Zwitterionic modification can prolong the blood circulation time of nanocarrier in vivo, but zwitterionic content will affect the functions of nanocarrier such as enzyme-responsive and intracellular or extracellular delivery. Therefore, it is necessary to explore the relationship between the zwitterionic content and circulation time of nanocarrier so as to figure out what content of zwitterion can enable the nanocarrier to obtain both the long blood circulation ability and other functions mentioned above. Herein, using nanocapsule as a research model, we investigated the nanocapsule modified with zwitterion of phosphorylcholine (PC) or carboxybetaine (CB) respectively, and through ¹H-NMR quantification we determined the zwitterionic surface content, so as to study the effect of PC or CB surface content on blood circulation performance of nanocapsule. In vivo study showed that the nanocapsule possessed an optimal surface filling ratios range for blood circulation of 43–68% for PC and of 20–68% for CB, with the longest t_1/2=37.35 h for PC-nanocapsule and t_1/2=45.27 h for CB-nanocapsule. Furthermore, the protein adsorption and macrophage endocytosis experiments indicated that when the surface filling ratio reached 43% for PC-nanocapsule and 20% for CB-nanocapsule, it could effectively reduce the protein adsorption and weaken macrophage endocytosis, thus explaining the phenomenon of long circulation time of nanocapsules from the point of protein adsorption and interaction with immune cells. This study proposes a new direction for designing long-circulating nanocarrier, and provides basis for constructing enzyme-responsive and intracellular or extracellular delivery platform.

两性离子修饰可以延长纳米载体在体内的血液循环时间，但两性离子含量会影响纳米载体的酶响应和细胞内或细胞外递送等功能。因此，有必要探索纳米载体的两性离子含量与循环时间之间的关系，以找出什么样的两性离子含量才能使纳米载体同时获得长血液循环能力和上述其他功能。在此，我们以纳米胶囊为研究模型，分别研究了磷酸胆碱 (PC) 或羧基甜菜碱 (CB) 两性离子修饰的纳米胶囊，并通过¹H-NMR定量我们确定了两性离子表面含量，以研究PC或CB表面含量对纳米胶囊血液循环性能的影响。体内研究表明，纳米胶囊具有最佳的血液循环表面填充率范围，PC 为 43-68%，CB 为 20-68% ，PC-纳米胶囊最长 t _1/2 = 37.35 h，t _{1 /2}= 45.27 小时，CB-纳米胶囊。此外，蛋白质吸附和巨噬细胞内吞实验表明，当PC-纳米胶囊表面填充率达到43%，CB-纳米胶囊表面填充率达到20%时，可以有效减少蛋白质吸附，减弱巨噬细胞内吞作用，从而解释了长循环现象。从蛋白质吸附和与免疫细胞相互作用的角度来看纳米胶囊的时间。该研究为长循环纳米载体的设计提出了新的方向，为构建酶响应和细胞内或细胞外递送平台提供了基础。