Mechanically Adaptive Hydrogels Reprogram Apoptotic Cell Clearance to Prevent Tissue Fibrosis.
Abnormal mechanical stimulation drives fibrotic scar formation in active wounds by sustaining mechanotransduction, promoting apoptotic cell accumulation and pro-fibrotic amplification that constrain functional regeneration. To address this challenge, we developed a mechanically adaptive hydrogel patch (Gel/VP) through the integration of an interpenetrating polymer network and CNC@PDA@ZIF8 dynamic nanofillers, in which the interpenetrating network provides structural load-bearing and adaptive deformation, while the nanofillers form a force-induced, reconfigurable dissipative network via hydrogen bonding and π-π interactions, collectively dissipating tensile energy upon pre-stretched application, establishing a reverse mechanical buffer at the wound interface, suppressing sustained Piezo1-YAP activation, restoring macrophage efferocytosis-mediated apoptotic cell clearance, and ultimately limiting fibrotic scar formation. The interpenetrating architecture endows the patch with a tunable elastic window matched to the mechanical environment of skin (elastic modulus of 7-15 kPa with twofold extensibility). Under reverse mechanical buffering, the macrophage phagocytic rate increases from 22.50% to 64.50%, significantly enhancing apoptotic cell clearance. In vivo, the patch achieves near-complete wound closure (>95%) within two weeks, markedly reduces α-SMA+ myofibroblast accumulation, promotes ordered collagen remodeling, and substantially decreases scar formation. Overall, by leveraging material-mediated reverse stress buffering to restore macrophage efferocytosis, this study targets apoptotic cell clearance at an early stage of fibrosis and provides a robust antifibrotic material strategy for the functional regeneration of active wounds. STATEMENT OF SIGNIFICANCE: Abnormal mechanical stretching during wound healing is a key yet underrecognized driver of fibrotic scar formation, and current therapies rarely address this physical cue. Here, we develop a stress-adapted hydrogel patch that forms a "reverse mechanical buffer" under pre-stretch, actively redistributing tensile forces at the wound interface. This buffering suppresses mechanotransduction (Piezo1-YAP signaling) while restoring macrophage-mediated clearance of apoptotic cells. By integrating an interpenetrating polymer network with dynamic nanofillers, the material achieves adaptive energy dissipation and mechanical compatibility with skin. This work establishes a mechanically guided, immunomodulatory approach to limit fibrosis, offering a promising biomaterials strategy for scarless healing and functional tissue regeneration.