O2-Cu/ZIF-8@Ce6/ZIF-8@F127 Composite as a Tumor Microenvironment-Responsive Nanoplatform with Enhanced Photo-/Chemodynamic Antitumor Efficacy

Hypoxia and overexpression of glutathione (GSH) are typical characteristics of the tumor microenvironment, which severely hinders cancer treatments. Here, we design a novel biodegradable therapeutic system, O₂-Cu/ZIF-8@Ce6/ZIF-8@F127 (OCZCF), to simultaneously achieve GSH depletion and O₂-enhanced combination therapy. Notably, the doped Cu²⁺ doubles the O₂ storage capacity of the ZIF-8 matrix, which makes OCZCF an excellent pH-sensitive O₂ reservoir for conquering tumor hypoxia, enhancing the photodynamic therapy (PDT) efficiency of chlorin e6 (Ce6) under 650 nm laser irradiation. Moreover, the released Cu²⁺ can act as a smart reactive oxygen species protector by consuming intracellular GSH. The byproduct Cu⁺ will undergo highly efficient Fenton-like reaction to achieve chemodynamic therapy (CDT) in the presence of abundant H₂O₂. The accompanying O₂ will further alleviate hypoxia. The in vitro and in vivo experimental data indicate that OCZCF could cause remarkable tumor inhibition through enhanced synergetic PDT and CDT, which may open up a new path for cancer therapy.