H<sub>2</sub>O<sub>2</sub> Self-Supplying CaO<sub>2</sub> Nanoplatform Induces Ca<sup>2+</sup> Overload Combined with Chemodynamic Therapy to Enhance Cancer Immunotherapy
Xin Wang Mo, Ngoc Man Phan, Thanh Loc Nguyen, Jaeyun Kim
Abstract
Integrating chemodynamic therapy (CDT) with Ca 2+ overload offers a potent strategy for enhancing cancer immunotherapy. However, the effectiveness of this approach is significantly constrained by the scarce availability of H 2 O 2 in solid tumors. Here, we engineered a nanoplatform based on CaO 2 nanoparticles (NPs) capable of encapsulating curcumin (CUR) and self-supplying H 2 O 2 for synergistic CDT-augmented antitumor immunotherapy (CaO 2 @CUR@ZIF-Cu, denoted as CCZC). In the acidic tumor microenvironment, CCZC disintegrated to release CUR and copper(II) ions (Cu 2 + ), revealing the core CaO 2 NPs. CDT was amplified by escalating hydroxyl radical ( • OH) production through a Fenton-like reaction mediated by H 2 O 2 from the hydrolysis of CaO 2 NPs. Ca 2+ sourced from CaO 2 NPs and CUR, an initiator of Ca 2+ overload, induced Ca 2+ overload in tumor cells, thereby promoting apoptosis. Subsequently, apoptotic tumor cells released tumor-associated antigens and pro-inflammatory cytokines, triggering adaptive immune responses and enhancing antitumor immunotherapy effects. In vivo experiments demonstrated that the intratumoral administration of CCZC displayed significant inhibitory effects, with an inhibition rate of up to 78% on B16-OVA-tumor-bearing mice compared to untreated. Moreover, an elevated proportion of mature dendritic cells were observed in the tumor-draining lymph nodes, along with an increase in cytotoxic T lymphocytes in the spleen. These findings suggest that our engineered nanoplatform effectively curtailed tumor growth via enhanced cancer immunotherapy by synergizing Ca 2+ overload and CDT, proposing a novel strategy for synergistic cancer treatment.