Lipoic Acid‐Intervened Decellularized Stem Cell Spheroid‐Based Injectable Granular Gel for Diabetic Tissue Regeneration

ABSTRACT Advancements in tissue engineering have revolutionized therapeutic paradigms for diabetic tissue defects; however, the lack of applicable scaffold containing various bioactive substance aggregates remained a critical bottleneck hindering satisfactory repair effect. In this study, adipose‐derived stem cells (ADSCs) were functionally re‐engineered using lipoic acid (LA) to fabricate a novel LA‐intervened stem cell spheroid (LA‐SCS) with enhanced paracrine activity and extracellular matrix (ECM) biosynthetic capacity. Subsequent decellularization mitigated immunogenicity, yielding LA‐intervened decellularized stem cell spheroid (LA‐dSCS). In vitro assays confirmed its immunomodulatory potency, as evidenced by the activation of signaling cascades associated with macrophage reprogramming, homeostasis, and autophagy. Furthermore, leveraging the intrinsic viscoelastic properties of the LA‐dSCS, a convenient preparation method for preparing LA‐dSCS derived injectable material was established, wherein LA‐dSCS micro‐particles assemble into LA‐dSCS granular gel. In vivo studies using diabetic rat models demonstrated closure of both wound and cranial defects. Collectively, this study established a biomimetic engineering strategy that integrates cell‐free bioactive aggregates with injectable granular gels, offering a novel proof‑of‑concept strategy for the regeneration of complex diabetic tissue defects.