Mitochondrion‐Targeted Type I Photodynamic Therapy for Agonist Independent cGAS‐STING Activation

Abstract CGAS‐STING agonists generally lead to hyperimmunity and systemic toxicity, hindering their immunotherapeutic outcomes. Herein, a mitochondrion‐targeted nanoagonist (termed HABH) containing boron dipyrromethene (BODIPY)‐derived type I photosensitizer (BDP) and Au nanoparticle‐engineered hollow mesoporous silica (HMSN/AuNPs) has been fabricated for light‐controlled mitochondrial stress‐inducing and agonist‐independent cGAS‐STING pathway activation. The HABH nanoagonist can actively target tumor tissues and release the mitochondrion‐targeted BDP. Under light illumination, BDP achieves type I photodynamic therapy (PDT) in mitochondria, generating massive hydroxyl radicals (•OH) and inducing mitochondrial stress in an oxygen‐independent manner, promoting the release of mitochondrial DNA (mtDNA). Simultaneously, the HMSN/AuNPs act as dual nanozymes to derive cascade reactions for •OH production, elevating the intracellular oxidative state, and together with the BDP‐induced mitochondrial stress, finally evoking the cGAS‐STING pathway and facilitating the release of type I interferon. In the orthotopic breast tumor models, the HABH nanoagonist achieved intratumoral and systemic immunoactivation for eradicating primary tumors and preventing metastasis tumors. Therefore, the constructed mitochondrion‐targeted nanoagonist enabled light‐controlled and agonist‐independent cGAS‐STING activation, providing a paradigm for photoimmunotherapy.