Abstract

The dysregulation of neutrophil death pathways constitutes a critical barrier to diabetic tissue regeneration, in which pyroptosis perpetuates chronic inflammation while apoptosis promotes tissue homeostasis. However, achieving reliable control over neutrophil death patterns to tune inflammation and repair processes remains a major challenge. Here, we develop a multifunctional aerogel scaffold based on piezoelectric ceramic nanofibers to synergistically direct neutrophil fate. Specifically, (K,Na)NbO 3 piezoceramics are incorporated into gelatin/polylactic acid nanofiber membranes, homogenized via high-speed fragmentation, and freeze-dried to form a porous aerogel scaffold. Conjugation with the retinoid derivative peretinoin yields the final piezoelectric ceramic nanofiber aerogel (KAP). Peretinoin released from KAP suppresses caspase-3-mediated cleavage of gasdermin E (GSDME), switching neutrophil death from pyroptosis to apoptosis. Meanwhile, upon ultrasound activation, KAP generates surface potentials to enhance macrophage phagocytic capacity via calcium influx and lysosomal acidification. This dual mechano-chemical approach promotes efferocytosis and reprograms macrophages toward a pro-regenerative phenotype, thereby breaking the cycle of chronic inflammation in diabetic microenvironments. In diabetic rodent models, KAP significantly accelerates the healing of both soft and hard tissues. This study presents a piezoelectric ceramic nanofiber aerogel that offers a potential therapeutic approach for diabetic tissue regeneration.