摘要Virus-capsid mimicking mucus-permeable nanoparticles are promising oral insulin carriers which surmount intestinal mucus barrier.However,the impact of different virus-capsid mimicking structure remains unexplored.In this study,utilizing biotin grafted chitosan as the main skeleton,virus-mimicking nanoparticles endowed with biologic-shell(streptavidin coverage)and polymeric-shell(hyaluronic acid/alginate coating)were designed with insulin as a model drug by self-assembly processes.It was demonstrated that biologic-shell mimicking nanoparticles exhibited a higher intestinal trans-mucus(＞80%,10 min)and transmucosal penetration efficiency(1.6-2.2-fold improvement)than polymeric-shell counterparts.Uptake mechanism studies revealed caveolae-mediated endocytosis was responsible for the absorption of biologic-shell mimicking nanoparticles whereas polymeric-shell mimicking nanoparticles were characterized by clathrin-mediated pathway with anticipated lysosomal insulin digestion.Further,in vivo hypoglycemic study indicated that the improved effect of regulating blood sugar levels was virus-capsid structure dependent out of which biologic-shell mimicking nanoparticles presented the best performance(5.1%).Although the findings of this study are encouraging,much more work is required to meet the standards of clinical translation.Taken together,we highlight the external structural dependence of virus-capsid mimicking nanoparticles on the muco-penetrating and uptake mechanism of enterocytes that in turn affecting their in vivo absorption,which should be pondered when engineering virus-mimicking nanoparticles for oral insulin delivery.