Mechanically responsive yes-associated protein-inhibiting peptide hydrogel for scarless wound healing.

Abstract

Persistent fibrotic scarring after cutaneous wound closure remains a major clinical burden that current prophylactic and therapeutic strategies fail to resolve, leading to marked compromise of both aesthetic and functional outcomes. Mechanotransduction cascades, and in particular Hippo-YAP signalling, are now recognised as pivotal drivers of fibrogenesis. In this study, we engineered an in situ mechanoresponsive hydrogel dressing that enables spatiotemporal control of wound-edge tension while simultaneously delivering a rationally designed peptide that antagonises YAP-TEAD association. C-terminal extension of the peptide with a cationic glycine-rich segment endowed broad-spectrum antibacterial activity and promoted self-assembly into monodisperse nanoparticles. These nanoparticles were homogeneously entrapped within a gelatin-sodium alginate network that was further functionalised with poly(N-isopropylacrylamide) to impart thermally reversible contraction. The resultant GAPNP hydrogel underwent pronounced radial shrinkage of 63.83 % at 45 °C, thereby validating its robust mechanoadaptability. In murine full-thickness excisional wounds, the dressing accelerated re-epithelialisation to 60.35 % within 48 h. Histopathological and immunohistochemical analyses revealed pronounced downregulation of YAP and alpha smooth-muscle actin, and a rabbit ear hypertrophic scar model ultimately achieved scarless regeneration. Collectively, this work establishes a previously unreported paradigm that integrates mechanomodulation with peptide-based molecular intervention and provides a clinically translatable strategy for fibrosis-free cutaneous repair. STATEMENT OF SIGNIFICANCE: Hypertrophic scars develop in 40-70 % of wounds, particularly in high-tension anatomical sites such as joints, and inflict persistent pain, contractures, and substantial socioeconomic costs. Existing hydrogels cannot modulate the dynamic mechanical environment of healing tissue, whereas pharmacological YAP-TEAD blockade is hindered by suboptimal release profiles, unpredictable kinetics, and inadequate targeting. To overcome these limitations, we engineered a self-contractile peptide hydrogel that couples a PNIPAAm-reinforced gelatin-sodium alginate matrix with Peptide8, a YAP-TEAD antagonist rationally modified to self-assemble into antibacterial nanoparticles and to be released in a sustained manner. This concomitant mechanomodulatory and molecular intervention offers a comprehensive, clinically translatable strategy for scar-free cutaneous repair.