Science
High-density Lipoprotein Inspired Lipid Nanoparticles for Systemic RNA delivery to the Brain
Key Points
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...
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.