Degradable H₂O₂-Self-Supplying Iron-Doped Phosphate-based Glass Nanoenzyme For Cancer Therapy

In recent years,nanozymes have gained significant attention from researchers due to their efficient and modifiable catalytic activity,good biocompatibility and high stability for cancer therapy.However,nanozymes often face problems of non-specific distribution and difficult in vivo degradation/clearance when applied in vivo,leading to abnormal accumulation and slow metabolism at non-targeted sites,thus increasing systemic toxicity.In addition,the lack of hydrogen peroxide(H₂O₂)as a reaction substrate at the tumor site is a detrimental factor limiting the efficient Fenton reaction of the nanozymes.Therefore,there is an urgent need to develop a degradable nanozyme with tumor microenvironment(TME)responsiveness,which could circumvent the lack of oxygen or H₂O₂in the tumor and achieve efficient and selective anti-tumor performance.The ability of Fe-based pH-sensitive nanozyme to exhibit peroxidase(POD)-like in acidic environment but catalase(CAT)-or peroxidase(SOD)-like in a neutral environment.In this thesis,an iron-doped phosphate glass(Fe PBG)nanoparticle with a regular spherical structure of?410 nm was first synthesized.Subsequently,a biodegradable self-supplied H₂O₂cascade nanoenzyme(Fe PBG@GOX)was prepared by sequentially loading polyethyleneimine(PEI)and glucose oxidase(GOX)onto the surface of Fe PBG nanoparticles through a layer-by-layer self-assembly method.Firstly,GOX on the surface of Fe PBG@GOX acts as a preliminary reaction catalyst to consume glucose to generate large amounts of H₂O₂in tumor tissue,after which the Fe PBG nanozyme catalyzes the specific production of large amounts of toxic·OH from the substrate H₂O₂via the Fenton reaction,which in turn induces apoptosis of cancer cells.The element Fe of Fe PBG nanozyme is present at+3 valence,ensuring an efficient Fenton reaction.In addition,Fe PBG nanozyme is biodegradable with a degradation rate of 13.7%within 24 h in neutral buffer,which can circumvent the risk of toxicity due to long-term metabolism of inorganic nanomaterials in vivo.In vitro cytotoxicity studies showed that the cascade catalytic reaction exerted by Fe PBG@GOX exhibited a concentration dependence on the substrate glucose.In high glucose media,GOX and Fe PBG co-mediated an efficient cascade reaction,resulting in the generation of large amounts of reactive oxygen species(ROS)in tumor cells,leading to a decrease in mitochondrial membrane potential and the induction of apoptosis.In in vivo anti-tumor study,tumor growth was significantly inhibited following in situ injection of Fe PBG@GOX nanozyme,achieving 94.65%tumor inhibition rate.In summary,this thesis successfully achieved the selective and safe tumor killing effect of Fe PBG@GOX by exploiting the unique microenvironment of tumor tissue,including lower pH,abundant glucose and excess H₂O₂.The constructed cascade nanomaterial was able to overcome the shortcomings of nanozymes for in vivo application,address the issue of long-term toxicity and broaden the application of inorganic nanozymes for efficient chemokinetic therapy.