A Novel CaCu‐Metal–Organic‐Framework Based Multimodal Treatment Platform for Enhanced Synergistic Therapy of Hepatocellular Carcinoma

Abstract Metal ions have attracted a lot of interest in antitumor therapy due to their unique mechanism of action. 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‐associated multimodal treatment platforms. Hence, a series of glutathione‐activatable CaCu‐based metal–organic‐frameworks loaded with doxorubicin and ovalbumin are successfully designed and synthesized with an “all in one” strategy, which is modified by galactosamine‐linked hyaluronic acid to prepare multimodal treatment platform (SCC/DOX@OVA‐HG) for targeted delivery and synergistic antitumor therapy. SCC/DOX@OVA‐HG can be rapidly degraded by the overexpressed glutathione and then releases the “cargoes” in the tumor microenvironment. The released Cu + efficiently catalyzes H 2 O 2 to produce highly toxic ROS for CDT, and the up‐regulation of calcium ion concentration in tumor cells induced by the released Ca 2+ enables calcium overload therapy, which synergically enhances the metal‐related death pattern. Meanwhile, OVA combined with Ca 2+ /Cu 2+ further activates macrophages into an M1‐like 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‐HG reveals significantly improved antitumor efficacy through a multimodal synergistic therapy of chemotherapy, chemodynamic therapy, calcium overload, and immunotherapy.