Fluorinated covalent organic framework hydrogel reprograms Piezo1/YAP mechanotransduction for sustained prevention of...

Postoperative peritendinous adhesion arises from sustained fibroblast activity, collagen overproduction, and dysregulated mechanical signaling during tendon repair; however, few current treatments can deliver a prolonged molecular intervention across the proliferative stage of healing. Here, we developed a fluorinated covalent organic framework hydrogel, Thi@FCOF@Gel, that enables temporally controlled delivery of thioridazine hydrochloride for sustained prevention of peritendinous adhesion. Through phenotypic drug screening, thioridazine hydrochloride (Thi) is identified as a previously unrecognized anti-adhesion agent capable of selectively suppressing fibroblast proliferation and myofibroblast activation while exerting limited inhibitory effects on tendon-derived stem cells. To synchronize drug exposure with adhesion formation, thioridazine was encapsulated into a fluorinated COF and incorporated into a hyaluronic acid/quaternized chitosan hydrogel, yielding an injectable, self-healing and mechanically reinforced local depot with prolonged release behavior. Mechanistically, thioridazine-containing hydrogels attenuated extracellular matrix-associated mechanosignaling by downregulating Piezo1, increasing YAP phosphorylation and suppressing α-SMA and collagen III expression. In a rat Achilles tendon repair model, Thi@FCOF@Gel markedly reduced fibrotic bridging, collagen deposition and adhesion scores, while improving gait recovery without compromising tendon biomechanical integrity or systemic safety. This study not only reveals a new anti-adhesion application of Thi, but also provides a COF-enabled hydrogel strategy for precise local drug delivery in postoperative adhesion management.