Biomimetic Nanoplatform for Dual Target Nano‐Metabolic Therapy in Diabetes‐Associated Biofilm Infections

ABSTRACT Metabolism alterations significantly influence the behavior of both bacteria and immune cells in the microenvironment of diabetes‐associated biofilm infections, ultimately determining the outcome of infections. Here, we propose a dual‐target nano‐metabolic therapy based on a biomimetic nanoplatform to combat these infections. The nanoplatform, coated with cellular membranes from pre‐infected macrophages and loaded with glucose oxidase (GOx) and L‐arginine (Arg), facilitates targeted drug delivery. Nitric oxide (NO), generated in situ through the catalytic cascade reaction of GOx and Arg, acts as a dual‐target metabolic regulator. It disrupts bacterial carbon and nitrogen metabolism, particularly the tricarboxylic acid (TCA) cycle and amino acid metabolism, effectively eliminating biofilms. Simultaneously, NO modulates macrophage metabolism, shifting it from oxidative phosphorylation to aerobic glycolysis by suppressing TCA cycle enzymes and electron transport chain complexes, while preserving mitochondrial integrity. This energy metabolism transition reverses macrophage immunosuppression, enhancing their phagocytic and invasive functions to promote infection clearance. Experiments with multiple clinical bacterial strains and various diabetic infection models highlight the therapeutic potential of combining metabolism interference with immune modulation, offering new insights for the treatment of diabetes‐associated biofilm infections.