A Photothermally Amplified Enzyme-Nitric Oxide Co-Regulatory System Reprograms Pathological ECM-Fibroblast Crosstalk...

Hypertrophic scars (HS) are sustained by a self-perpetuating extracellular matrix (ECM)-fibroblast feedback loop, in which activated fibroblasts drive excessive ECM deposition, while the resulting matrix stiffening in turn reinforces fibroblast activation. Although advanced fibroblast-suppression strategies are being actively developed, this matrix-driven profibrotic feedback remains poorly integrated into HS therapeutic strategies and insufficiently targeted. Here, we introduce an enzyme-nitric oxide (NO) co-regulatory system for HS: enzymatic degradation of pre-existing ECM relieves aberrant mechanical cues, while NO-mediated modulation of fibroblast phenotypes restrains excessive collagen synthesis, thereby inducing mutually reinforcing remodeling across the ECM-fibroblast axis. Specifically, a microneedle platform is developed for localized co-delivery of the thermosensitive protease bromelain (Bro) and NO-donor-functionalized polydopamine nanoparticles (PDA-NO). Upon near-infrared irradiation, precise photothermal stimulation further enhances Bro activity and accelerates NO release, enabling controlled amplification of the co-regulatory effect. In vivo studies demonstrate that this system alleviates HS and restores balanced fibrotic remodeling, as evidenced by coordinated suppression of YAP signaling and the TGF-β1/α-SMA/Collagen I axis, supporting effective interruption of the fibrotic feedback loop. Distinct from existing fibroblast-centric approaches, this study establishes pathological ECM-fibroblast crosstalk as a key mechanistic entry point for HS, advancing a mechanism-driven, materials-enabled framework for antifibrotic strategy design.