TROP2‐guided aggregation‐induced emission‐luminogen nanoparticles overcome sacituzumab govitecan resistance via mitochondrial oxidative stress and immunogenic cell death in triple‐negative breast cancer

Abstract Chemoresistance and immune evasion constitute formidable obstacles in triple‐negative breast cancer (TNBC) therapy, exacerbated by the suboptimal pharmacokinetics and acquired resistance of antibody–drug conjugates (ADCs). Herein, we describe the engineering of antibody‐guided nanoparticles (NPs) co‐delivering the trophoblast cell‐surface antigen 2 (TROP2)‐targeting ADC sacituzumab govitecan (SG) with the mitochondria‐directed near‐infrared (NIR) photosensitizer AIE780. These AIE780–SG nanoconstructs exploit hRS7 antibody–mediated targeting to preferentially accumulate in TROP2‐overexpressing, SG‐resistant TNBC cells and patient‐derived organoid. Upon NIR irradiation, AIE780 induces a mitochondrial redox imbalance via localized reactive oxygen species generation, precipitating tumor‐selective immunogenic cell death (ICD) through membrane destabilization and oxidative necrosis. Concurrently, SG undergoes acid‐responsive cleavage to release SN‐38—a potent topoisomerase I inhibitor—and the hRS7 antibody fragment, which orchestrates natural killer (NK) cell recruitment and activation. In murine TNBC xenograft models, AIE780–SG NPs achieved synergistic chemophotodynamic tumor eradication, surmounting SG resistance and revitalizing antitumor immunity. This TROP2‐targeted, light‐sensitive theranostic platform offers a multimodal paradigm to potentiate ADC efficacy and reprogram the immunosuppressive TNBC microenvironment, heralding a novel strategy against SG‐resistant TNBC. A dual‐therapeutic nanoplatform combining targeted ADC delivery with photodynamic induction of ICD overcomes SG resistance in TNBC and amplifies NK cell‐mediated antitumor responses.