Precise Photothermal/Fluorescence Imaging-Guided Dual-Targeted Photothermal Therapy for Tuberculosis.

Tuberculosis (TB) remains a major global public health challenge, while current first-line regimens are often compromised by drug resistance, high toxicity, and poor targeting. Herein, we develop a lesion-pathogen dual-targeting theranostic nanoparticle (ICG-PEG-Tar) for imaging-guided photothermal therapy (PTT). The ICG enables fluorescence/photothermal imaging while serving as the photothermal agent, and the anti-Ag85B (marked as Tar in ICG-PEG-Tar NPs) precisely targets antigen 85B of Mycobacterium tuberculosis. The binding specificity of ICG-PEG-Tar NPs toward Ag85B was validated by ELISA, confirming the molecular recognition capability of the conjugated antibody on ICG-PEG-Tar NPs. The therapeutic efficacy is systematically evaluated in a well-established murine tail granuloma model induced by Mycobacterium marinum (M.m), a pathogen phylogenetically close to Mycobacterium tuberculosis. While the M.m murine tail granuloma has inherent limitations in fully mimicking human pulmonary TB, it remains a widely used surrogate that recapitulates key human tuberculosis hallmarks, including caseating granulomas and conserved virulence determinants. Importantly, it offers the practical advantage of BSL‑2 operability with direct laser access. Upon administration, ICG-PEG-Tar first passively accumulates at granuloma lesions by extravasating via leaky vasculature of inflamed granulomas, a process analogous to the enhanced permeability and retention (EPR) effect, and then actively binds to M.m through anti-Ag85B recognition. Under laser irradiation, the nanoparticles generate potent localized hyperthermia that effectively ablates viable M.m, achieving a 96.5% reduction in bacterial CFU counts in vitro and significantly suppressing granuloma progression in vivo. Moreover, real‑time infrared thermal imaging confirmed that the PTT effect was precisely confined to the granuloma site, with the surrounding healthy tissue temperature remaining within the normal physiological range throughout the irradiation period, indicating a favorable safety profile. Overall, the nanoparticles demonstrate excellent targeting specificity, robust antibacterial efficacy against M.m, prolonged lesion-site retention, and favorable biocompatibility, collectively offering a paradigm for precise TB management.