The limitations imposed on brain therapy by the blood–brain barrier (BBB) have warranted the development of carriers that can overcome and deliver therapeutic agents into the brain. We strategically designed liposomal nanoparticles encasing plasmid DNA for efficient transfection and translocation across the in vitro BBB model as well as in vivo brain-targeted delivery. Liposomes were surface modified with two ligands, cell-penetrating peptide (PFVYLI or R9F2) for enhanced internalization into cells and transferrin (Tf) ligand for targeting transferrin-receptor expressed on brain capillary endothelial cells. Dual-modified liposomes encapsulating pDNA demonstrated significantly (P < 0.05) higher in vitro transfection efficiency compared to single-modified nanoparticles. R9F2Tf-liposomes showed superior ability to cross in vitro BBB and, subsequently, transfect primary neurons. Additionally, these nanoparticles crossed in vivo BBB and reached brain parenchyma of mice (6.6%) without causing tissue damage. Transferrin receptor-targeting with enhanced cell penetration is a relevant strategy for efficient brain-targeted delivery of genes.

血脑屏障（BBB）对脑部治疗造成的限制需要开发能够克服血脑屏障并将治疗药物输送到大脑中的载体。我们战略性地设计了包裹质粒 DNA 的脂质体纳米颗粒，用于在体外BBB 模型中有效转染和易位以及体内脑靶向递送。脂质体用两种配体进行表面修饰，细胞穿透肽（PFVYLI 或 R9F2）用于增强细胞内化，转铁蛋白（Tf）配体用于靶向脑毛细血管内皮细胞上表达的转铁蛋白受体。与单修饰纳米颗粒相比，封装 pDNA 的双修饰脂质体具有显着更高的体外转染效率（ P < 0.05）。 R9F2Tf-脂质体表现出优异的体外BBB 交叉能力，并随后转染原代神经元。此外，这些纳米粒子穿过体内BBB 并到达小鼠 (6.6%) 的脑实质，而不会造成组织损伤。具有增强细胞渗透性的转铁蛋白受体靶向是有效脑靶向基因递送的相关策略。