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 associated with metal ions to synergistic antitumor have few studies mainly due to the serious challenges in designing and building metal‐associated multimodal treatment platform. Hence, a series of glutathione‐activatable CaCu‐based metal‐organic‐frameworks loaded with doxorubicin and ovalbumin were successfully designed and synthesized with an “all in one” strategy, which was 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 released the “cargoes” in tumor microenvironment. The released Cu + efficiently catalyzed 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+ enabled calcium overload therapy, which synergically enhanced the metal‐related death pattern. Meanwhile, OVA combined with Ca 2+ /Cu 2+ further activated macrophages into M1‐like phenotype to accelerate tumor cell death through immunotherapy. Besides, the released DOX could also insert into the DNA double helix for chemotherapy. Consequently, the developed SCC/DOX@OVA‐HG revealed significantly improved antitumor efficacy through a multimodal synergistic therapy of chemotherapy, chemodynamic therapy, calcium overload, and immunotherapy. This article is protected by copyright. All rights reserved