工程化仿生PEG/PLA纳米颗粒通过选择性自噬清除胞内亨廷顿异聚蛋白的研究

Most of the neurodegenerative disorders are caused by the accumulation of intracytoplasmic aggregate-prone proteins. Metabolic system in eukaryocyteis is composed of ubiquitin-proteasome system and autophagy-lysosomal pathway. As the protein aggregates in neurodegenerative disorder cells are too large to gain access to the proteasome cavities， these aggregate-prone proteins are mainly degraded by autophagy. Thus， elevating the autophagy level to enhance degradation of these proteins presents an emerging viable approach for the treatment of neurodegenerative diseases. Our previous study showed that, inorganic nanomaterials could effectively enhance the clearance of mutant huntingtin, the aggregate-prone protein underlying the pathogenesis of HD. However, inorganic nanomaterials could not distinguish the aggregates and specifically target these aggregates for degradation, additionally, these nanoparticles cannot be metabolically degraded, all of these restrict their clinicalapplication. Based on the crucial role of receptor protein in selective autophagy, we proposed and designed an engineered bionic Organic nanomaterials PEG/PLA, imitating the function of autophagy receptor，for the first time. When autophagy was induced, these bionic nanomaterials can specifically bind protein aggregates and autophagy related protein LC3 through peptides modified on the surface, which can improve the recognition efficiency and degradation specificity. In addition, its degradability increased the clinical application of this bionic nanomaterials.

大多神经退行性疾病是由于细胞内具有聚集倾向的变异蛋白的堆积造成的。由于泛素蛋白酶体系统的尺寸限制等原因，自噬则成为蛋白异聚体的主要降解途径。因此，通过提高自噬水平来加强对蛋白异聚体的降解能力是治疗神经退行性疾病的有效方案。我们前期工作显示，无机纳米材料可通过提高细胞自噬水平加速胞内蛋白异聚体的降解。但其对蛋白异聚体的识别力不足引发的异聚体降解特异性差及材料本身比较难降解等因素限制了无机纳米材料的临床应用。基于选择性自噬过程中自噬接头蛋白的关键性作用，我们创新性地提出工程化仿生纳米颗粒模拟自噬接头蛋白通过选择性自噬特异性降解亨廷顿异聚蛋白的理念，设计合成的仿生纳米颗粒PEG/PLA能够通过表面修饰肽高效进入细胞并同时特异性结合亨廷顿异聚蛋白及自噬相关蛋白LC3，在自噬发生时展示出对亨廷顿异聚蛋白高度的识别力及强大的降解能力。同时该仿生纳米颗粒本身的可降解特性也大大增加了其临床应用的潜力。

基于目前神经退行性疾病治疗的局限性，本项目发现了一批可有效降解蛋白异聚体，从而改善疾病鼠认知及运动协调功能的纳米材料。包括氧化石墨烯通过最大限度地减轻淀粉样蛋白聚集体生成改善疾病模型鼠术后认知功能障碍；MnFe2O4纳米材料通过泛素-蛋白酶体途径降解异聚蛋白；工程化仿生PEG/PLA纳米颗粒通过选择性自噬清除胞内亨廷顿异聚蛋白等，为纳米材料在神经退行性疾病临床治疗中的应用提供了新策略新方法。此外，利用工程化PEG/PLA表面修饰功能多肽及利用多肽调控诊疗用纳米颗粒体内诊疗效果这一创新思想，我们通过体内噬菌体筛选技术发现了能够显著延长体内循环时间的延时肽，并将其修饰的纳米颗粒应用于抗肿瘤治疗及抗菌治疗的研究中，取得了一批有特色、有影响的研究成果。