A novel brain-targeted delivery system, VIP (vinpocetine-derived ionizable-lipidoid nanoparticles), was developed to enhance the delivery of nucleic acid drugs to the brain. This system leverages the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, to improve brain targeting. VIP nanoparticles efficiently cross the blood-brain barrier, have high gene-loading capacity, and facilitate endosomal escape and intracellular transport. They are safe with minimal immunogenicity and exhibit potent pharmacologic brain-protective activity. VIP was tested in various brain disease models, including Alzheimer's disease (AD), brain tumors, and fungal meningitis, demonstrating effective delivery of siRNA, mRNA, and small-molecule drugs. VIP showed enhanced brain targeting through selective regulation of cerebral blood flow, efficient loading and delivery capacity, and reduced toxicity compared to existing ionizable lipid systems. In AD models, VIP@siBACE1 significantly improved cognitive performance and reduced amyloid plaques and tau pathology. VIP also showed promise in treating fungal meningitis by enhancing drug delivery and reducing fungal burden. VIP demonstrated good biocompatibility and safety, with no significant toxicity or immunogenicity. The study highlights the potential of VIP as a versatile delivery platform for brain-targeted therapies, combining the benefits of cerebral blood flow regulation and nucleic acid delivery. The findings suggest that VIP-based strategies may have multidimensional therapeutic effects, offering a promising approach for the treatment of brain diseases.A novel brain-targeted delivery system, VIP (vinpocetine-derived ionizable-lipidoid nanoparticles), was developed to enhance the delivery of nucleic acid drugs to the brain. This system leverages the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, to improve brain targeting. VIP nanoparticles efficiently cross the blood-brain barrier, have high gene-loading capacity, and facilitate endosomal escape and intracellular transport. They are safe with minimal immunogenicity and exhibit potent pharmacologic brain-protective activity. VIP was tested in various brain disease models, including Alzheimer's disease (AD), brain tumors, and fungal meningitis, demonstrating effective delivery of siRNA, mRNA, and small-molecule drugs. VIP showed enhanced brain targeting through selective regulation of cerebral blood flow, efficient loading and delivery capacity, and reduced toxicity compared to existing ionizable lipid systems. In AD models, VIP@siBACE1 significantly improved cognitive performance and reduced amyloid plaques and tau pathology. VIP also showed promise in treating fungal meningitis by enhancing drug delivery and reducing fungal burden. VIP demonstrated good biocompatibility and safety, with no significant toxicity or immunogenicity. The study highlights the potential of VIP as a versatile delivery platform for brain-targeted therapies, combining the benefits of cerebral blood flow regulation and nucleic acid delivery. The findings suggest that VIP-based strategies may have multidimensional therapeutic effects, offering a promising approach for the treatment of brain diseases.