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bioRxiv · 10.64898/2026.05.27.727842

Combinatorial screening of nanoparticles for nose-to-brain RNA delivery to modulate neuroinflammation after traumatic brain injury

Xing, Y.·Do, V.·Xu, Z.·Do, C.·Yang, C.·Zhu, Z.·Gao, J.
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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 non-invasive route for brain access but is often limited by low delivery efficiency. Here we constructed a combinatorial library of DNA-barcoded 103 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 highest brain accumulation. Intranasal delivery of an antagomir targeting microRNA-9-5p loaded 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.

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Xing, Y., Do, V., Xu, Z., Do, C., Yang, C., Zhu, Z., Gao, J.. 2026-05-30. Combinatorial screening of nanoparticles for nose-to-brain RNA delivery to modulate neuroinflammation after traumatic brain injury. https://doi.org/10.64898/2026.05.27.727842

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