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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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