Encapsulating Therapeutic Proteins with Polyzwitterions for Lower Macrophage Nonspecific Uptake and Longer Circulation Time

Numerous efforts have been made to promote the efficiency of protein delivery through tuning the protein surface properties such as grafting polymers on protein surface, but limited successes have been achieved, and their great clinical expectation has not yet been realized. The main reason is that proteins are readily recognized as foreign materials under physiological conditions due to the genetic distance between species, leading to rapid decrease in activity and clearance by mononuclear phagocyte system. In this study, we encapsulated proteins within nonfouling polyzwitterionic shells, which offer the protein with the significantly improved stability, reduced phagocytosis, and prolonged circulation time. Exemplified with urate oxidase (UOx), the encapsulated UOx noted as n(UOx) could facilely escape from macrophage uptake in medium with or without serum. In contrast, the native protein rapidly induced high-uptake and accumulated into the macrophages under the same conditions. Moreover, the similar result is also observed in liver-resident kupffer cells, which were isolated from the mice after treated with fluorescent-labeled native UOx and n(UOx). Furthermore, n(UOx) exhibited significantly improved stability in vivo and a more than eightfold improvement in circulation time when compared with native UOx. Because of its superior ability to reduce macrophage uptake and promote the circulation time, this technique also makes it an ideal candidate for the enhancement of targeting efficiency in drug delivery and biodetection, which affords an alternative method for diverse medical applications.