Piezoelectric Nanofibers Synchronize Mitochondrial Dynamics and Immune Responses for Regeneration of Infected Wounds

Mitochondria play a central role in coordinating wound repair by integrating bioenergetic activity with immune-metabolic signaling. Although electrical cues are known to influence mitochondrial behavior, most existing methods depend on implanted electrodes. Besides, how electrical stimulation precisely regulates the fate of mitochondrial function during infection remains incompletely defined. In this study, we use piezoelectric poly(L-lactic acid) (PLLA) nanofibers upon ultrasound stimulation to act as a wireless interface for spatiotemporally precise mitochondrial regulation during infected wound repair. During the inflammatory stage, piezoelectric activation led to a rapid mitochondrial Ca²⁺ influx and membrane depolarization within seconds, followed by a minute-scale rise in mitochondrial reactive oxygen species (ROS). This sequence initiated the Ca²⁺-ROS-mtDNA-STING cascade, enhancing antimicrobial activity via cytosolic DNA sensing and promoting mitochondrial fission associated with proinflammatory defense. As healing progressed to the proliferative phase, electrical cues from the nanofibers shifted cellular metabolism and drove macrophage polarization toward a regenerative phenotype, as indicated by a higher Arg1/iNOS ratio and lower IL-6 and TNF-α expression, while promoting mitochondrial fusion and tissue remodeling. <i>In vivo</i> experiments confirmed that these time-scaled mitochondrial responses facilitated the immune response, angiogenesis, and epithelial regeneration, resulting in markedly accelerated closure of infected wounds. Collectively, this work demonstrates how piezoelectric charges regulate mitochondrial Ca²⁺, ROS, and mtDNA, identifying mitochondria as spatiotemporal mediators of electrostimulation-driven immune reprogramming, offering a wireless bioelectronic strategy to overcome chronic infection barriers and promote functional tissue regeneration.