Self-Cascading Copper-Based Nanoassemblies Trigger Bacterial Cuproptosis-Like Death and Promote Wound Healing for Diabetic Drug-Resistant Bacterial Infections.

Abstract

Diabetes mellitus leads to systemic immunosuppression, increasing susceptibility to persistent infections and elevating the risk of severe complications. Concurrently, multidrug-resistant (MDR) pathogens such as methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) further exacerbate therapeutic difficulties. To address this challenge, we engineered peroxidase (POD)-like nanoassemblies (DC/Cu) through the copper-coordinated self-assembly of ε-poly(L-lysine)-derived carbon dots (CDs) and anti-inflammatory agent diclofenac sodium (DS). These nanoassemblies integrate antibacterial, anti-inflammatory, and tissue-reparative functionalities for the treatment of MDR bacteria-induced diabetic infections. Cationic DC/Cu can selectively adhere to bacterial membranes, enabling microenvironment-responsive spatiotemporal drug release. The POD-like activity of CDs catalyzes the endogenous H₂O₂, inducing membrane lipid peroxidation and enhancing cell membrane permeability, which facilitates copper influx. This self-cascade induces lethal intracellular copper overload in MRSA, with transcriptomic profiling confirming Cu²⁺-mediated inhibition of Fe-S cluster proteins and disruption of the tricarboxylic acid cycle, leading to subsequent activation of cuproptosis-like death pathway. Simultaneously, the released DS mitigates the inflammatory response, while Cu²⁺ facilitates tissue regeneration. MRSA-infected diabetic foot ulcers and diabetic MRSA keratitis models validated DC/Cu's multifunctional efficacy in bacterial eradication, inflammatory mitigation, and tissue regeneration. Collectively, these multifunctional nanoassemblies demonstrate a promising and effective approach for precision therapeutic intervention against MDR pathogen-aggravated diabetic complications.