Low‐Crosslinked Hydrophilic Decellularized Adipose Matrix Hydrogels Achieve Efficient and Functional Xenotransplant Fat Regeneration by Optimizing Stem Cell Niche

Abstract Xenogeneic decellularized adipose matrix(DAM) scaffolds are significant in soft tissue regeneration by addressing donor site morbidity and limited donor availability. However, natural DAM xenotransplantation remains unachieved. Previous efforts have relied on chemical modifications to reduce foreign body reactions, with inherent drawbacks and limited outcomes. This xenotransplantation study proposes a natural DAM hydrogel scaffold that achieves efficient and functional xenotransplant fat regeneration. Primarily, hydrophilic DAM(H‐DAM) is confirmed to have lower antigen content, but its regenerative potential is constrained by encapsulation that impedes seed cell infiltration. Thus, H‐DAM hydrogel is prepared to enhance the speed and extent of cell infiltration. It is observed that the topological structure impacts cell infiltration, immune inflammatory response, and regenerative outcomes. Low‐crosslinked hydrogels emerged as optimal for adipogenic differentiation due to loose networks and natural degradation rates synchronizing with cell infiltration. Furthermore, the wall‐like rather than filamentous structure provides a superior niche for stem cell engraftment and activity. Finally, integrated multi‐omics data analysis demonstrated that the regenerated fat tissue functionally mimics native fat tissue. These findings indicate that xenogeneic H‐DAM gel scaffolds support both structural and functional reconstruction of adipose tissue, offering novel insights and a promising approach for clinical translation in DAM‐based therapies.