Sele-targeted siRNA liposome nanoparticles inhibit pathological scars formation via blocking the cross-talk between monocyte and endothelial cells: a preclinical study based on a novel mice scar model

Background: Pathological scars (PS) are one of the most common complications in patients with trauma and burns, leading to functional impairments and aesthetic concerns. Mechanical tension at injury sites is a crucial factor in PS formation. However, the precise mechanisms remain unclear due to the lack of reliable animal models.

Results: We developed a novel mouse model, the Retroflex Scar Model (RSM), which induces PS by applying controlled tension to wounds in vivo. RNA Sequencing identified significant transcriptome changes in RSM-induced scars. Elevated expression of E-Selectin (Sele) was observed in endothelial cells from both the RSM model and human PS (Keloid) samples. In vitro studies demonstrated that cyclic mechanical stretching (CMS) increased Sele expression, promoting monocyte adhesion and the release of pro-inflammatory factors. Single-cell Sequencing analysis from the GEO database, complemented by Western blotting, immunofluorescence, and co-immunoprecipitation, confirmed the role of Sele-mediated monocyte adhesion in PS formation. Additionally, we developed Sele-targeted siRNA Liposome nanoparticles (LNPs) to inhibit monocyte adhesion. Intradermal administration of these LNPs effectively reduced PS formation in both in vivo and in vitro studies.

Conclusions: This study successfully established a reliable mouse model for PS, highlighting the significant roles of mechanical tension and chronic inflammation in PS formation. We identified Sele as a key therapeutic target and developed Sele-targeted siRNA LNPs, which demonstrated potential as a preventive strategy for PS. These findings provide valuable insights into PS pathogenesis and open new avenues for developing effective treatments for pathological scars.

Animal model; Liposome nanoparticles; Mechanical tension; Pathological scar; RNAi therapy.