A Three-Dimensional Printable Supramolecular Granular Hydrogel Enhances Stemness Maintenance and In Vivo Retention in Stem Cell Delivery

Mesenchymal stem cells (MSCs) have attracted considerable interest for therapeutic delivery owing to their multilineage differentiation capacity, low immunogenicity, and broad immunomodulatory functions. However, the development of biomaterials that simultaneously enable efficient stem cell encapsulation, minimally invasive delivery, and improved retention remains a significant challenge. Herein, we report a supramolecular granular hydrogel matrix with an intrinsic macroporous architecture designed to enhance the MSC viability and in vivo retention. The resulting granular hydrogel exhibits robust self-healing and dynamic mechanical properties arising from reversible physical interactions and can be readily processed as a three-dimensional (3D) printable ink for continuous and stable extrusion. This granular hydrogel supports long-term 3D culture of MSCs and markedly enhances cell adhesion and stemness maintenance compared with conventional two-dimensional culture conditions. In a murine cell delivery model, MSC-laden GMU granular hydrogels maintained a stable 3D matrix following injection, leading to significantly improved cell retention in vivo. These results demonstrate that the GMU granular hydrogel is a promising carrier platform for stem cell delivery and regenerative therapy.