Full text linksMultidisciplinary Digital Publishing Institute (MDPI)Free PMC article 1 Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China. munyendollw@yahoo.com. 2 Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China. lvhuixia@163.com. 3 Institut de Chimie Pharmaceutique Albert Lespagnol (Lille 2) (ICPAL), 3 rue du Professeur Laguesse 59006, France. biba0707@live.com. 4 Department of Pure and Applied Chemistry, Masinde Muliro University of Science and Technology, P.O. Box 190-50100, Kakamega, Kenya. danstone_baraza@yahoo.com. 5 Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China. iamzhoujianping@163.com. 1 Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China. munyendollw@yahoo.com. 2 Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China. lvhuixia@163.com. 3 Institut de Chimie Pharmaceutique Albert Lespagnol (Lille 2) (ICPAL), 3 rue du Professeur Laguesse 59006, France. biba0707@live.com. 4 Department of Pure and Applied Chemistry, Masinde Muliro University of Science and Technology, P.O. Box 190-50100, Kakamega, Kenya. danstone_baraza@yahoo.com. 5 Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, China. iamzhoujianping@163.com. The cell membrane is a highly selective barrier. This limits the cellular uptake of molecules including DNA, oligonucleotides, peptides and proteins used as therapeutic agents. Different approaches have been employed to increase the membrane permeability and intracellular delivery of these therapeutic molecules. One such approach is the use of Cell Penetrating Peptides (CPPs). CPPs represent a new and innovative concept, which bypasses the problem of bioavailability of drugs. The success of CPPs lies in their ability to unlock intracellular and even intranuclear targets for the delivery of agents ranging from peptides to antibodies and drug-loaded nanoparticles. This review highlights the development of cell penetrating peptides for cell-specific delivery strategies involving biomolecules that can be triggered spatially and temporally within a cell transport pathway by change in physiological conditions. The review also discusses conjugations of therapeutic agents to CPPs for enhanced intracellular delivery and bioavailability that are at the clinical stage of development. Futaki S, et al. Acc Chem Res. 2017 Oct 17;50(10):2449-2456. doi: 10.1021/acs.accounts.7b00221. Epub 2017 Sep 14. Acc Chem Res. 2017. PMID: 28910080 Hoyer J, et al. Acc Chem Res. 2012 Jul 17;45(7):1048-56. doi: 10.1021/ar2002304. Epub 2012 Mar 28. Acc Chem Res. 2012. PMID: 22455499 Shin MC, et al. J Biomed Mater Res A. 2014 Feb;102(2):575-87. doi: 10.1002/jbm.a.34859. Epub 2013 Jul 30. J Biomed Mater Res A. 2014. PMID: 23852939 Free PMC article. Review. Reissmann S. J Pept Sci. 2014 Oct;20(10):760-84. doi: 10.1002/psc.2672. Epub 2014 Aug 11. J Pept Sci. 2014. PMID: 25112216 Ruseska I, et al. Nanomaterials (Basel). 2021 Jun 7;11(6):1508. doi: 10.3390/nano11061508. Nanomaterials (Basel). 2021. PMID: 34200384 Free PMC article. Review. Keum T, et al. Pharmaceuticals (Basel). 2020 Nov 21;13(11):408. doi: 10.3390/ph13110408. Pharmaceuticals (Basel). 2020. PMID: 33233392 Free PMC article. Ruseska I, et al. Beilstein J Nanotechnol. 2020 Jan 9;11:101-123. doi: 10.3762/bjnano.11.10. eCollection 2020. Beilstein J Nanotechnol. 2020. PMID: 31976201 Free PMC article. Review. Allen J, Najjar K, Erazo-Oliveras A, Kondow-McConaghy HM, Brock DJ, Graham K, Hager EC, Marschall ALJ, Dübel S, Juliano RL, Pellois JP. Allen J, et al. ACS Chem Biol. 2019 Dec 20;14(12):2641-2651. doi: 10.1021/acschembio.9b00585. Epub 2019 Oct 31. ACS Chem Biol. 2019. PMID: 31633910 Free PMC article. Schachner-Nedherer AL, et al. ACS Omega. 2019 Apr 18;4(4):7014-7022. doi: 10.1021/acsomega.8b03562. eCollection 2019 Apr 30. ACS Omega. 2019. PMID: 31459813 Free PMC article. De Coupade C., Fittipaldi A., Chagnas V., Michel M., Carlier S., Tasciotti E., Darmon A., Ravel D., Kearsey J., Giacca M., Cailler F. Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules. Biochem. J. 2005;390:407–418. Veerle K., Cornelissen B. Targeting the tumour: Cell penetrating peptides for molecular imaging and radiotherapy. Pharmaceuticals. 2010;3:600–620. Nathan S., Abhijit M., Ghee H.L., Gerard W.C.L. Arginine-rich cell-penetrating peptides. FEBS Lett. 2010;3:1806–1813. Heitz F., Morris M.C., Divita G. Twenty years of cell-penetrating peptides: From molecular mechanisms to therapeutics. Br. J. Pharmacol. 2009;157:195–206. Deshayes S., Morris M.C., Divita G., Heitz F. Cell-penetrating peptides: Tools for intracellular delivery of therapeutics. Cell. Mol. Life Sci. 2005;62:1839–1849.