Therapeutic Nanoplatform Integrating Photothermal Effect and Silver Nanoparticles for the Treatment of Intracellular Mycobacterium tuberculosis.

The global challenge of tuberculosis (TB), particularly in the context of rising drug resistance and intracellular bacterial persistence, highlights the need for innovative therapeutic strategies. In this study, we develop a multifunctional nanoplatform (CuS-Ag@FA) that integrates near-infrared (NIR)-responsive photothermal CuS, antimicrobial Ag nanoparticles (Ag NPs), and folate-receptor-mediated macrophage targeting for enhanced intracellular Mycobacterium tuberculosis (M.tb) clearance. Our work represents the first FA-functionalized CuS-Ag nanoplatform designed for dual-targeting of M.tb-infected macrophages and the first evaluation of this nanoplatform in an M.tb-infected animal model. FA functionalization markedly improves macrophage uptake, enabling precise intracellular delivery. Upon 808 nm irradiation, CuS-Ag@FA generates localized hyperthermia that synergizes with Ag NPs-induced oxidative and membrane-disruptive effects, resulting in potent intracellular bactericidal efficacy. Transcriptomic analysis reveals simultaneous inhibition of M.tb DNA replication, redox homeostasis, and metabolic pathways, supporting a multidimensional mechanism of action. In vivo studies confirm potent therapeutic efficacy, pulmonary accumulation, and favorable biosafety, establishing CuS-Ag@FA as a promising next-generation nanotherapeutic for combating drug-resistant and intracellular M.tb.