Engineering Single-Atom Iron Nanozymes with Radiation-Enhanced Self-Cascade Catalysis and Self-Supplied H₂O₂ for Radio-enzymatic Therapy

Abstract

Single-atom nanozymes (SAzymes), with individually isolated metal atom as active sites, have shown tremendous potential as enzyme-based drugs for enzymatic therapy. However, using SAzymes in tumor theranostics remains challenging because of deficient enzymatic activity and insufficient endogenous H2O2. We develop an external-field-enhanced catalysis by an atom-level engineered FeN4-centered nanozyme (FeN4-SAzyme) for radio-enzymatic therapy. This FeN4-SAzyme exhibits peroxidase-like activity capable of catalyzing H2O2 into hydroxyl radicals and converting single-site FeII species to FeIII for subsequent glutathione oxidase-like activity. Density functional theory calculations are used to rationalize the origin of the single-site self-cascade enzymatic activity. Importantly, using X-rays can improve the overall single-site cascade enzymatic reaction process via promoting the conversion frequency of FeII/FeIII. As a H2O2 producer, natural glucose oxidase is further decorated onto the surface of FeN4-SAzyme to yield the final construct GOD@FeN4-SAzyme. The resulting GOD@FeN4-SAzyme not only supplies in situ H2O2 to continuously produce highly toxic hydroxyl radicals but also induces the localized deposition of radiation dose, subsequently inducing intensive apoptosis and ferroptosis in vitro. Such a synergistic effect of radiotherapy and self-cascade enzymatic therapy allows for improved tumor growth inhibition with minimal side effects in vivo. Collectively, this work demonstrates the introduction of external fields to enhance enzyme-like performance of nanozymes without changing their properties and highlights a robust therapeutic capable of self-supplying H2O2 and amplifying self-cascade reactions to address the limitations of enzymatic treatment.

Single-Atom Nanozyme Based on Mn-Center with Enhanced Peroxidase-like Activity for Organic Dye Degradation

“…The effect of temperature on the POD-like activity of Mn-SAzymes was measured by adding Mn-SAzymes (20 μL, 1 mg/mL) into the water to adjust the total volume to 2 mL, the TMB concentration to 1 mM, and the H 2 O 2 concentration to 1 M. The mixture was then incubated at a set temperature (10,20,30,40,50,60, 70 °C) for 5 min, and the absorbance at 652 nm of the mixture was detected with a UV− Vis spectrophotometer.…”

“…Since the emergence of single-atom nanozymes, numerous reports have been made on single-atom nanozymes. They mainly focus on sensing and detection − and biomedicine, − and there are relatively few studies on dye degradation. , Single-atom catalysts can greatly reduce the use of precious metals because of their high atomic utilization, which is a great help for cost control. In the field of nanozymes, there are more research studies on manganese oxides, but there are few studies on single-atom nanozymes with manganese as the metal center, mostly with the coordination structure of Mn and N, and the effects of other heteroatom doping on the activity of manganese-based nanozymes need to be further studied.…”

Enhancing Catalytic Activity of a Nickel Single Atom Enzyme by Polynary Heteroatom Doping for Ferroptosis-Based Tumor Therapy

“…Ferroptosis is a cell-death pathway via the accumulation of lipid peroxides in an iron-dependent manner. , Diverse iron-based nanozymes have been reported to induce ferroptosis via oxidization of polyunsaturated fatty acids (PUFAs) and then lipid peroxidization (LPO). , However, the Fe-based nanozyme-induced ferroptosis stress is suboptimal owing to weak Fenton activities and the intrinsic high glutathione (GSH) level in the tumor microenvironment (TME). − Additionally, glutathione peroxidase 4 (GPx-4) can effectively regulate ferroptosis, which uses GSH as a cofactor to reduce lipid peroxides . Previous studies demonstrated that depletion of GSH could inactivate GPx-4 and induce irreversible LPO. ,, SAEs have been extensively exploited and made profound progresses of ferroptosis-based tumor therapy. For instance, Chang et al prepared nitrogen (N)-doping carbon-supported Pd SAE with superior peroxidase (POD)-like and glutathione oxidase (GSHOx)-like catalytic performances, significantly boosting the intracellular oxidative stress, resulting in LPO-induced ferroptosis .…”

“…8 Previous studies demonstrated that depletion of GSH could inactivate GPx-4 and induce irreversible LPO. 24,36,37 SAEs have been extensively exploited and made profound Pd SAE with superior peroxidase (POD)-like and glutathione oxidase (GSHOx)-like catalytic performances, significantly boosting the intracellular oxidative stress, resulting in LPOinduced ferroptosis. 18 Cao et al reported an engineered DNA modulator-based Fe SAE for ferroptosis-based cancer therapy.…”

Rational design of atomic site catalysts for electrochemical CO2reduction

“…In addition, the adjustable coordination environment and structure of ASCs make it feasible to obtain uniform catalytic active centers, making them an ideal bridge between homogeneous catalysts and heterogeneous catalysts. [27][28][29][30][31][32][33] For CO 2 R, the reaction often involves multiple proton-coupled electron transfer processes and complex intermediates, and the well-defined structure of ASCs will help us to understand the reaction mechanism, thereby guiding the design and development of advanced catalysts. At present, a variety of ASCs have been developed, such as atomically dispersed Fe, Co, Ni, etc.…”