血脑屏障是药物治疗脑部疾病效果不佳的主要因素。迄今，还没有穿透血脑屏障的药物载体上市。申请人根据仿生原理，制备了纳米铁蛋白粒子，首次在国际上证明其天然靶向肿瘤的特性 (Nat Nanotech 2012)。随后，又证明其有效携带化疗药物并精准到达肿瘤部位，显著抑制肿瘤的生长与转移 (PNAS 2014)。更重要的是，最近发现铁蛋白具有穿越血脑屏障的能力，然而其分子机制尚不清楚。据此，本项目将以原位神经胶质瘤为模型，系统研究纳米铁蛋白载体穿越血脑屏障的分子机制，解析铁蛋白与其受体相互作用的分子结构基础，探讨其抑瘤效果、生物安全性及给药机制，发展一种既能穿越血脑屏障，又能靶向脑瘤的新型药物载体，为脑瘤治疗提供新策略。

The blood-brain barrier (BBB) is a physiologic obstruction to the delivery of systemic chemotherapy to the brain parenchyma and central nervous system (CNS) to treat brain diseases. A drug carrier which could cross the BBB effectively is urgently needed. Our previous work found that H-ferritin(HFn) can naturally target to tumor cells (Nature Nanotechnol, 2012), and based on this finding, we design a novel HFn-based antitumor drug delivery system, which could deliver high dose of drugs to tumor cells and inhibit the growth of tumor by only one dose (PNAS, 2014). Recently, our preliminary data demonstrated that HFn can cross the BBB effectively, but the molecular mechanisms are still unclear. In this application, employing the glioma orthotopic models, we will study the mechanisms of HFn crossing BBB and specific targeting property of HFn nanocarrier for barin tumors, analyze the structure of HFn-TfR1 complex to identify the binding site and binding affinity of HFn to TfR1, evaluate the biosafty and the antitumor activity of HFn nanocarrier in vivo, and identify the relevant molecular mechanisms. This study will pave the way for the clinical translation of a novel drug delivery vehicle effectively crossing the blood-brain barrier to target to brain tumors.