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However, multiple death mechanisms associate with metal ions to synergistic antitumors have few studies mainly due to the serious challenges in designing and building metal\u2010associated multimodal treatment platforms. Hence, a series of glutathione\u2010activatable CaCu\u2010based metal\u2013organic\u2010frameworks loaded with doxorubicin and ovalbumin are successfully designed and synthesized with an \u201call in one\u201d strategy, which is modified by galactosamine\u2010linked hyaluronic acid to prepare multimodal treatment platform (SCC\/DOX@OVA\u2010HG) for targeted delivery and synergistic antitumor therapy. SCC\/DOX@OVA\u2010HG can be rapidly degraded by the overexpressed glutathione and then releases the \u201ccargoes\u201d in the tumor microenvironment. The released Cu<jats:sup>+<\/jats:sup> efficiently catalyzes H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> to produce highly toxic ROS for CDT, and the up\u2010regulation of calcium ion concentration in tumor cells induced by the released Ca<jats:sup>2+<\/jats:sup> enables calcium overload therapy, which synergically enhances the metal\u2010related death pattern. Meanwhile, OVA combined with Ca<jats:sup>2+<\/jats:sup>\/Cu<jats:sup>2+<\/jats:sup> further activates macrophages into an M1\u2010like phenotype to accelerate tumor cell death through immunotherapy. Besides, the released DOX can also insert into the DNA double helix for chemotherapy. Consequently, the developed SCC\/DOX@OVA\u2010HG reveals significantly improved antitumor efficacy through a multimodal synergistic therapy of chemotherapy, chemodynamic therapy, calcium overload, and immunotherapy.<\/jats:p>","DOI":"10.1002\/adhm.202304000","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T10:30:53Z","timestamp":1710844253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A Novel CaCu\u2010Metal\u2013Organic\u2010Framework Based Multimodal Treatment Platform for Enhanced Synergistic Therapy of Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Weijun","family":"Chen","sequence":"first","affiliation":[{"name":"School of Life Sciences and Health Engineering Jiangnan University  Wuxi 214122 China"},{"name":"School of Chemical and Material Engineering Jiangnan University  Wuxi 214122 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