Journal Browser
Journal Insights

Frequency: Half-yearly                    

Time to first decision: 2.4 Weeks

Submission to publication: 4 Weeks        

Acceptance rate: 26%

ISSN:  2972-3418

Open Access Review

Overcoming the challenge: cell-penetrating peptides and membrane permeability

by Yuan Gu a,1 orcid Long Wu b,1 orcid Yasir Hameed c,* orcid  and  Mohsen Nabi-Afjadi d,* orcid
a
The Statistics Department, The George Washington University, Washington, United States
b
Department of Surgery, University of Maryland, Baltimore, United States
c
Department of Applied Biological Sciences, Tokyo University of Science, Tokyo, Japan
d
Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
*
Author to whom correspondence should be addressed.
BAB  2023, 7; 2(1), 7; https://doi.org/10.58567/bab02010002
Received: 15 June 2023 / Accepted: 28 June 2023 / Published: 29 June 2023

Abstract

Cell-penetrating peptides (CPPs) have emerged as a promising strategy for enhancing the membrane permeability of bioactive molecules, particularly in the treatment of central nervous system diseases. CPPs possess the ability to deliver a diverse array of bioactive molecules into cells using either covalent or non-covalent approaches, with a preference for non-covalent methods to preserve the biological activity of the transported molecules. By effectively traversing various physiological barriers, CPPs have exhibited significant potential in preclinical and clinical drug development. The discovery of CPPs represents a valuable solution to the challenge of limited membrane permeability of bioactive molecules and will continue to exert a crucial influence on the field of biomedical science.


Copyright: © 2023 by Gu, Wu, Hameed and Nabi-Afjadi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Show Figures

Share and Cite

ACS Style
Gu, Y.; Wu, L.; Hameed, Y.; Nabi-Afjadi, M. Overcoming the challenge: cell-penetrating peptides and membrane permeability. Biomaterials and Biosensors, 2023, 2, 7. https://doi.org/10.58567/bab02010002
AMA Style
Gu Y, Wu L, Hameed Y, Nabi-Afjadi M. Overcoming the challenge: cell-penetrating peptides and membrane permeability. Biomaterials and Biosensors; 2023, 2(1):7. https://doi.org/10.58567/bab02010002
Chicago/Turabian Style
Gu, Yuan; Wu, Long; Hameed, Yasir; Nabi-Afjadi, Mohsen 2023. "Overcoming the challenge: cell-penetrating peptides and membrane permeability" Biomaterials and Biosensors 2, no.1:7. https://doi.org/10.58567/bab02010002
APA style
Gu, Y., Wu, L., Hameed, Y., & Nabi-Afjadi, M. (2023). Overcoming the challenge: cell-penetrating peptides and membrane permeability. Biomaterials and Biosensors, 2(1), 7. https://doi.org/10.58567/bab02010002

