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Therapeutic protein drugs are extensively successful in the treatment of several diseases including cancers, autoimmune, and infectious diseases. However, the failure of proteins to penetrate cell and tissue barriers due to the low cellular membrane permeability limits their potentials as therapeutics. Recently, cell-penetrating peptides (CPPs), a group of small amino acids sequences capable of penetrating into the plasma membrane, have been emerged as important tools for delivering molecular cargos such as nucleic acids, synthetic drugs, and therapeutic proteins to living cells. Although the exact molecular mechanisms of cellular uptake remain still unclear, numerous studies have reported that CPPs facilitate the intracellular delivery of macromolecules with superior efficacy as well as low toxicity compared to other drug carriers. These preclinical investigations showing promising results have encouraged clinician trials for a variety of therapeutic applications. Furthermore, other approaches are utilizing CPPs in stem cell manipulation, reprogramming, and genome editing to establish efficient virus-free delivery strategies. This review summarizes recent advances in intracellular protein delivery using CPPs, as well as the types and uptake mechanisms of CPPs.
