High-density Lipoprotein Inspired Lipid Nanoparticles for Systemic RNA delivery to the Brain
Abstract
Systemic delivery of nucleic acids to the central nervous system (CNS) remains fundamentally limited by the blood-brain barrier (BBB) and the lack of cell-type specificity. Inspired by endogenous high-density lipoproteins (HDLs) that naturally traverse the BBB, we engineered a library of 112 HDL-inspired lipid nanoparticles (HLNPs) to deliberately program protein corona composition and direct nanoparticle trafficking across the BBB. High-throughput in vivo screening identified HLNPs with robust brain accumulation and preferential enrichment within distinct neural cell populations. Quantitative proteomic analysis revealed that elevated apolipoprotein A-I/apolipoprotein E and vitronectin/apolipoprotein E ratios correlate with enhanced BBB transport. We further demonstrated that neuron-targeted HLNPs delivering PTEN siRNA produced functional recovery and lesion reduction in a murine traumatic brain injury model, while microglia-targeted HLNPs carrying interleukin-10 mRNA potently suppressed neuroinflammation. Together, these findings establish HLNPs as a versatile RNA delivery platform that leverages protein corona programming for enhanced brain delivery and cell-type-selective targeting.
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Research works printed but not linked: 2
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- Authors
- Xu, Z., Shalin, K., Do, V., Yan, A., & Gao, J.
- Affiliations
- Department of Biomedical Engineering
- University of Massachusetts Amherst (US)
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2026-06-01
- OpenAlex
- W7163123713
- Cited by
- 0
- References
- 43
- Type
- posted content
- Open access
- closed
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- blood-brain barrier, protein corona, apolipoprotein A-I, apolipoprotein E, vitronectin, cell type-specific targeting, traumatic brain injury, IL-10, neuroinflammation, nanoparticle trafficking
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