Article Metrics

Article Access Statistics

References

  1. Guidotti G, Brambilla L, Rossi D. Cell-Penetrating Peptides: From Basic Research to Clinics. Trends Pharmacol Sci. 2017;38(4):406-424. doi:10.1016/j.tips.2017.01.003
  2. Demeule M, Régina A, Ché C, et al. Identification and design of peptides as a new drug delivery system for the brain. J Pharmacol Exp Ther. 2008;324(3):1064-1072. doi:10.1124/jpet.107.131318
  3. Zhang F, Xu CL, Liu CM. Drug delivery strategies to enhance the permeability of the blood-brain barrier for treatment of glioma. Drug Des Devel Ther. 2015;9:2089-2100. doi:10.2147/DDDT.S79592
  4. Frankel AD, Pabo CO. Cellular uptake of the tat protein from human immunodeficiency virus. Cell. 1988;55(6):1189-1193. doi:10.1016/0092-8674(88)90263-2
  5. Green M, Loewenstein PM. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell. 1988;55(6):1179-1188. doi:10.1016/0092-8674(88)90262-0
  6. Joliot A, Pernelle C, Deagostini-Bazin H, Prochiantz A. Antennapedia homeobox peptide regulates neural morphogenesis. Proc Natl Acad Sci U S A. 1991;88(5):1864-1868. doi:10.1073/pnas.88.5.1864
  7. Derossi D, Joliot AH, Chassaing G, Prochiantz A. The third helix of the Antennapedia homeodomain translocates through biological membranes. J Biol Chem. 1994;269(14):10444-10450.
  8. Vivès E, Brodin P, Lebleu B. A truncated HIV-1 Tat protein basic domain rapidly translocates through the plasma membrane and accumulates in the cell nucleus. J Biol Chem. 1997;272(25):16010-16017. doi:10.1074/jbc.272.25.16010
  9. Park J, Ryu J, Kim KA, et al. Mutational analysis of a human immunodeficiency virus type 1 Tat protein transduction domain which is required for delivery of an exogenous protein into mammalian cells. J Gen Virol. 2002;83(Pt 5):1173-1181. doi:10.1099/0022-1317-83-5-1173
  10. Elliott G, O’Hare P. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell. 1997;88(2):223-233. doi:10.1016/s0092-8674(00)81843-7
  11. Futaki S, Suzuki T, Ohashi W, et al. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem. 2001;276(8):5836-5840. doi:10.1074/jbc.M007540200
  12. Oehlke J, Scheller A, Wiesner B, et al. Cellular uptake of an alpha-helical amphipathic model peptide with the potential to deliver polar compounds into the cell interior non-endocytically. Biochim Biophys Acta. 1998;1414(1-2):127-139. doi:10.1016/s0005-2736(98)00161-8
  13. Ramsey JD, Flynn NH. Cell-penetrating peptides transport therapeutics into cells. Pharmacol Ther. 2015;154:78-86. doi:10.1016/j.pharmthera.2015.07.003
  14. Raucher D, Ryu JS. Cell-penetrating peptides: strategies for anticancer treatment. Trends in Molecular Medicine. 2015;21(9):560-570. doi:10.1016/j.molmed.2015.06.005
  15. Bechara C, Sagan S. Cell-penetrating peptides: 20 years later, where do we stand? FEBS Lett. 2013;587(12):1693-1702. doi:10.1016/j.febslet.2013.04.031
  16. Copolovici DM, Langel K, Eriste E, Langel Ü. Cell-penetrating peptides: design, synthesis, and applications. ACS Nano. 2014;8(3):1972-1994. doi:10.1021/nn4057269
  17. Heitz F, Morris MC, Divita G. Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. Br J Pharmacol. 2009;157(2):195-206. doi:10.1111/j.1476-5381.2009.00057.x
  18. Regberg J, Srimanee A, Langel U. Applications of cell-penetrating peptides for tumor targeting and future cancer therapies. Pharmaceuticals (Basel). 2012;5(9):991-1007. doi:10.3390/ph5090991
  19. Wang T, Meng Z, Kang Z, et al. Peptide Gene Delivery Vectors for Specific Transfection of Glioma Cells. ACS Biomater Sci Eng. 2020;6(12):6778-6789. doi:10.1021/acsbiomaterials.0c01336
  20. Wu J, Han H, Jin Q, Li Z, Li H, Ji J. Design and Proof of Programmed 5‑Aminolevulinic Acid Prodrug Nanocarriers for Targeted Photodynamic Cancer Therapy. ACS applied materials & interfaces. 2017;9(17):14596-14605. doi:10.1021/acsami.6b15853
  21. Yang H, Liu S, Cai H, et al. Chondroitin sulfate as a molecular portal that preferentially mediates the apoptotic killing of tumor cells by penetratin-directed mitochondria-disrupting peptides. J Biol Chem. 2010;285(33):25666-25676. doi:10.1074/jbc.M109.089417
  22. Xie J, Bi Y, Zhang H, et al. Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application. Front Pharmacol. 2020;11:697. doi:10.3389/fphar.2020.00697
  23. Bera S, Kar RK, Mondal S, Pahan K, Bhunia A. Structural Elucidation of the Cell-Penetrating Penetratin Peptide in Model Membranes at the Atomic Level: Probing Hydrophobic Interactions in the Blood-Brain Barrier. Biochemistry. 2016;55(35):4982-4996. doi:10.1021/acs.biochem.6b00518
  24. Ostenson CG, Zaitsev S, Berggren PO, Efendic S, Langel U, Bartfai T. Galparan: a powerful insulin-releasing chimeric peptide acting at a novel site. Endocrinology. 1997;138(8):3308-3313. doi:10.1210/endo.138.8.5307
  25. Alaybeyoglu B, Sariyar Akbulut B, Ozkirimli E. Insights into membrane translocation of the cell-penetrating peptide pVEC from molecular dynamics calculations. J Biomol Struct Dyn. 2016;34(11):2387-2398. doi:10.1080/07391102.2015.1117396
  26. Bobone S, Piazzon A, Orioni B, et al. The thin line between cell-penetrating and antimicrobial peptides: the case of Pep-1 and Pep-1-K. J Pept Sci. 2011;17(5):335-341. doi:10.1002/psc.1340
