Leveraging self-healing CASH gel for enhanced paracrine secretion of mesenchymal stem cells to boost endometrial regeneration.

Locally delivering mesenchymal stem cells (MSCs) has been recently demonstrated to be successful in the treatment of intrauterine adhesions (IUA) by taking advantage of the immunomodulatory, pro-angiogenic, and anti-fibrotic properties of MSCs to facilitate endometrial regeneration and restore uterine function. However, direct exposure of these donor cells to the detrimental pathological microenvironment in the uterine cavity invariably leads to a low cell survival rate, poor control over cell fates, and impaired cellular functionalities, which can significantly compromise the therapeutic efficacy. Herein, we proposed a gelatin-based, colloid-assembled self-healing (CASH) hydrogel to deliver and retain the donor MSCs locally in the uterine cavity. The shear-thinning and self-healing behavior of CASH gel served as delivery vehicles to enable minimally invasive implantation and as extracellular matrix (ECM)-mimicking scaffolds to adapt locally to the complicated and pathological intrauterine environment. Importantly, CASH gel supports the adhesion and proliferation of MSCs in a 3D environment. We revealed that CASH gel enhances MSCs' paracrine activity through the PI3K signaling pathway, thereby reversing IUA and improving fertility via a four-pronged strategy involving immune remodeling, fibrosis deconstruction, vascular remodeling, and endometrial regeneration. Overall, this study has provided important insights into how it enhances the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for IUA.