对肿瘤微环境具有灵敏响应的高分子纳米载体能够实现在病变部位的选择性富集和药物释放。基于肿瘤细胞内含巯基生物活性分子(如谷胱甘肽等)浓度较高的特点，能够设计含二硫键的高分子纳米药物载体并实现胞内还原性微环境响应的特异性药物输运。针对目前还原性响应纳米载体的设计主要依赖于二硫键-自由巯基平衡交换反应的局限性，本申请项目拟设计能与含巯基生物分子发生迈克尔加成/亲核取代反应的两亲性聚合物囊泡载体，利用这些高效化学反应触发囊泡双层膜的微结构和亲疏水性发生转变，以调控所负载活性物质的释放和跨膜传输；同时，含巯基分子参与的反应将触发荧光信号显著变化，从而实现囊泡渗透性和药物释放过程的可视化；还拟进一步结合酶催化反应和酶促产物的连锁触发能力，构建囊泡双层膜的渗透性、药物释放速率和荧光信号增强程度都具有正反馈和循环放大特征的仿生纳米载体体系。相关研究结果预期将为新一代纳米药物载体的设计提供新思路和重要参考。

Polymeric nanocarriers sensitively responding to tumor microenvironments could achieve selective accumulation and drug release at the disease site. By taking advantage of the high content thiol-containing bioactive molecules (e.g., GSH) within tumor cells, disulfide-containing polymeric drug nanocarriers have been designed, aiming to achieve site-specific drug delivery triggered by intracellular reductive microenvironments. However, the current design of reduction-sensitive polymeric nanocarriers mainly relies on equilibrium exchange reactions between free thiols and disulfide linkages. In this proposal, we attempt to design polymersomes of amphiphilic polymers which could react with thiol-containing bioactive molecules via Michael addition or nucleophilic substitution mechanisms. These high-efficiency reactions will trigger transformation of the microstructure and hydrophobicity/hydrophilicity of polymersome bilayers, thus modulating the release profile and membrane transport of encapsulated bioactive agents; concurrently, thiol-involved reactions will trigger prominent changes of fluorescence signals, achieving image-guided in situ monitoring of changes in polymersome permeability and drug release process; we attempt to further integrate enzymatic reactions and the triggering capability of enzymatic products, and to construct biomimetic nanocarrier systems exhibiting positive feedback and circle amplification features in the context of polymersome permeability, drug release rate, and the extent of fluorescence signal enhancement. Research results of this proposal are expected to provide new insights and important guide for the design of next-generation smart drug nanocarriers.