Insulin therapy plays an essential role in the treatment of diabetes mellitus.However,frequent injections required to effectively control the glycemic levels lead to substantial inconvenience and low patient compliance.In order to improve insulin delivery,many efforts have been made,such as developing the nanoparticles(NPs)-based release systems and oral insulin.Although some improve-ments have been achieved,the ultimate results are still unsatisfying and none of insulin-loaded NPs sys-tems have been approved for clinical use so far.Recently,nano-protein interactions and protein corona formation have drawn much attention due to their negative influence on the in vivo fate of NPs systems.As the other side of a coin,such interactions can also be used for constructing advanced drug delivery systems.Herein,we aim to provide an insight into the advance and flaws of various NPs-based insulin delivery systems.Particularly,an interesting discussion on nano-protein interactions and its potentials for developing novel insulin delivery systems is initiated.