Identification of fibroblast-derived sFRP2 as a new therapeutic target and engineering of siRNA therapies for uterine scarring

Uterine scarring (US) is a common complication following uterine injury, characterized by abnormal wound healing in the endometrial or myometrial tissue. However, the underlying mechanisms contributing to scar formation remain unclear, impeding the development of effective drugs for US. Here, we identified that secreted frizzled-related protein 2 (sFRP2) is highly expressed in human and mouse uterine tissues with US, particularly in uterine fibroblasts (UFIBs). Using mouse models, we demonstrated that sFRP2 overexpression in the healthy uterus induced US features and exacerbated surgery-induced scarring, while sFRP2 knockout inhibited US development and scarring-transformation in UFIBs, highlighting the critical role of sFRP2 in mediating US. Mechanistically, sFRP2 promotes uterine scar formation by activating the non-canonical Wnt signaling pathway and calcium influx in UFIBs. Additionally, therapeutic potential of targeting sFRP2 was demonstrated by developing siRNA against sFRP2 and engineering delivery systems of lipid nanoparticles and injectable hydrogel. These siRNA therapies effectively inhibited sFRP2 expression, alleviated uterine scar formation, and improved pregnancy outcomes in mice, underscoring the great potential of sFRP2 as a promising therapeutic target for US.