Targeting NRP1 in Endothelial Cells Facilitates the Normalization of Scar Vessels and Prevents Fibrotic Scarring

Abstract Current clinical treatments for skin scars primarily reduce vascular density in situ. But, outcomes remain unsatisfactory due to limited understanding of scar vascular structure, endothelial cell (EC) heterogeneity, and functional changes. Through dermatoscopy, scanning electron microscopy, and immunofluorescence staining, our study revealed substantial vascular remodeling in scars, including increased neovascularization density, branching complexity, and incomplete vascular wall coverage. Single‐cell sequencing constructed an EC atlas of scar patients, identifying upregulated ATP synthesis, decomposition, and oxidative phosphorylation in scar ECs—characteristics resembling tumor vasculature. Notably, a subset of ECs with high neuropilin‐1 (NRP1) expression exhibited mesenchymal characteristics. In vitro experiments demonstrated that NRP1 knockdown blocked the transforming growth factor‐beta (TGF‐β)/SMAD family member 2 (SMAD2) signaling pathway and mitigated endothelial‐to‐mesenchymal transition (EndMT). Importantly, NRP1 inhibition reduced EndMT, restored normal vascular function and structure, and prevented scar formation in mice. Based on these findings, a functional hydrogel spray was developed using an NRP1‐targeting peptide, effectively preventing scar formation by promoting vascular normalization.