Self-cascade catalytic single-atom nanozyme for enhanced breast cancer low-dose radiotherapy

One of the most widely used therapeutic approaches is radiotherapy (RT), which uses high-energy radiation to destroy tumor cells [1], [2]/ Nanomedicine with high-z elements (elements with a large atomic number) can significantly raise the local dose of radiation at the cellular level and thus improve the effectiveness of radiation therapy [3], [4], [5]. However, both experimental and simulation studies suggest that the physical dose is not significantly enhanced, especially considering the small reaction probability between nanomedicine and radiated rays when the cellular drug concentration is relatively low [6], [7], [8], [9]. Recently, taking advantage of special chemical properties of designed nanomaterials and the unique tumor microenvironment (TME), a possible way was developed by "re-programing" bio-molecules, such as reactive oxygen species (ROS) in tumor cells, which can profoundly promote RT efficacy [10], [11], [12]. These approaches can also be classified in catalytic therapy or chemodynamic therapy (CDT) these days [13], [14], [15].

Among all those chemically modified nanomaterials, nanozyme that mimic nature enzyme is great for their high catalysis efficiency, low cost, and fantastic stability [16], [17], [18], [19], [20], [21]. Recently, many remarkable nanoenzymes, such as oxide [22], [23] or metal nanoparticles [24], [25], were used in tumor therapy. Despite achieving reasonable tumor therapy efficiency, the unit activity remains relatively low. Furthermore, oxide nanodrugs tend to dissolve and release a significant amount of metal ions in the acidic tumor microenvironment. These metal ions may then be transported into normal cells via the intracellular circulatory system, inadvertently causing toxicity to healthy cells. To this end, single atom nanozyme (SAE) was recently developed to achieve high efficiency and specific enzyme catalytic therapy [26], [27], [28], [29]. The most popular one is peroxidase (POD)-like SAE since it could transform endogenous H2O2 into cytotoxicity hydroxyl radicals (•OH) and effectively destroy tumor cells. [30], [31], [32], [33], [34], [35], [36], [37], [38] However, implementing an H2O2 self-generating hydrogen system could be a viable solution to this problem, significantly improving the anti-cancer effectiveness of nanomedicine [39]. Since glucose oxidase (GOx) is capable of catalyzing the conversion of endogenous glucose to H2O2 [40], combining innovative materials like SAE with GOx presents a promising strategy to bolster the synergistic effects of both components, ultimately enhancing the anti-cancer capabilities of the whole system [41], [42], [43], [44].

A very straight approach is to load the GOx into an SAE-based drug delivery system, but the drug delivery system always encounters the problem of unstableness; drugs will easily leak into the body's circulation system [45]. Better formula could be constructing a hybrid multiple nanozyme with different functions. Herein, a Fe SAE dual-nanoenzyme system with Au nanoparticles embedded in ([email protected]) was developed to induce H2O2 self-producing cascade catalytic therapy, achieving highly efficient RT (Scheme 1). The embedded Au nanoparticles can not only provide service as an energy enhancement agent that boosts local X-ray deposited dose but also possess the ability to specially catalyze the oxidization reaction of β-D-glucose to generate gluconic acid and H2O2. Interestingly, this generated H2O2 would further be catalyzed by FeSAE in situ, producing plenty of •OH and promoting RT efficiency. Further evidence from in vivo studies showed that [email protected] might successfully stop tumor growth during the treatment. [email protected] is the first study of hybrid SAE-based nanomaterials utilized to produce cascade catalytic RT, to the best of our understanding. The findings will encourage the development efforts of SAE-based treatment options.

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