A mechanically active microneedle platform integrated with engineered exosomes for enhanced tendon-bone regeneration.

Abstract

Functional regeneration of the tendon-bone interface remains a major challenge because early healing is constrained by an adverse inflammatory microenvironment and insufficient mechanical cues. Here, we developed a mechano-regenerative strategy that combines YAP-primed engineered exosomes with localized biomaterial-based delivery and active mechanical stimulation. Exosomes derived from a YAP agonist (PY-60) preconditioned TDSCs (P-Exo) showed enhanced uptake and promoted the osteogenic and chondrogenic differentiation of bone marrow mesenchymal stem cells, accompanied by activation of YAP-associated signaling and PI3K-Akt-related pathways. To improve local retention, P-Exo were incorporated into a ROS-responsive adhesive hydrogel, which accelerated fibrocartilage formation, bone ingrowth, and biomechanical restoration in a rabbit tendon-bone healing model. To address more complex repair conditions, we engineered a three-layer self-contracting microneedle platform for deep-tissue delivery of P-Exo with concurrent active mechanical stimulation. In an infected rat rotator cuff model, this system reduced bacterial burden and oxidative stress, promoted a reparative macrophage polarization and angiogenesis, and improved tendon-bone structural regeneration, biomechanical strength, and functional recovery. Together, these findings support a therapeutic framework in which engineered exosome signaling and active mechanoregulation act in concert to enhance tendon-bone repair.