Volumetric Engineered 3D Drug Reservoir Against Diabetic Implant Infection via Cuproptosis-Like Bacterial Death and Hunger-Triggered Maintenance of Mitochondrial Integrity

Abstract

Implant-associated infections in diabetic patients pose critical challenges due to immune-metabolic dysregulation that exacerbates biofilm persistence and tissue damage. This study introduces a “dimensional rise” strategy integrating 3D-printed porous titanium frameworks with micro-nano hierarchical structures to establish a mechanically robust, high-capacity drug reservoir, surpassing the limitations of conventional 2D surface modifications. Copper-doped carbon quantum dots, synthesized from luteolin, synergize with polydopamine-mediated photothermal activation to disrupt bacterial copper homeostasis, inducing tricarboxylic acid cycle collapse and cuproptosis-like death via reactive oxygen species bursts and lipoylated protein aggregation. Concurrently, glucose oxidase depletes local glucose to activate adenosine 5'-monophosphate-activated protein kinase phosphorylation in host cells, restoring mitochondrial integrity and metabolic homeostasis through deacetylation. This dual-action system achieves differential regulation—targeting bacteria while protecting host tissues—and ensures therapeutic coverage across acute infection and chronic healing phases. Validated in three animal models, including Beagles with clinical-grade implants, the strategy demonstrates potent anti-biofilm efficacy, prevention of secondary infections, and accelerated diabetic osseogenesis. By upgrading surface engineering to 3D volumetric drug reservoirs, this work establishes a paradigm for differentiated multimodal therapy against implant-related infections in metabolically compromised hosts, addressing both immediate bactericidal demands and long-term tissue recovery.