Activation of the YAP1/pSTAT3/NRP1 axis in peritendinous sensory nerves promotes tendon healing
2026-02-18
Chemotactic migration of peritendinous nerves is essential for tendon regeneration, yet the underlying neuroelectrical mechanisms remain unclear. Here, we identify an electrically responsive yes-associated protein 1 (YAP1)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/neuropilin-1 (NRP1) signaling axis in sensory neurons. Electrical stimulation enhances YAP1-pSTAT3 interaction, promotes pSTAT3 nuclear translocation and transcriptional activity, and up-regulates NRP1 to support growth of calcitonin gene-related peptide (CGRP)–positive sensory fibers. Guided by these findings, we engineered a bifunctional piezoelectric patch composed of poly(vinylidene difluoride-trifluoroethylene) [P(VDF-TrFE)] and regenerated silk fibroin@poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (RSF@P:P), coupling mechanically induced electrical cues with dynamic lubrication. Under ultrasound activation, the P(VDF-TrFE) layer generates localized electrical signals that facilitate sensory-nerve and vascular ingrowth, while the RSF@P:P layer undergoes piezoelectric-triggered gel-sol transition to form a low-friction interface and reduce adhesion. In rat and Bama minipig models, the patch markedly enhanced tendon regeneration and decreased adhesion scores by ~50%. These findings establish a neuroelectrically guided strategy for enhancing tendon healing.