Functional hydrogel for modulating lipid droplets and neuroinflammation in head injury

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, we report a new formulation of an injectable hydrogel 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 were observed in a mouse model of TBI, andimplantation 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 droplet and promoted polarization toward a less inflammatory phenotype. In summary, our 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.