A bimetallic catalyst core-shell nanoplatform enabling all-stage management of infected diabetic wound healing

The impaired healing of diabetic wounds is largely attributable to the pathological microenvironment, which promotes susceptibility to bacterial infection, hyperinflammation, vasculopathy, and neuropathy. To address these issues, a bimetallic catalyst core-shell nanoplatform ((Cu@Ce)HM) with Cu-bonded Ce-MOF as core and HHC36-loaded hyaluronic acid (HA) as shell is constructed. (Cu@Ce)HM demonstrates potent antibacterial efficacy (eliminating 97.01 % of Staphylococcus aureus (S. aureus) and 99.55 % of Escherichia coli (E. coli)) through the responsive release of Cu ions and HHC36 in infected diabetic microenvironment. Furthermore, (Cu@Ce)HM effectively scavenges excessive reactive oxygen species (ROS) via its superoxide dismutase (SOD)- and catalase (CAT)-mimicking enzymatic activities. Density functional theory (DFT) calculations reveals that Cu bonding induces electron rearrangement within the Ce-MOF, stabilizing the coexistence of Cu⁺/Cu²⁺ and Ce³⁺/Ce⁴⁺ redox couples. This bimetallic synergy enables efficient catalysis, improving ROS scavenging performance of (Cu@Ce)HM. (Cu@Ce)HM improves the pathological microenvironment by scavenging ROS and supplying low-dose Cu ions, and thus promotes the recovery and M2 phenotype of M1 macrophages, enhancing anti-inflammatory cytokine secretion. This immunomodulation further augments the biofunctions of endothelial cells (HUVECs) and neural cells (PC12). Transcriptome sequencing analysis indicates that the antioxidant properties and Cu supplementation provided by (Cu@Ce)HM promotes the recovery and differentiation of damaged PC12 cells by upregulating key signaling pathways, including PI3K/Akt/CREB, Ras/ERK/CREB, and Ras/ERK/MAPK. This study presents a promising "all-stage" management strategy for infected diabetic wound regeneration, integrating infection elimination, immunoregulation, and the facilitation of neuroangiogenesis and extracellular matrix (ECM) remodeling.