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However, the immunosuppressive microenvironment and insufficient response rate significantly limit the practical efficacy. This study presents an autologous cell\u2010derived exosomes (Exo)\u2010engineered nanoagonist (MnExo@cGAMP) containing with metalloimmunotherapeutic agent (Mn<jats:sup>2+<\/jats:sup> ions) and nucleotidyltransferase (2\u2032,3\u2032\u2010cGAMP, a STING agonist) for boosting melanoma\u2010targeted radio\u2010immunotherapy by cascade cGAS\u2010STING pathway activation. The MnExo@cGAMP can efficiently accumulate in tumor cells due to the autologous targeting performance. Once internalized by tumor cells, the released Mn<jats:sup>2+<\/jats:sup> ions will enhance stimulator of interferon gene (STING) binding and sensitize cyclic GMP\u2010AMP (cGAS) to radiotherapy\u2010induced double\u2010straned DNA (dsNDA), resulting in amplification of cGAS\u2010STING pathway activation together with X\u2010ray irradiation. Meanwhile, loaded 2\u2032,3\u2032\u2010cGAMP can directly augment pathway activity acting as a secondary messenger. These cascade activations of cGAS\u2010STING pathway trigger the overexpression of type I interferon, promote dendritic cells (DCs) maturation, antigen presentation, and increase CD8<jats:sup>+<\/jats:sup> T cell activation, resulting effective radio\u2010immunotherapeutic outcome by overcoming immune\u2010suppression in melanoma. This study demonstrates a targeted therapeutic modality involving metalloimmunotherapy and agonist for efficient melanoma radio\u2010immunotherapy by cascade cGAS\u2010STING pathway activation.<\/jats:p>","DOI":"10.1002\/smll.202408769","type":"journal-article","created":{"date-parts":[[2024,11,28]],"date-time":"2024-11-28T06:37:43Z","timestamp":1732775863000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Engineering Autologous Cell\u2010Derived Exosomes to Boost Melanoma\u2010Targeted Radio\u2010Immunotherapy by Cascade cGAS\u2010STING Pathway Activation"],"prefix":"10.1002","volume":"21","author":[{"given":"Fangming","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organic\u2010Inorganic Composites College of Life Science and Technology Beijing University of Chemical Technology  Beijing 100029 P. R. 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