Dopamine-evolved hollow mesoporous nanospheres anchoring Mn-Cu dual single-atoms for NIR-II reinforced catalytic therapy

Single-atom nanozymes (SAzymes) have emerged as promising candidates for tumor catalytic therapy. However, the challenge of a single catalytic site managing multiple catalytic reactions and intermediates restricts further enhancement of catalytic activity. Herein, we designed and synthesized a self-reinforcing nanocatalyst (termed CaO₂@P-DAzyme), featuring dual metal active sites embedded on N-doped hollow mesoporous carbon spheres, loaded with CaO₂ and modified with polyethylene glycol, to achieve intrinsic triple enzyme-like (peroxidase, catalase, and oxidase) activity for tumor catalytic therapy. Density functional theory calculations revealed that the increased electron density around the Mn atom, attributed to the introduction of Cu, imparts CaO₂@P-DAzyme with a minimal H₂O₂ adsorption energy (-0.118 eV), resulting in a higher V_max (2.37 × 10⁻⁷ M s⁻¹) and lower K_m (2.57 mM) compared to SAzyme-Cu (V_max = 1.45 × 10⁻⁷ M s⁻¹, K_m = 6.57 mM) and SAzyme-Mn (V_max = 1.82 ×10⁻⁷ M s⁻¹, K_m = 4.46 mM). Additionally, the hollow mesoporous structure enhances the exposure of active sites, improves H₂O₂ and O₂ adsorption, and allows CaO₂ loading to facilitate H₂O₂ self-supplementation and hypoxia relief, further amplifying the triple enzyme-like activities of CaO₂@P-DAzyme. Moreover, the high photothermal conversion efficiency (51.95 %) of CaO₂@P-DAzyme in the near-infrared-II region (NIR-II) window induced photothermal therapy (PTT) to augment the catalytic efficiency of the dual metal active sites. Overall, CaO₂@P-DAzyme represents a promising approach for NIR-II-triggered and self-reinforcing PTT-catalytic therapy, offering a viable strategy for designing diverse SAzymes with enhanced catalytic activities for cancer therapy.