Chemoresistance together with immune evasion presents substantial barriers to effective therapy for triple-negative breast cancer (TNBC). These issues are intensified by the inadequate pharmacokinetic profiles and the emergence of resistance to antibody–drug conjugates (ADCs). Here, we report the design of antibody-directed nanoparticles (NPs) that simultaneously carry the TROP2-targeted ADC sacituzumab govitecan (SG) and the mitochondria-targeted near-infrared (NIR) photosensitizer AIE780. The constructed AIE780–SG nanoconjugates take advantage of hRS7 antibody guidance to achieve selective accumulation within TROP2-high, SG-resistant TNBC cells as well as patient-derived organoids. Under NIR light exposure, AIE780 provokes mitochondrial redox disruption by generating localized reactive oxygen species, thereby inducing tumor-specific immunogenic cell death (ICD) through membrane damage and oxidative necrotic pathways. Simultaneously, SG experiences acid-triggered cleavage that liberates SN-38, a highly active topoisomerase I inhibitor, along with the hRS7 antibody fragment that facilitates recruitment and stimulation of natural killer (NK) cells. In mouse models of TNBC xenografts, these AIE780–SG NPs demonstrated synergistic chemophotodynamic antitumor activity, successfully bypassing SG resistance and reinvigorating antitumor immune function. This light-responsive, TROP2-directed theranostic nanoplatform establishes a multimodal strategy to augment ADC performance and reshape the immunosuppressive milieu of TNBC, introducing an innovative approach for managing SG-resistant disease. A dual-action nanoplatform integrating targeted ADC delivery with photodynamic induction of ICD effectively circumvents SG resistance in TNBC while potentiating NK cell-driven antitumor immunity.
