The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood–brain barrier (BBB) penetrance. These challenges signify an unmet need for drug carriers that can cross the BBB and deliver drugs to targeted sites with high drug-loading efficiency and long-term stability. We herein leverage the enhanced stability and targeting ability of engineered high-density lipoprotein-mimetic nanoparticles (eHNPs) to cross the BBB and deliver a SHH inhibitor effectively to the cancer stem-like cell population in SHH MB. Our microfluidic technology enabled highly reproducible production of multicomponent eHNPs incorporated with apolipoprotein A1, anti-CD15, and a SHH inhibitor (LDE225). We demonstrate the dual-targeted delivery and enhanced therapeutic effect of eHNP-A1-CD15-LDE225 via scavenger receptor class B type 1 (SR-B1) and CD15 on brain SHH MB cells in vitro, ex vivo, and in vivo. Moreover, we show that eHNP-A1 not only serves as a stable drug carrier, but also has a therapeutic effect itself through SR-B1-mediated intracellular cholesterol depletion in SHH MB cells. Through the facilitated and targeted cellular uptake of drugs and direct therapeutic role of this engineered biomimetic nanocarrier in SHH MB, our multifunctional nanoparticle provides intriguing therapeutic promise as an effective and potent nanomedicine for the treatment of SHH MB.

髓母细胞瘤（SHH MB）的声音刺猬亚型与治疗失败和不良预后相关。利用全脑放射疗法的当前策略导致对正常发育的儿童大脑有害的脱靶效应。大多数常规化学疗法仍然受到无效的血脑屏障（BBB）渗透性的限制。这些挑战表明对可以跨过血脑屏障并以高载药效率和长期稳定性将药物运送到目标部位的药物载体的需求尚未得到满足。我们在本文中利用工程化的高密度脂蛋白模拟纳米颗粒（eHNPs）增强的稳定性和靶向能力来穿越BBB，并向SHH MB中的癌干样细胞群有效递送SHH抑制剂。我们的微流控技术能够高度可重复地生产载有载脂蛋白A1，抗CD15和SHH抑制剂（LDE225）的多组分eHNP。我们证明了eHNP-A1-CD15-LDE225通过清除剂受体B类1型（SR-B1）和CD15在体外，离体和体内对大脑SHH MB细胞的双重靶向递送和增强的治疗效果。此外，我们显示eHNP-A1不仅充当稳定的药物载体，而且还通过SR-B1介导的SHH MB细胞中的胆固醇减少而自身具有治疗作用。通过促进药物的靶向吸收以及这种工程仿生纳米载体在SHH MB中的直接治疗作用，我们的多功能纳米颗粒作为治疗SHH MB的有效而有效的纳米药物提供了令人感兴趣的治疗前景。