Bioinspired Protein-Mineralized Single-Atom Nanozymes for Tumor-Specific Cascade Therapy via Self-Amplifying Catalytic Synergy

Abstract

Single-atom catalysts (SACs) are highly promising in biomedical applications due to their unmatched catalytic activity and atomic-level precision, yet their clinical translation is hindered by limited biocompatibility, instability, and lack of tumor targeting. Here, a universal, bioinspired strategy is proposed to construct flexible, biocompatible SACs by leveraging enzymatic protein scaffolds for mineralization of single-atom platinum (Pt). This protein-mineralized platform enables the fabrication of stable dual-functional nanozymes, exemplified by glucose oxidase-coordinated Pt (GOx-Pt), which simultaneously catalyze glucose oxidation and H₂O₂-to-•OH conversion, generating a self-amplifying cascade for reactive oxygen species (ROS) production. To ensure tumor specificity, the GOx-Pt nanozyme is encapsulated within a pH-responsive zeolitic imidazolate framework (ZIF-8), which remains stable under physiological conditions but disintegrates in mildly acidic tumor environments, enabling localized and selective therapeutic activation. This synergistic design not only enhances antitumor efficacy by inducing oxidative stress and glucose depletion but also minimizes systemic toxicity. The resulting ZIF-8@GOx-Pt system achieves robust catalytic stability, selective cytotoxicity, and significant tumor inhibition (53%) in vivo without discernible side effects. This work pioneers a versatile biomineralization approach for engineering SAC-based nanozymes with dual catalytic and tumor-responsive functions, offering a generalizable strategy for next-generation precision cancer therapeutics.