阳离子基因载体在体内的稳定性差且递送效率低，是基因治疗领域亟待解决的重要科学问题。纳米粒静脉注射后，血液中的蛋白质会在其表面形成蛋白冠状物，成为其与生物体作用的关键界面，进而影响纳米粒的体内行为。本课题创新性地利用一种能特异结合体内白蛋白的多肽对透明质酸进行修饰，然后将经修饰的透明质酸通过静电作用结合到载基因阳离子纳米粒表面，构建一种可调控蛋白冠的生成和解离的纳米递药系统。该递药系统不仅可通过特异性结合白蛋白来调控蛋白冠生成进而延长血液循环时间，提高其在肿瘤的分布，而且可以在肿瘤的酸性微环境作用下使表面的蛋白冠解离，暴露出透明质酸，进而通过CD44受体介导进入肿瘤细胞发挥疗效。本课题将以CD44受体高表达的黑色素瘤为疾病模型，miR-34a为模型药物，阐明该递药系统调控蛋白冠生成和解离的机制，为纳米载体的临床应用提供理论基础和实验依据。

Cationic gene vectors are not stable in the body and their delivery efficiency is limited, which is an important scientific problem to be solved in the field of gene therapy. After intravenous injection of nanoparticles, the protein in the blood will form a layer of protein corona on their surface, which becomes the key interface of their interaction with the organism and affects the in vivo behavior of nanoparticles. In this study, the hyaluronic acid is modified by a polypeptide that specifically binds to the endogenous albumin, and then the modified hyaluronic acid is bound to the surface of the gene loaded cationic nanoparticles by electrostatic interaction to construct a nanoparticulate drug delivery system which could modulate the formation and dissociation of protein corona. The delivery system could modulate the formation of protein corona via specifically binding albumin and thus extend the blood circulation time of the nanoparticles and increase their distribution in the tumor. After reaching the tumor site, the nanoparticles could dissociate the protein corona in the acidic tumor microenvironment and expose the hyaluronic acid. Subsequently, the nanoparticles could enter the tumor cells via the CD44 receptor and exert the pharmacological effects. In the study, the melanoma with high expression of CD44 receptor was selected as the disease model and the miR-34a was used as the model drug to elucidate how the delivery system modulated the formation and dissociation of protein corona, providing theoretical and experimental basis for the clinical application of nanocarrier.