Degradable Tumor-Responsive Iron-Doped Phosphate-Based Glass Nanozyme for H₂O₂ Self-Supplying Cancer Therapy

Abstract

Tumor microenvironment (TME)-responsive chemodynamic therapy (CDT) mediated by nanozymes has been extensively studied both experimentally and theoretically, but the low catalytic efficiency due to insufficient H2O2 in the TME and the poor biodegradability of the nanozymes are still main challenges for clinical translation of nanozymes. Herein, we designed a H2O2 self-supplying nanozyme bearing glucose oxidase (GOX) and polyethyleneimine based on a degradable iron-doped phosphate-based glass (FePBG) nanomimic (FePBG@GOX), which can convert endogenous glucose into toxic hydroxyl radicals. The GOX loaded on the nanozyme can effectively consume glucose in tumor cells to produce a large amount of H2O2 to make up for the lack of H2O2 in the TME. Thereafter, enormous hydroxyl radicals, based on a Fenton reaction of FePBG without any exogenous H2O2, are generated to induce severe apoptosis of tumor cells. The nanozyme exhibits enhanced in vitro cytotoxicity in a high-glucose medium than in a low-glucose medium, illustrating sufficient generation of H2O2 by GOX. The excellent in vivo antitumor efficacy is manifested by a high tumor growth inhibition ratio of 94.65% in model mice. Excellent intrinsic biodegradability owing to its phosphate-based glass nature is a remarkable advantage of the prepared FePBG nanozyme over most other reported nanozymes. Big concerns about side effects caused by long-time residence in living organisms are eliminated since it degrades not only in an acid medium but also in a neutral physiological environment. Therefore, this novel strategy of the TME-responsive H2O2 self-supplying nanozyme based on an endogenous cascade catalytic reaction opens up an avenue for designing degradable nanozymes in CDT.

Metal‐Based Nanozymes with Multienzyme‐Like Activities as Therapeutic Candidates: Applications, Mechanisms, and Optimization Strategy

“…Additionally, GOx-like, NOX-like, GPx-like, and GSHOx-like activities destroy the cellular antioxidant system by consuming endogenous antioxidant molecules (such as glucose, nicotinamide adenine dinucleotide, and glutathione), thereby rendering cells more susceptible to cytotoxic oxidative stress. [1,[34][35][36] Notably, the products of upstream enzymes can be used as substrates by downstream enzymes to induce a catalytic cascade. [6,9,16,[37][38][39][40][41][42] For example, nanozymes with GOx-like, NOX-like, or SOD-like activities (e.g., platinum (Pt) and cobalt (Co)) may produce H 2 O 2 , which is a substrate of their POD-like and CAT-like activities, thereby generating •OH and O 2 , respectively.…”

Progress and prospects of nanozymes for enhanced antitumor therapy

“…Nanozymes with multiple enzymatic activities can effectively produce reactive oxygen species in the tumor microenvironment through cascade catalytic reactions, thereby promoting the apoptosis of cancer cells (Zhao et al, 2021b;Yao et al, 2022b;Wang et al, 2022f). Ma et al (2022) designed nanozymes with three nanoceria structures including nanoceria-cube, nanoceria-poly and nanoceria-rod.…”

Dual-Functional Nanoplatform Based on Bimetallic Metal–Organic Frameworks for Synergistic Starvation and Chemodynamic Therapy

“…11 However, the low levels of hydrogen peroxide in the tumor microenvironment (10−50 μM) limit the efficiency of CDT. 12 The rapid metabolism and proliferation of tumor cells depend on glucose. 13,14 Therefore, tumor cells are sensitive to changes in glucose concentration.…”