Single-Atom Nanoisland with Dual-Nanoconfinement Effects for Cascade Self-Amplified Synergistic Antitumor Therapy via Redox/Metabolism Disruption

Abstract Enzyodynamic therapy (EDT) represents a promising cancer therapeutic modality; however, its efficacy is constrained by the catalytic activity of nanozymes and intrinsic tumor-adaptive defense mechanisms. Leveraging the atomic–nano structure and nanoconfined effect of single-atom nanoislands (SANIs), a SANI-based nanozyme (CPH) is elaborately constructed through vapor filling and spatially confined reduction/growth of metal species, featuring ultrasmall Pt nanoislands with embedded Ce single atoms confined within the channels of hollow carbon spheres. CPH exhibits multienzymatic activities resembling those of oxidase, catalase, peroxidase, glucose oxidase, glutathione peroxidase, and nicotinamide adenine dinucleotide oxidase, sustaining a self-reinforcing catalytic cascade that disrupts redox homeostasis and blocks energy metabolism. This process facilitates H2O2 self-supplementation while alleviating hypoxia and elicits reactive oxygen species storm and lipid peroxidation, thereby establishing an apoptosis/ferroptosis dual-pathway therapeutic strategy. Mechanism investigation reveals that the enhanced catalytic properties can be ascribed to the favorable shift of the d-band center and synergistic effects among multiactive centers after Ce single-atom embedding. Concurrently, the nanoconfined photothermal effect facilitates heat concentration while minimizing thermal dissipation, further augmenting the catalytic efficiency and enabling synergistic mild-photothermal therapy (mild-PTT)/EDT synergistic therapy. This study provides a proof of concept of SANI-based nanozymes as efficient therapeutic tools toward tumor ablation.