口服给药安全方便，但基因口服给药面临胃肠道剧变的pH、多种核酸酶、黏膜上皮等多重屏障，使其稳定通过胃肠道并高效递送至靶组织及靶细胞是极具挑战性的难点，必须借助安全有效的递送载体。故需对基因口服高效递送载体的合理设计及作用机制进行系统深入研究。根据我们已有的工作基础，设计、筛选和制备可同时调节纳米粒粒径、表面电荷、亲疏水性和黏膜黏附性的壳聚糖类聚合物纳米粒作为递送载体。系统研究载体理化性质对其包载基因（pDNA）及释放、保持基因在递送过程中的稳定性、克服多重递送屏障、肠道吸收并高效转运至靶组织和靶细胞的影响及机制。全面解析纳米递送载体的理化性质对基因口服高效递送的影响规律。根据机理研究结果合理设计基因口服递送载体，包载Survivin shRNA表达pDNA（shSur-pDNA），进行体内外转染效果与治疗功效研究及机制验证。为基因口服高效递送系统的合理设计提供理论和方法指导。

Despite the easiness of oral administration, it is a challenging task for genes to remain stable in the gastrointestinal (GI) tract and arrive at the target tissues and cells owing to multiple obstacles including dramatic pH change in the GI tract, abundant nuclease, and mucous epithelia, which called for safe and efficient gene delivery vehicles. Consequently, comprehensive investigations on the rational design and mechanisms of gene delivery systems are significant for improved in vivo therapeutic efficacy after oral administration. Based on our previous studies, in the current project, chitosan-based nanoparticles with simultaneously controllable particle size, potential, hydrophobicity/hydrophilicity, and mucoadhesive property were designed, screened, and synthesized as oral gene delivery vectors. The impact and mechanisms of physiochemical properties of nanoparticles exerted on the encapsulation efficiency toward plasmid DNA (pDNA), release profile, gene stability, overcoming multiple delivery barriers, intestinal adsorption, and efficiently arriving at target tissues and cells were investigated. These studies would favor revealing how the physiochemical properties of nanocarriers influence the efficiency of oral gene delivery. Optimal delivery vehicle, which was rationally designed and synthesized according to the resultant mechanisms, was employed to encapsulate Survivin shRNA expressing pDNA (shSur-pDNA). In vitro and in vivo transfection efficiency and in vivo therapeutic efficacy were studied for further verification of the mechanisms. These results would shed light on the rational design of oral gene delivery systems with maximized therapeutic efficacy.