Achieving Hierarchical Selective Ablation and Remodeling “Cold” Tumors via a Dual‐Organelle‐Targeted AIE Nanoplatform: Synergizing Ferroptosis, ICD, and cGAS–STING Activation

Abstract

Immunotherapy has created new opportunities for treating triple‐negative breast cancer (TNBC), but its benefit is often limited by an immunosuppressive tumor microenvironment. Here, we report BMFL, a folate receptor‐targeted liposomal nanoplatform that co‐delivers a near‐infrared aggregation‐induced emission luminogens (AIEgens), BITT, and the STING agonist MSA‐2 for dual‐organelle‐directed photoimmunotherapy. BMFL enables fluorescence discrimination of lipid droplets and lysosomes and, under phototherapy, couples lipid droplet peroxidation‐driven ferroptosis with lysosome‐associated immunogenic cell death (ICD). Ferroptosis‐associated mitochondrial stress promotes endogenous mtDNA leakage, which cooperates with the delivered exogenous MSA‐2 to drive upstream activation of the STING pathway; meanwhile, immunostimulatory signals released during ICD further synergize with the STING‐mediated inflammatory microenvironment to achieve downstream amplification of adaptive antitumor immunity. In a bilateral tumor model, BMFL‐mediated therapy not only eradicates primary tumors but also elicits systemic antitumor immunity and suppresses distal tumor growth. In this study, BMFL functions as a dual‐organelle‐targeting nanoplatform that enhances therapeutic efficacy by coupling ferroptosis with ICD through the cGAS–STING pathway, offering a potential strategy for treating poorly immunogenic breast tumors.