Multistage‐Responsive Dual‐Enzyme Nanocascades for Synergistic Radiosensitization‐Starvation Cancer Therapy

Abstract

Radiotherapy is a common cancer treatment approach in clinical practice, yet its efficacy has been restricted by tumor hypoxia. Nanomaterials‐mediated systemic delivery of glucose oxidase (GOx) and catalase (CAT) or CAT‐like nanoenzymes holds the potential to enhance tumor oxygenation. However, they face the challenge of intermediate (hydrogen peroxide [H2O2]) escape during systemic circulation if the enzyme pair is not closely placed to largely decompose H2O2, leading to oxidative stress on normal tissues. In the present study, a oxygen‐generating nanocascade, n(GOx‐CAT)C7A, constructed by strategically placing an enzymatic cascade (GOx and CAT) within a polymeric coating rich in hexamethyleneimine (C7A) moieties, is reported. During blood circulation, C7A remains predominantly non‐protonated , achieving prolonged blood circulation due to its low‐fouling surface. Once n(GOx‐CAT)C7A reaches the tumor site, the acidic tumor microenvironment (TME) induces protonation of C7A moieties, resulting in a positively charged surface for enhanced tumor transcytosis. Moreover, GOx and CAT are covalently conjugated into close spatial proximity (<10 nm) for effective H2O2 elimination. As demonstrated by the in vivo results, n(GOx‐CAT)C7A achieves effective tumor retention and oxygenation, potent radiosensitization and antitumor effects. Such a dual‐enzyme nanocascade for smart O2 delivery holds great potential for enhancing the hypoxia‐compromised cancer therapies.

Microfluidic-Enabled Assembly of Multicomponent Artificial Organelle for Synergistic Tumor Starvation Therapy

“…The dual-enzyme cascade system of GOx and CAT has been extensively investigated for tumor therapy. , In this approach, GOx converted glucose into gluconic acid and toxic hydrogen peroxide (H 2 O 2 ), which could be rapidly converted into H 2 O and oxygen (O 2 ) by CAT in situ , resulting in rapid glucose depletion (Figure e). The catalytic effect is the basis for enzymatic oncotherapy.…”

Transition-Metal-Based Nanozymes: Synthesis, Mechanisms of Therapeutic Action, and Applications in Cancer Treatment

“…10,182 To overcome this bottleneck, numerous nanozymes based on transition metals containing high atomic number (Z) elements have been developed as radiosensitizers to augment tumor responses to radiation and enhance treatment efficacy. 185,186 These nanozymes not only alleviate hypoxia through CAT-like activity but also generate abundant ROS via Auger and photoelectrons emitted from their high-Z metal elements under X-ray irradiation to induce DNA damages. 187,188 For example, Choi et al developed the synthesis of mPEG-conjugated porous platinum nanoparticles (PtNPs) with exceptional CAT-like activity and a high-Z Pt element, which served as a radiosensitizer to enhance RT in vivo (Figure 17A).…”

“…X-ray therapy, also known as radiotherapy (RT), is a widely employed clinical modality for cancer treatment, characterized by the induction of ROS and DNA damage through X-ray irradiation to effectively eliminate malignant cells. − However, the treatment of cancer with RT alone often presents a significant challenge due to the development of radioresistance caused by DNA damage repair mechanisms and hypoxia. , To overcome this bottleneck, numerous nanozymes based on transition metals containing high atomic number ( Z ) elements have been developed as radiosensitizers to augment tumor responses to radiation and enhance treatment efficacy. , These nanozymes not only alleviate hypoxia through CAT-like activity but also generate abundant ROS via Auger and photoelectrons emitted from their high- Z metal elements under X-ray irradiation to induce DNA damages. , For example, Choi et al developed the synthesis of mPEG-conjugated porous platinum nanoparticles (PtNPs) with exceptional CAT-like activity and a high- Z Pt element, which served as a radiosensitizer to enhance RT in vivo (Figure A) . The results from the O 2 generation experiment demonstrated that PtNPs efficiently converted H 2 O 2 into O 2 , highlighting their nanozyme properties resembling CAT.…”

Ti3C2 MXene Nanosheet-Based Dual-Enzyme Cascade Reaction to Facilitate Dual-Stimulation-Mediated Breast Cancer Therapy

“…Taking glucose as an example, cancer cells proliferate faster compared to normal cells, which leads to accelerated glucose metabolism through glycolysis, and the consumption of glucose as a metabolic substrate increases; if the supply of glucose is reduced at this time, the cancer cells will be “starved to death” due to the lack of nutrients, which is a strategy known as “starvation therapy”. , Glucose oxidase-mediated starvation therapy (GST) is widely used in tumor therapy because of its low side effects and remarkable effectiveness. , However, the enzyme produces excess H 2 O 2 while oxidizing glucose, causing irreversible damage to normal cells. , The above shortcomings limit the further development of glucose oxidase in tumor therapy. Fortunately, a cascade of enzymes composed of glucose oxidase (GOX) and horseradish peroxidase (HRP) could smoothly eliminate the H 2 O 2 generated in the reaction, and the O 2 produced also alleviate the hypoxic state of the TME. ,− The cascade will further promote the glucose consumption of tumor cells, making the reaction cycle like a motor and accelerating the rate of glycolysis. − …”