Tumor Microenvironment-responsive Nanoenzymes For Synergistic Enhancement Of Tumor Therapy

At present,the high incidence and mortality of malignant tumors have seriously threatened human health.Conventional tumor treatment methods have problems such as high recurrence rate and large side effects.Today,from simply killing tumor cells to metastasis to the tumor microenvironment(TME)that interferes with its occurrence and development,the use of TME as a therapeutic target has great research significance.The tumor microenvironment is different from the microenvironment composed of normal cells and their tissues.Studies have shown that tumor cells are surrounded by a low-oxygen,low-nutrient,and low-p H microenvironment,which is a complex system that regulates various biological behaviors of tumors.Based on this,we have separately explored and constructed natural enzymes and nanoenzyme systems that are only targeted at TME for the catalytic oxidation treatment of tumors.This treatment system does not only have one treatment method,it is usually accompanied by starvation treatment or photothermal treatment.Significantly improve the efficiency of tumor treatment,the main research content of this paper is as follows:(1)Emerging natural-enzyme-based nanocatalytic tumor therapy depending on the high catalytic performance of natural enzymes has inspired great research interest in clinical applications.Nevertheless,the natural-enzyme-based catalytic therapy efficiency is seriously hampered by the low operational stability,poor delivery efficiency,and the short lifetime of enzymes.Herein,a bioreactor based on zeolitic imidazolate framework-8(ZIF-8)was fabricated through one-pot embedding horseradish peroxidase(HRP)and glucose oxidase(Gox)strategy(ZIF-8@Gox/HRP)for synergistic cancer therapy.Notably,the obtained ZIF-8@Gox/HRP can efficiently consume endogenous glucose to generate gluconic acid and H2O2 for starving tumors,and subsequently,H2O2 was decomposed by encapsulated HRP to release high-toxic?OH radicals,inducing cancer cell apoptosis for oxidation therapy.Importantly,in vivo results showed that ZIF-8@Gox/HRP had an impressive tumor-suppression rate based on cascade catalytic reaction.Therefore,this work paves a new avenue to design smart enzyme-based platforms for safe and efficient cancer therapy.(2)Nanocatalysts-mediated cancer therapy has been developed and showed enormous potential in biomedicine,however,the therapeutic efficacy is often limited by the dramatically decreased the activity of nanocatalysts because of the complex microenvironment within the biological systems.Herein,a novel oxygen vacancy-enhanced nanocatalytic theranostic platform was developed based on Au-loaded MnO2nanoconstructs(MnO2@AuNCs)via a facile one-step synthesis strategy.The obtained MnO2@AuNCs with rich oxygen vacancies exhibited enhanced oxidase-mimic activity with high-toxic superoxide radical(·O2~-)generation for the effective oxidation therapy of tumor.Meanwhile,the MnO2@AuNCs also showed a high photothermal conversion efficiency of 50.1%for heat ablation of tumor,and well photothermal effect of MnO2@AuNCs could further enhance oxidase-mimic activity of MnO2@AuNCs achieving photothermal-enhanced oxidation therapy.Furthermore,MnO2@AuNCs was able to regulate intracellular oxygen and glutathione levels facilitating superoxide radical(·O2~-)generation.Thus,a facile Au-doped MnO2 NCs with well biocompatibility and tumor microenvironment regulation capacity creates a promising multifunctional theranostic agent with oxygen vacancy-enhanced photothermal/oxidation therapy efficacy so as to almost complete destruction of tumor.