Orbital Coupling‐Induced Ce–Cu Heterogeneous Dual‐Single‐Atom Hybrid for Programmable and Adaptive Catalytic Therapy of Diabetic Wounds

ABSTRACT Chronic diabetic wounds featuring interlocked biofilm infection, vascular damage, and oxidative stress, demand smart nanomedicines that dynamically respond and concurrently address these pathologies. Here, a coordination‐disparity‐driven strategy is used to construct a copper‐cerium heterogeneous dual‐single‐atom on carbon dots (CeCu DSAEs). Theory and experiment show that Ce–Cu d–f orbital hybridization suppresses Ce aggregation, elevates the Ce 3+ fraction to 55.07%, and reduces the peroxidase‐like reaction energy barrier to 0.44 eV. Atomic‐level electronic regulation endows CeCu DSAEs with exceptional, switchable cascade catalysis. Upon integration with glucose oxidase (GOx), the resulting CeCu@GOx nanoplatform performs pH‐programmed, microenvironment‐adaptive catalytic therapy: in the infection stage, Ce‐mediated hydrolytic disruption of biofilms achieves 89% matrix breakdown, followed by hetero Fenton‐like bactericidal activity with >99.999% reduction; in the reparative stage, the catalyst switches to reactive oxygen species scavenging (90% clearance) and enhances angiogenesis (+299%). In diabetic mice, CeCu@GOx achieves 96% wound closure by day 11, with 2.19‐fold collagen densification and 2.8‐fold neovascularization. Transcriptomics confirms inflammatory pathway suppression and tissue regeneration activation. This work introduces an integrated all‐in‐one therapeutic strategy for chronic diabetic wounds and establishes a paradigm for designing adaptive nanozymes by tuning interatomic electron interactions via orbital coupling, providing generalizable principles for next‐generation smart responsive biomaterials.