以阿尔茨海默病（AD）为主要疾病类型，开展脑靶向药物递送研究。以安全、有效、精准为设计理念，基于仿生构建、经鼻入脑、靶向核心致病物质和靶向小胶质细胞等关键策略，完 成一系列新型纳米递释系统的设计、构建和功能研究。构建靶向核心 致病物质并具有AD治疗活性的仿生纳米递释系统；靶向小胶质细胞，实现AD特异性细胞调控治疗；构建新型纳米递释系统，高效促进药物经鼻入脑主动转运。在本领域知名刊物发表第一/通讯作者SCI研究论文35篇，其中包括ACS Nano 3篇、Nat Commun 1篇、Biomaterials 12篇、JCR 2篇。代表性成果获美国化学会周刊报道、ACS Nano同期述评。论文他引1400 余次，单篇入选SCI高被引论文。以第一完成人获中国药学会科学技术奖二等奖、全国优博提名；主要完成人获教育部自然科学奖、科技进步奖各一项。拟开展基于AD多靶点治疗的创新仿生纳米递释系统研究。

The research focused on brain-targeted drug delivery mainly for the treatment of Alzheimer's disease (AD). To achieve safe, efficient and precise brain drug delivery, novel nanoparticulate drug delivery systems (DDS) were constructed by taking advantage of the strategies such as bionics design, nose-to-brain transport, targeting the core pathogenic substances and targeting microglia. The innovative achievements have been accomplished and highly evaluated. For example, a lipoprotein-biomimetic nanostructure was set up with dual-functions which included targeting amyloid beta (Aβ), the key pathogenic substances of AD, as well as facilitating Aβ clearance in AD. Specific cell modulation targeting microglia was achieved by utilizing nanoparticles. A series of novel nanocarriers were developed for enhanced nose-to-brain drug delivery to improve the pharmacokinetic properties of the anti-AD candidates. Based on these works in China, the applicant has published 35 SCI papers as first/corresponding author in the peer-reviewed journals such as ACS Nano, Nat Commun, Biomaterials and J Control Release. The papers have been cited more than 1400 times by other researchers, and one of them was listed as the most highly-cited SCI paper. Some findings has been reported by Chemical & Engineering News and highlighted in ACS Nano Perspective. As the first contributor, the applicant won the 2nd prize for Progress in Science and Technology awarded by Chinese Pharmaceutical Association, and received the nomination award of China Top 100 Excellent Doctoral Dissertations. As a main contributor, the applicant also won the 1st Prize for Progress in Science and the 1st Prize for Progress in Technology, awarded by the Chinese Ministry of Education. The current proposal will focus on the development of novel biomimetic nanoparticulate DDS for AD multi-target therapy.

粘膜是很多病原体入侵的主要入口，这里存在丰富的粘膜相关淋巴组织，能够引起广泛的粘膜保护；对这些病原体的预防，如果能诱导粘膜免疫应答的产生，将在“入口”降低病原体感染的几率。但是，经粘膜途径免疫，能够产生的免疫应答都比较弱。这主要是因为这些组织中存在的天然生理屏障，阻碍了抗原提呈细胞对抗原的摄取。例如鼻腔中存在的酶、鼻粘膜纤毛的运动都会加速疫苗的失活和清除。此外，鼻腔上皮也是疫苗体内传递的一道重要屏障。为此，我们成功构建了聚乙烯亚胺（PEI）聚合物作为载体、RS09为佐剂的腺病毒疫苗递送系统，PEI聚合物促进了疫苗的鼻腔滞留和摄取，RS09佐剂增强了疫苗的免疫原性，我们证实该载体是一种免疫效果好、有潜力的鼻腔疫苗递送系统。此外，我们还成功构建了基于环糊精-聚乙烯亚胺的mRNA 鼻腔疫苗传递系统和基于混合胶束的亚单位疫苗鼻腔疫苗传递系统。而对于阴道免疫来说，阴道黏膜表面厚的黏液层作为强大的物理屏障，对于外来粒子的渗透造成阻碍；同时由于疫苗的分子量很大，难以通过上皮细胞屏障，从而降低经阴道免疫的疫苗的有效性。为了克服重组腺病毒疫苗在阴道免疫中的这两重屏障，我们合成了不同分子量的阳离子 PEG 衍生物来包裹重组腺病毒载体，优选的载体不仅提供了亲水表面使腺病毒能顺利通过黏液层，还能被上皮细胞有效摄取，进而显著增强免疫应答。对小鼠采用阴道初免-肌注增强免疫的新策略，有效地诱导了针对特异性抗原的细胞、体液和粘膜免疫应答。在此研究基础上，又成功构建了一种穿膜肽TAT和PEG 同时包裹腺病毒的阴道疫苗，TAT的加入提高了转导效率，体内免疫效果得到了进一步提高。这种PEG包裹腺病毒形成的纳米复合物有希望应用于其他治疗基因的阴道给药。在本项目的资助下，共发表SCI论文22篇，其中包括Adv.Funct.Mater.1篇（IF 11.805），Biomaterials 4篇（IF 8.402）， J. Controlled Release 5 篇（IF 7.786）等；申请专利一项，在国内外权威学术会议报告10余次。