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.