Cascade catalytic nanoplatform based on ions interference strategy for calcium overload therapy and ferroptosis

Intracellular ions played prominent part in cell function and behavior. Disrupting intracellular ions homeostasis might switch ions signal from "regulating" to "destroying". Inspired by this, we introduced the ions interference strategy for tumor therapy. Herein, curcumin (CUR) and transferrin (Tf) co-loaded calcium peroxide nanoparticles (CaO₂ NPs) were formulated. With tumor targeting ability, CaO₂/Tf/CUR pinpointed tumor cells and then instantaneously decomposed in acidic lysosomes, concurrently accompanying with the release of Ca²⁺ and CUR, as well as the production of H₂O₂. Then H₂O₂ not only damaged structure of Tf to release Fe³⁺, but also was converted to hydroxyl radicals via ferric ions mediated Fenton reaction for ferroptosis. In addition, the released Ca²⁺ and CUR induced Ca²⁺ overload via exogenous and endogenous calcium ions accumulation, respectively, further activating mitochondria apoptosis signaling pathway for cell injury. Therefore, based on calcium and ferric ions interference strategy, the cascade catalytic CaO₂/Tf/CUR offered synergistic combination of ferroptosis, Ca²⁺ overload therapy and chemotherapy, which held a great promise in cancer treatment.