to the lungs and spleen of mice and B) the pulmonary pathology in the infected animals throughout the experimental period [359]. Reprint published from an open access article by MDPI.

Fig. 14

A) Accumulation of nanoparticles in tubal neural granulomas and B) Survival analysis comparing the therapeutic efficacy of free BQ versus NP-BQ. Reprinted/adapted with permission from Ref. [361]. Copyright Royal Society of Chemistry 2023.