高分子纳米药物的表面特性控制及其对细胞免疫功能的干预

Immune cells are playing intensive and pivotal roles in the development and progression of diseases. The intervention of disease-related immune cell functions is beneficial to effective disease control and prevention. Although antibodies, small molecule inhibitors, and ex vivo cell-based immunotherapy have revealed remarkable merits in modulating immune functions and favorable outcomes of disease treatments, each has its significant drawbacks and it is urgently needed to develop novel immune cell-targeting drug delivery strategies and approaches. The current proposal is grounded in the previous research and focused on "how to more efficiently regulate cell-mediated immune functions via tailoring the surface characteristics of the polymer-based nano-drugs, thereby applied to treat diverse diseases" through synthesizing a variety of polymer materials with different chemical properties and exploring immune cell-targeting drug delivery nano-carriers. The project will systematically investigate the effects of surface characteristics of nano-carriers on the distribution of nano-drugs in immune tissues and local lesions as well as the interactions between nano-drugs and immune cells, therefore to guide and screen more potent nano-drug delivery system to achieve efficient intervention of specific immune cell functions in given tissues, contributing to the enhanced immune response of vaccines, better treatment outcomes of inflammatory diseases and cancer. The project will provide theoretical support and guidance to the research and application of nano-carriers for the immunotherapy of immune-relevant diseases via the modulation of cellular immune functions.

免疫细胞与疾病发生、发展关系十分密切，干预疾病相关免疫细胞功能有助于疾病的有效控制或防治。尽管抗体、小分子抑制剂、离体细胞免疫疗法在干预免疫功能和疾病治疗方面作用明显，但各有其显著缺点，亟需发展以免疫细胞为靶细胞的药物递送手段和新策略。本项目基于前期研究基础，拟围绕“如何通过对高分子纳米药物的表面特性控制更有效干预细胞免疫功能，从而治疗疾病”的关键科学问题，通过合成不同化学特性的高分子材料，发展以免疫细胞为靶细胞的药物递送纳米载体；并将重点通过调控载体表面纳米特性，发展干预细胞免疫功能的高分子纳米药物载体，系统研究纳米特性对纳米药物在免疫器官和病灶部位的分布及其与免疫细胞的相互作用；进而优选纳米药物递送体系，实现高效干预特定器官组织中细胞的免疫功能，增强疫苗的免疫应答效果、炎症性疾病和肿瘤的治疗效果。项目研究将为干预细胞免疫功能和相关疾病治疗的药物载体研究和应用提供理论支持和指导。

本项目旨在发展以免疫细胞为靶细胞的药物递送纳米载体，利用纳米载体表面特性调控实现了高效干预免疫细胞的功能，增强了疫苗的免疫应答效果、炎症性疾病和肿瘤等的治疗效果。主要成果包括：（1）建立了调控高分子纳米药物载体表面纳米特性的方法，并在此基础上构建了不同纳米特性的载体库、可响应性调节纳米特性的iCluster载体体系及可控荷载不同种类和数量抗体分子的纳米适配子载体等；（2）系统研究了表面纳米特性影响纳米载体的体内命运及与免疫器官和细胞的相互作用；（3）利用优选的纳米载体荷载小分子药物、疫苗和免疫佐剂、CRISPR/Cas9基因编辑系统、小干扰RNA等，实现在体内调控DC细胞、巨噬细胞、中性粒细胞、T细胞、B细胞等的功能，治疗肿瘤、炎症性疾病、细菌感染等疾病。本项目的研究成果在Nat Nanotech、Nat Commun、PNAS、Adv Mater、ACS Nano、Nano Today等发表论文55篇（IF>10论文30篇），申请发明专利17项，授权专利3项，完成了预期目标。