Chemical substrate-enabled piezoelectric metabolic reprogramming therapy unlocks the vicious triad of diabetic wounds

The complex pathological environment of infection, inflammation, and immune dysfunction in diabetic wounds often contributes to chronic non-healing wounds. Here, we present an emerging piezoelectric metabolic reprogramming therapy dual-enabled by chemical catalysis and macrophage efferocytosis, aimed at disrupting this pathological triad through calcium-peroxidized barium titanate. The chemical substrate-enabling strategy decreases the energy barriers through catalytic substrate modulation, enabling efficient bacterial clearance via reactive oxygen species radicals. Furthermore, this strategy reprogrammed macrophage metabolism via a low-intensity ultrasound-triggered piezoelectric-calcium-mediated signaling pathway, restoring impaired efferocytosis and expanding the macrophage pool through efferocytosis-induced macrophage proliferation. In diabetic mouse models, such a strategy cleared persistent biofilm infections, promoted macrophage polarization toward the M2 phenotype, and facilitated the distribution of Th2 cells and regulatory T cells that promote healing, ultimately accelerating wound closure. These findings establish a paradigm-shifting approach that integrates piezocatalysis with immune-metabolic remodeling, providing a transformative strategy for diabetic wound management.