Combinatorial Screening of Nanoparticles for Nose-to-Brain RNA Delivery to Modulate Neuroinflammation after Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI)-induced neuroinflammation can evolve over weeks or months, contributing to ongoing secondary damage and worsening neurological recovery. RNA-based therapeutics hold great potential to regulate inflammatory signaling, but delivery to the brain remains challenging because of the blood–brain barrier. Intranasal administration offers a direct, noninvasive route for brain access but is often limited by low delivery efficiency. Here, we constructed a combinatorial library of 103 DNA-barcoded lipid nanoparticles by varying lipid components with diverse headgroup chemistries and bioreactive moieties. A high-throughput screening of these nanoparticles in vivo following intranasal administration led to the identification of top candidates with the highest normalized DNA barcode brain delivery. Intranasal delivery of an antagomir targeting microRNA-9-5p loaded in a nanoparticle effectively reduced cerebral microRNA-9-5p levels, suppressed inflammatory markers, and improved neurological outcomes in TBI. These results demonstrate a systematic approach for optimizing intranasal lipid nanoparticle design and support the feasibility of RNA delivery to modulate neuroinflammation after brain injury.