Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

尽管在血脑屏障穿透的主动药物靶向方面取得了进展，但仍然存在两个关键挑战：首先，将靶向配体附着到药物或药物载体上并不能增强其脑生物分布；其次，许多脑部疾病与微循环障碍有着错综复杂的联系，微循环障碍会严重阻碍药物在脑部病变内的积累，甚至在药物穿过屏障后也是如此。受长春西汀调节脑血流的神经保护特性的启发，我们提出了以此类环状叔胺化合物为中心的分子库设计，并开发了一种自我增强的脑靶向核酸递送系统。我们的研究结果表明：（i）长春西汀衍生的可电离类脂纳米颗粒有效突破血脑屏障； (ii) 它们具有高基因负载能力，促进内体逃逸和细胞内运输； (iii) 即使长期使用，它们的给药也是安全的，免疫原性也很小； (iv) 它们具有有效的药理学脑保护活性，并且可能与雄性 APP/PS1 小鼠中所证明的脑部疾病治疗具有协同作用。