Oligoarginine vectors for intracellular delivery: design and cellular-uptake mechanisms

Intracellular delivery using membrane-permeable peptide vectors is a recently developed methodology that has been employed successfully to transport various bioactive molecules into cells to modify cell functions. The efficient delivery of proteins, peptides, nucleic acids, liposomes, and so on has been accomplished using this methodology by conjugation of a peptide vector with the cargo molecules. The potentials of this approach for medical and pharmaceutical applications has also attracted our attention. Arginine-rich peptides, including a basic peptide segment derived from the human immunodeficiency virus type 1 (HIV-1) Tat protein, are categorized into one of the most frequently used peptide vectors, and the efforts of designing novel vectors have been ongoing. Internalization of these peptides has previously been regarded as not employing endocytosis. However, recent reevaluations have demonstrated the significant involvement of endocytosis in the cellular uptake of these peptides. These arginine-rich peptide vectors share many common features in internalization. However, there seem to be certain simultaneous dissimilarities observed in the modes of internalization among these peptides. In this review, the structural features of these arginine-rich peptide vectors have been focused on and the current understandings of their internalization mechanisms are summarized.