A Photothermally Amplified Enzyme–Nitric Oxide Co‐Regulatory System Reprograms Pathological ECM–Fibroblast Crosstalk to Alleviate Hypertrophic Scarring

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. An enzyme–nitric oxide (NO) co‐regulatory strategy reprograms pathological extracellular matrix (ECM)–fibroblast crosstalk in hypertrophic scars. Enzymatic degradation of pre‐existing ECM relieves aberrant mechanical cues, while NO‐mediated fibroblast phenotypic modulation restrains excessive collagen synthesis. Supported by photothermal amplification and localized microneedle delivery, this strategy interrupts the fibrotic feedback loop and restores balanced remodeling to alleviate hypertrophic scarring.