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In this study, a glutathione\u2010responsive polymeric nanoparticle platform for the co\u2010delivery of the USP1 inhibitor SJB3\u2010019A and the PARP inhibitor Niraparib is developed. This system synergistically enhances DNA damage accumulation, suppresses homologous recombination repair, and robustly activate the STING signaling pathway, leading to enhanced type I interferon responses and mitigation of immune evasion. Mechanistically, USP1 inhibition significantly impairs DNA repair, amplifying the synthetic lethality of PARP inhibition and promoting immunogenic cell death. In vivo studies demonstrated precise, glutathione\u2010responsive drug release and substantial tumor accumulation of the nanoparticles, resulting in remarkable antitumor efficacy in murine ovarian cancer models. Importantly, this combinational approach effectively remodels the tumor microenvironment by increasing CD8\u207a T cell infiltration and enhancing tumor sensitivity to immune checkpoint blockade therapies. This innovative strategy targeting DNA damage responses presents a promising platform for precise and effective ovarian cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202512962","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T13:46:01Z","timestamp":1758289561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Polymer\u2010PARPi Conjugates Delivering USP1i for Maximizing Synthetic Lethality to Stimulate STING Pathway in High\u2010Grade Serous Ovarian Cancer"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3283-8620","authenticated-orcid":false,"given":"He","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gynecology, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100021 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