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Herein, a mitochondrion\u2010targeted nanoagonist (termed HABH) containing boron dipyrromethene (BODIPY)\u2010derived type I photosensitizer (BDP) and Au\u00a0nanoparticle\u2010engineered hollow mesoporous silica (HMSN\/AuNPs) has been fabricated for light\u2010controlled mitochondrial stress\u2010inducing and agonist\u2010independent cGAS\u2010STING pathway activation. The HABH nanoagonist can actively target tumor tissues and release the mitochondrion\u2010targeted BDP. Under light illumination, BDP achieves type I photodynamic therapy (PDT) in mitochondria, generating massive hydroxyl radicals (\u2022OH) and inducing mitochondrial stress in an oxygen\u2010independent manner, promoting the release of mitochondrial DNA (mtDNA). Simultaneously, the HMSN\/AuNPs act as dual nanozymes to derive cascade reactions for \u2022OH production, elevating the intracellular oxidative state, and together with the BDP\u2010induced mitochondrial stress, finally evoking the cGAS\u2010STING 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\u2010targeted nanoagonist enabled light\u2010controlled and agonist\u2010independent cGAS\u2010STING activation, providing a paradigm for photoimmunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202418894","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T17:27:06Z","timestamp":1740504426000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Mitochondrion\u2010Targeted Type I Photodynamic Therapy for Agonist Independent cGAS\u2010STING Activation"],"prefix":"10.1002","volume":"37","author":[{"given":"Yin","family":"Xu","sequence":"first","affiliation":[{"name":"School of Chemistry &amp; Materials Science Jiangsu Normal University  101 Shanghai Road Xuzhou 221116 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daokuan","family":"An","sequence":"additional","affiliation":[{"name":"School of Chemistry &amp; Materials Science 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