Multifunctional “Add-On” Module Enabled NIR-II Imaging-Guided Synergistic Photothermal and Chemotherapy of Drug-Resistant Lung Cancer

Imaging-guided chemo-photothermal combination therapy (chemo-PTT) is recognized for its synergistic therapeutic effects, reduced side effects, and minimal drug resistance, while the development of such theranostics has been hampered by poor imaging and therapy performance and tedious formulation. Herein, we introduce an all-in-one "add-on" module (BBT-C6) for the convenient construction of doxorubicin (DOX)-loaded nanoparticles (DOX@BBT) and efficient second near-infrared (NIR-II) fluorescence imaging (FLI)-guided synergistic chemo-PTT of drug-resistant lung cancer. The delicate Janus amphiphilic structure of BBT-C6 enables multifunctionality, including NIR-II FLI, aggregation-induced emission (AIE) characteristics, moderate photothermal conversion efficiency (PCE), excellent photostability, and polyethylene glycolation (PEGylation), which could improve the NIR-II FLI and PTT performance, relieve the complexity in theranostics, and enable high reproducibility of the multifunctional theranostics. Confocal microscopy revealed that BBT@DOX efficiently delivers DOX into cells, resulting in an increased accumulation of DOX that exceeds the efflux capacity of DOX-resistant cells. Both in vitro and in vivo studies demonstrate that BBT-C6 enhances the effectiveness of BBT@DOX, achieving highly effective photothermal-chemo synergistic therapy against DOX-resistant lung cancer. Beyond developing a versatile "add-on" module for conveniently constructing multifunctional nanosystems, this study provides new insights into the design of advanced theranostics for precise biomedical applications.