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

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.