A multifunctional cascade enzyme system for enhanced starvation/chemodynamic combination therapy against hypoxic tumors

Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO 3 @MnO 2 -NH 2 @GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO 3 nanoparticles wrapped in a MnO 2 shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO 2 decomposes H 2 O 2 in cancer cells into O 2 , which enhances the efficiency of GOx-mediated starvation therapy. CaCO 3 can be decomposed in the acidic cancer cell environment, causing Ca 2+ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H 2 O 2 and gluconic acid produced during glucose consumption by GOx are utilized by MnO 2 with catalase-like activity to enhance O 2 production and Mn 2+ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO 3 decomposition, promoting the Ca 2+ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca 2+ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.