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Intracellular transduction and potential of Tat PTD and its analogs: from basic drug delivery mechanism to application

Introduction: It has been 20 years since the discovery of the membrane-translocating property of the HIV-1 transactivator of transcription (Tat) protein. The Tat protein transduction domain (Tat PTD) is a very promising tool for non-invasive cellular import of cargos and has been successfully applied to in vitro and in vivo delivery of different therapeutic agents for the treatment of many diseases. A growing number of reports on Tat PTD-mediated delivery have extensively revealed the mechanisms involved. Yet, due to the varied conditions used, the reports on the internalization mode of Tat PTD-cargo chimera are often varied. Areas covered: This article reviews the possible intracellular trafficking mechanisms of Tat PTD including its binding, cellular entry process, and the roles of participants of the cell membrane. The therapeutic applications via local administration, such as those for the treatment of skin, ocular, cardiac and cerebral diseases, are also reviewed. In addition, some novel systems built by different groups are elucidated, which are utilized to overcome the poor targeting efficiency of Tat PTD for the treatment of CNS diseases, cancer and other diseases via systemic administration. Expert opinion: With the development of targeting factors, such as antibodies, some cell targeting peptides and novel polymers, Tat PTD is expected to play a more efficient and/or better tolerated therapeutic role in the drug delivery field.