High-density Lipoprotein Inspired Lipid Nanoparticles for Systemic RNA delivery to the Brain

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.