A Dual-Interaction Supramolecular Hydrogel System for siRNA Delivery to Enhance Endometrial Receptivity in Stem Cell Therapy

Endometrial receptivity is crucial for embryo implantation success. Stem cell therapy shows promise for improving endometrial health. We developed a supramolecular hydrogel scaffold based on stereocomplexed triblock copolymers (MPEG-(sc-PLA)-PEI) and α-cyclodextrin for codelivering menstrual blood-derived endometrial stem cells (MenSCs) and siRNA targeting DNA methyl transferase 1 (DNMT1), enabling RNAi-mediated gene silencing to improve endometrial receptivity. The resulting α-CD/MPEG-(sc-PLA)-PEI hydrogels exhibited high mechanical stability, excellent self-healing capabilities, and sustained siRNA release via a dual-interaction mechanism involving host-guest interaction and stereocomplexation. <i>In vitro</i> studies indicated superior cellular uptake of DNMT1 siRNA encapsulated within MPEG-(sc-PLA)-PEI complexes, resulting in significant upregulation of endometrial receptivity markers, including HOXA10, ITGB3, and E-cadherin. <i>In vivo</i> experiments showed that DNMT1 siRNA-loaded hydrogels facilitated endometrial remodeling through therapeutic transgene expression in MenSCs. These findings suggest that this multifunctional hydrogel system may serve as an effective tool for stem cell-based therapies aimed at enhancing endometrial receptivity.