Targeting hedgehog signaling with a smart microneedle system promotes tendon regeneration

Achilles tendon homeostasis and repair rely on progenitor cells, but the role of Hedgehog/Glioma-Associated Oncogene Homolog 1(Hh/GLI1) signaling remains elusive. In response to inflammatory insults, Hh signaling is activated and Gli1-lineage cells undergo rapid expansion in the injured Achilles tendon. These GLI1 + cells constitute a distinct progenitor cell subset with substantial proliferative capacity. Functionally, while this pathway supports tendon homeostasis under normal conditions, ablation of GLI1 + cells compromises tissue repair and promotes heterotopic ossification (HO). Based on these findings, a novel smart-responsive hyaluronic acid-based microneedle (MN) was developed. It delivers purmorphamine (Pur; a smoothened agonist) encapsulated within a bilayer of tenocyte membrane and ROS-responsive Poly(lactic-co-glycolic acid) (MN@TM-RRP-Pur). This design enhances the sustained penetration of the drug into dense tissue via the cell membrane coating, and enables drug release specifically at the inflammatory site via RRP degradation, thereby potentiating the stemness of progenitor cells and promoting regenerative repair. In vitro and in vivo experiments demonstrated that the degradation of MN@TM-RRP-Pur enables the stepwise release of Pur at the injury site, effectively inhibiting HO and promoting the restoration of Achilles tendon structure. These findings elucidate Hh signaling regulation of Achilles tendon progenitors and present a novel strategy to activate endogenous repair mechanisms.