Photoresponsive Nanocarriers for Potentiating Tuberculosis Therapy

Drug-resistant and multidrug-resistant tuberculosis (TB) remain major challenges to effective treatment. Given that TB arises from complex bacterial survival mechanisms, addressing this multifactorial disease requires innovative and combinatorial therapeutic approaches. Although various strategies have been employed to overcome these issues, concerns regarding therapeutic efficacy persist due to the prolonged treatment duration and high toxicity. Here, we developed photoresponsive nanocarriers coencapsulating isoniazid (INH) and rifampicin (RIF), with or without gold nanorods (AuNRs), as a multifunctional platform for laser-assisted TB therapy. AuNRs were synthesized and functionalized with PLGA-SH to enable photothermal activation and integration into polymeric carriers. The resulting systems exhibited an average size of approximately 180 nm, zeta potentials around -28 mV, particle concentrations on the order of 10¹¹ particles mL^-1, as measured by nanoparticle tracking analysis, and average encapsulation efficiencies of 90% for both drugs. In vitro, photoactivated nanocarriers significantly reduced Mycobacterium tuberculosis burden in murine alveolar epithelial (MLE-15) cells and macrophages (BMDMs), as well as in human macrophages (THP-1), without inducing cytotoxicity. TB preclinical models demonstrated that laser-triggered nanocarriers significantly reduced pulmonary bacterial load in infected mice compared with untreated groups, even at low doses. These findings demonstrate that the formulation's therapeutic efficacy depends on photothermal activation and support its potential as an adjuvant strategy for precision, light-assisted TB treatment, thereby reducing systemic exposure and minimizing toxicity.