Intravenously Delivered Lipid Nanoparticles Access Acute Spinal Cord Injury via Disrupted Vasculature.

Trauma to the spinal cord disrupts the blood-spinal cord barrier and triggers a secondary injury cascade characterized by inflammation and progressive neuronal and glial cell death. Therapeutic cytokines and growth factors have shown promise as a treatment in preclinical studies, though their clinical translation is limited by short protein half-lives and the need for invasive intraspinal administration. Lipid nanoparticle-mediated delivery of mRNA offers an alternative strategy that enables transient protein production. Here, we investigated whether intravenously administered mRNA-lipid nanoparticles could leverage the injury-induced disruption of the blood-spinal cord barrier to access the injured spinal cord for local transgene expression. After spinal cord injury in a rat, lipid nanoparticles loaded with reporter mRNA were administered intravenously, and transgene expression was quantified in the spinal cord and peripheral organs. Intravenous delivery within a 6-hours post-injury resulted in local transgene expression in the injured spinal cord, demonstrating that mRNA-lipid nanoparticles cross the disrupted blood-spinal cord barrier. Transgene expression was observed in astrocytes, oligodendrocytes, microglia, and neurons, detected within 3 hours and remained elevated for up to 5 days post-injury. These findings demonstrate that systemic mRNA-lipid nanoparticles delivery exploit transient blood-spinal cord barrier disruption to achieve local gene expression in the injured spinal cord.