In situ delivery of cannabidiol-loaded GelMA sponge attenuates cerebral edema and neuroinflammation in traumatic brain injury

Traumatic brain injury (TBI) remains a major cause of severe disability, and its secondary injury remains a key focus of interventional research. Cannabidiol (CBD) has neuroprotective potential, but conventional systemic administration still has limitations. In this study, we fabricated an in situ -implantable cannabidiol-loaded methacrylated gelatin (GelMA) sponge (GM-CBD) with short-term cytocompatibility and hemocompatibility and no detectable in vivo abnormalities. Under a non-equivalent dosing regimen, GM-CBD and intraperitoneally injected CBD (10 mg/kg) showed distinct concentration–distribution profiles: in the GM-CBD group, CBD continuously accumulated in the perilesional cortex over 48 h, whereas serum CBD remained persistently low. In a Feeney-model rat TBI model, combined behavioral and neuropathological evaluation identified a single sponge loaded with a nominal 15 μg CBD as the working dose. At this dose, GM-CBD reduced neurological deficit scores, altered locomotor and exploratory behaviors in TBI rats, and attenuated neuronal injury and apoptosis. GM-CBD concurrently upregulated tight junction proteins and CD31+ endothelial cell expression, downregulated GFAP+ astrocyte proliferation, and altered AQP4 distribution, thereby improving blood–brain barrier integrity and alleviating post-traumatic cerebral edema. Furthermore, GM-CBD decreased IL-6, IL-1β, and TNF-α levels, increased IL-10, and inhibited microglial activation, suggesting attenuated acute neuroinflammation after TBI. Transcriptomic sequencing further showed that GM-CBD-associated differentially expressed genes were mainly involved in immune, stress, and inflammatory responses, with significant enrichment of the NF-κB, PI3K-Akt, and TNF signaling pathways. In summary, GM-CBD provides an in situ sustained-release strategy that exerts neuroprotection by attenuating post-traumatic cerebral edema and neuroinflammation.