Functional Hydrogel for Modulating Lipid Droplets and Neuroinflammation in Head Injury

Abstract Excessive inflammatory responses following traumatic brain injury (TBI) hinder tissue healing and impair long‐term functional recovery. In addition to therapeutic strategies that directly target the core pathological mechanisms of TBI, biomaterials and regenerative medicine now offer promising new avenues. Here, a new formulation of an injectable hydrogel is reported, based on gelatin methacryloyl (GelMA) conjugated with β‐cyclodextrin (βCD), designed for implantation in TBI lesions. Compared to GelMA alone, βCD‐containing hydrogels (βCD‐GelMA) demonstrated a strong capacity to sequester cholesterol from cultured cells, thereby reducing lipid droplet formation and suppressing inflammatory responses. Notably, aberrant cholesterol accumulation and lipid droplet formation are observed in a mouse model of TBI, and implantation of βCD‐GelMA into the lesion area significantly reduced peak tissue cholesterol and lipid droplet levels post‐injury. More importantly, βCD‐GelMA mitigated gliosis, reduced inflammation and scar formation, and improved functional outcomes in the TBI model. Mechanistically, by scavenging cholesterol from injured tissue, βCD‐GelMA normalized microglial lipid droplets and promoted polarization toward a less inflammatory phenotype. In summary, this study highlights the strong therapeutic potential of βCD in restoring cholesterol homeostasis and resolving lipid droplet‐associated inflammation, and demonstrates that the βCD‐GelMA functional hydrogel represents a promising intervention strategy for head injuries.