(189m) Lipid Nanoparticle Delivery for Brain-Targeted Gene Therapies

Neurological conditions are the leading cause of illness and disability worldwide, affecting brain structure and function. Many of these disorders are caused by genetic mutations or protein misfolding, leading to cellular malfunction. Gene therapies offer promising strategies to treat these disorders; however, traditional drug delivery methods have not been able to achieve potent and targeted delivery to specific brain cells. Although lipid nanoparticles (LNPs) offer a clinically viable solution for RNA delivery, their systemic administration typically results in liver accumulation. To enable brain delivery and treatments for central nervous system (CNS) diseases, we designed bioinspired LNPs including novel helper lipids that target the brain following intrathecal administration in mice. These particles efficaciously deliver mRNA to the brain without causing systemic protein expression. They are capable of multiplexed mRNA delivery in addition to potent CRISPR-mediated gene editing of numerous brain cell types, including >50% of neurons and microglia. Together, these data demonstrate the potential of this bioinspired RNA delivery strategy for unlocking targeted gene therapy for neurological disorders.