基于超分子嵌段共聚物的智能型非病毒载体的构建及应用

当前，设计开发安全高效的非病毒载体是推动基因治疗进入临床应用的关键科学问题之一。与传统共价基因载体相比，超分子基因载体具有独特的结构和性能优势，比如低的细胞毒性、优异的生物降解性及智能的环境响应性，从而在基因治疗领域具有极大的应用前景。然而，超分子基因载体在生理条件下易被解离，致使其转染效率偏低。为了实现高效的基因治疗，超分子基因载体必须具备一定的生物稳定性以使其能够克服各种细胞障碍。为此，本项目拟结合共价聚合物的生物稳定性与超分子聚合物的动态可逆性，设计制备一类结构可控、生物性能可调的超分子两嵌段共聚物。这类超分子共聚物可与DNA形成核壳纳米复合物，其不仅具有显著改善的生物稳定性和长循环能力，而且在特定的生理环境下可以实现DNA的可控释放。通过调节载体的拓扑结构、电荷密度和环境响应性，进一步优化其在肿瘤组织中的转染效力。高效智能超分子基因载体的发展为将来特异性肿瘤基因治疗提供了新契机。

Currently, the design and development of safe and efficient nonviral vectors is one of the key scientific issues for the achievement of clinical gene therapy. In contrast to conventional covalent cationic polymers, supramolecular cationic polymers have several unique structural and performance advantages, such as low cytotoxicity, excellent biodegradability and smart environmental responsiveness, thereby showing great application prospect for gene therapy. However, supramolecular gene vectors are facile to be degraded under physiological condition, leading to a remarkable decrease of gene transfection efficacy. In order to achieve highly efficient gene expression, it is necessary for supramolecular gene vectors being provided with appropriate biostability to overcome various cell obstacles. To this end, by the combination of the biostability of covalent polymers and the dynamic/reversible nature of supramolecular polymers, a class of supramolecular diblock copolymers with controllable structure and tunable biological performance can be designed and prepared. The DNA core-shell nano-polyplexes can be formed by the electrostatic interaction between cationic supramolecular copolymers and DNA, which not only exhibit greatly improved biostability and long-term systemic circulation capability, but also have the ability to release DNA in response to certain physiological environmental stimuli. By tuning the topological structure, surface charge density and environmental responsiveness of these supramolecular block copolymers, their gene transfection efficacy in tumor tissues will be further optimized. The development of highly efficient and smart supramolecular gene vectors provides an opportunity for the achievement of specific cancer gene therapy in future.