Lipid Nanoparticles for RNA Delivery to the Central Nervous System: Biological Barriers, Engineering Strategies, and Therapeutic Applications

Abstract Lipid nanoparticles (LNPs) have emerged as an adaptable platform for the delivery of therapeutic RNA, as demonstrated by the clinical success of mRNA vaccines and RNA interference therapies. Despite this progress, translation of RNA LNPs to diseases of the central nervous system (CNS) remains challenging due to multiple biological barriers that restrict access to neural tissue and target cells. Beyond crossing the blood-brain barrier and related CNS interfaces, further obstacles include efficient tissue distribution, cell-specific uptake, and intracellular RNA delivery. This review summarizes CNS-relevant delivery routes, key anatomical and cellular barriers limiting therapeutic access to neural tissues, major therapeutic RNA modalities, and the chemical composition and design principles of LNPs. We further discuss engineering strategies developed to overcome these obstacles and highlight emerging therapeutic applications across neuro-oncology, acute CNS injury, and neurodegenerative disorders. Collectively, RNA LNPs demonstrate potential as a versatile carrier system for neurological disease. However, further advances in delivery strategies will likely be needed to improve brain access, distribution, cell-specific targeting, and intracellular RNA delivery across diverse CNS applications.