Tumor Microenvironment-responsive Molybdenum-Based Nanoenzymes For Radiosensitization Therapy

Hypoxia was an important feature of solid tumours.The imbalance between the supply and demand of oxygen leads to tumour hypoxia.Radiation resistance caused by tumor hypoxia and the high level of antioxidant expression in tumor can reduce the degree of DNA damage caused by radiotherapy,thus reducing the efficacy of radiotherapy.Rational design and development of nano-radiosensitizers with specific delivery to tumours has become one of the effective ways to address such problems.To date,researchers have taken several approaches to address these issues to enhance radiotherapy.For example,high Z-atomic number nanomaterials can induce an intratumoural radiation dose enhancement effect to improve the efficacy of radiotherapy.However,there are limitations to the improvements made by single radiotherapy treatments due to tumour microenvironment（TME）hypoxia and endogenous cellular antioxidant defence mechanisms.Studies have shown that multi-strategy synergistic therapy can compensate for these scientific problems in a single strategy.Based on this,a TME-responsive smart nano-radiotherapy sensitizer was designed in this paper.This novel radiotherapy sensitiser can differentiate between cancer and normal cells and selectively kill cancer cells,and sensitise radiotherapy by improving hypoxia and multi-strategy synergy.In this study,polyvinylpyrrolidone-modified molybdenum oxide-copper-cysteine（Mo O_x-Cu-Cys-PVP）monoatomic nanoenzymes（MCCP SAzymes）were synthesized by ligand-driven self-assembly using molybdenum oxide（Mo O_x）with peroxidase-like（CAT）activity as a substrate to construct a TME-responsive Fenton-like/CAT-like catalytic superimposed radiokinetic nanoplatform for sensitized radiotherapy.Studies on the catalytic properties of MCCP SAzymes revealed that MCCP SAzymes possess very superior peroxidase-like activity and can catalyse the high expression of H₂O₂to oxygen in TME,thereby ameliorating tumour hypoxia.MCCP SAzymes also have excellent glutathione（GSH）antioxidant scavenging ability,which allows for more free radical generation from Fenton-like reaction chemokinetic/radiokinetic processes,which in turn sensitizes radiotherapy.In addition,the biodegradability of MCCP SAzymes was investigated by X-ray near edge absorption combined with XPS and other techniques and was found to be good in biodegradability.The mechanism of selective killing and sensitization of cancer cells by MCCP SAzymes was investigated at the cellular level.The results showed that MCCP SAzymes can selectively kill cancer cells.MCCP SAzymes in TME under X-ray irradiation will sensitise radiotherapy through CAT/Fenton-like catalytic amplification of superimposed radiokinetics,ameliorating tumour hypoxia and generating large amounts of reactive oxygen radicals,causing DNA damage and ultimately inhibiting cancer cells more effectively.In addition,the effectiveness and safety of MCCP SAzymes was evaluated by both intravenous and intratumoral administration in live tumour-bearing mice.The results showed that MCCP SAzymes had a good radiosensitizing effect,improved tumour cell hypoxia,promoted apoptosis and inhibited cancer cell proliferation.Histological and haematological studies showed that MCCP SAzymes has a good biosafety profile.