Overexpression of BDNF by Astrocytes Targeted Delivery of mRNA Ameliorates Cognitive Impairment in Mouse Model of TBI.

Brain-derived neurotrophic factor (BDNF) plays an important role in synaptic development and plasticity. It is a promising therapeutic target for improving neurofunctional outcomes after traumatic brain injury (TBI). However, the delivery of BDNF faces several significant challenges including limited entry into the CNS due to blood-brain barrier (BBB), short half-life, and potential side effects. The use of viral vectors like AAV to deliver the BDNF gene directly to the brain has shown promise in animal models. However, issues with host immunogenicity and limited biodistribution remain. Herein, we report a successful restoration of cognitive function of a TBI mouse model by efficient delivery of BDNF mRNA loaded to a novel lipid nanoparticle (DA6 LNP). DA6 LNPs loaded with either luciferase mRNA or GFP mRNA were internalized by astrocytes and dose dependently expressed the corresponding protein. Two consecutive intravenous injections of DA6 LNPs loaded with BDNF mRNA to a TBI mouse model resulted in overexpression of BDNF in the brain and ameliorated cognitive impairment. Collectively, our data suggested that DA6 LNP is a promising carrier for CNS targeted delivery of therapeutic RNAs.