  27. Deshayes S, Plénat T, Charnet P, Divita G, Molle G, Heitz F. Formation of transmembrane ionic channels of primary amphipathic cell-penetrating peptides. Consequences on the mechanism of cell penetration. Biochim Biophys Acta. 2006;1758(11):1846-1851. doi:10.1016/j.bbamem.2006.08.010
  28. Silva S, Kurrikoff K, Langel Ü, Almeida AJ, Vale N. A Second Life for MAP, a Model Amphipathic Peptide. Int J Mol Sci. 2022;23(15):8322. doi:10.3390/ijms23158322
  29. Rydström A, Deshayes S, Konate K, et al. Direct translocation as major cellular uptake for CADY self-assembling peptide-based nanoparticles. PLoS One. 2011;6(10):e25924. doi:10.1371/journal.pone.0025924
  30. Rhee M, Davis P. Mechanism of uptake of C105Y, a novel cell-penetrating peptide. J Biol Chem. 2006;281(2):1233-1240. doi:10.1074/jbc.M509813200
  31. Guha S, Ferrie RP, Ghimire J, et al. Applications and evolution of melittin, the quintessential membrane active peptide. Biochem Pharmacol. 2021;193:114769. doi:10.1016/j.bcp.2021.114769
  32. Kim Y, Lillo A, Moss JA, Janda KD. A contiguous stretch of methionine residues mediates the energy-dependent internalization mechanism of a cell-penetrating peptide. Mol Pharm. 2005;2(6):528-535. doi:10.1021/mp050035b
  33. Vasconcelos L, Pärn K, Langel U. Therapeutic potential of cell-penetrating peptides. Ther Deliv. 2013;4(5):573-591. doi:10.4155/tde.13.22
  34. Deloche C, Lopez-Lazaro L, Mouz S, Perino J, Abadie C, Combette JM. XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study. Pharmacol Res Perspect. 2014;2(1):e00020. doi:10.1002/prp2.20
  35. Brandt F, O’Connell C, Cazzaniga A, Waugh JM. Efficacy and safety evaluation of a novel botulinum toxin topical gel for the treatment of moderate to severe lateral canthal lines. Dermatol Surg. 2010;36 Suppl 4:2111-2118. doi:10.1111/j.1524-4725.2010.01711.x
  36. Cirak S, Arechavala-Gomeza V, Guglieri M, et al. Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011;378(9791):595-605. doi:10.1016/S0140-6736(11)60756-3
  37. Cousins MJ, Pickthorn K, Huang S, Critchley L, Bell G. The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (εPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design. Pain Med. 2013;14(4):533-540. doi:10.1111/pme.12058
  38. Delfín DA, Xu Y, Peterson JM, Guttridge DC, Rafael-Fortney JA, Janssen PM. Improvement of cardiac contractile function by peptide-based inhibition of NF-κB in the utrophin/dystrophin-deficient murine model of muscular dystrophy. J Transl Med. 2011;9:68. doi:10.1186/1479-5876-9-68
  39. De Coupade C, Fittipaldi A, Chagnas V, et al. Novel human-derived cell-penetrating peptides for specific subcellular delivery of therapeutic biomolecules. Biochem J. 2005;390(Pt 2):407-418. doi:10.1042/BJ20050401
  40. Wender PA, Mitchell DJ, Pattabiraman K, Pelkey ET, Steinman L, Rothbard JB. The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci U S A. 2000;97(24):13003-13008. doi:10.1073/pnas.97.24.13003
  41. Tünnemann G, Ter-Avetisyan G, Martin RM, Stöckl M, Herrmann A, Cardoso MC. Live-cell analysis of cell penetration ability and toxicity of oligo-arginines. J Pept Sci. 2008;14(4):469-476. doi:10.1002/psc.968
  42. Koren E, Torchilin VP. Cell-penetrating peptides: breaking through to the other side. Trends Mol Med. 2012;18(7):385-393. doi:10.1016/j.molmed.2012.04.012
  43. Rothbard JB, Jessop TC, Lewis RS, Murray BA, Wender PA. Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells. J Am Chem Soc. 2004;126(31):9506-9507. doi:10.1021/ja0482536
  44. Binder H, Lindblom G. Charge-dependent translocation of the Trojan peptide penetratin across lipid membranes. Biophys J. 2003;85(2):982-995. doi:10.1016/S0006-3495(03)74537-8
  45. Futaki S. Oligoarginine vectors for intracellular delivery: design and cellular-uptake mechanisms. Biopolymers. 2006;84(3):241-249. doi:10.1002/bip.20421
  46. Kim GC, Cheon DH, Lee Y. Challenge to overcome current limitations of cell-penetrating peptides. Biochim Biophys Acta Proteins Proteom. 2021;1869(4):140604. doi:10.1016/j.bbapap.2021.140604
  47. Morris MC, Vidal P, Chaloin L, Heitz F, Divita G. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res. 1997;25(14):2730-2736. doi:10.1093/nar/25.14.2730
  48. Wang T, Wang C, Zheng S, et al. Insight into the Mechanism of Internalization of the Cell-Penetrating Carrier Peptide Pep-1 by Conformational Analysis. J Biomed Nanotechnol. 2020;16(7):1135-1143. doi:10.1166/jbn.2020.2950
  49. Morris MC, Deshayes S, Heitz F, Divita G. Cell-penetrating peptides: from molecular mechanisms to therapeutics. Biol Cell. 2008;100(4):201-217. doi:10.1042/BC20070116
  50. Eiríksdóttir E, Konate K, Langel U, Divita G, Deshayes S. Secondary structure of cell-penetrating peptides controls membrane interaction and insertion. Biochim Biophys Acta. 2010;1798(6):1119-1128. doi:10.1016/j.bbamem.2010.03.005
  51. Crombez L, Aldrian-Herrada G, Konate K, et al. A new potent secondary amphipathic cell-penetrating peptide for siRNA delivery into mammalian cells. Mol Ther. 2009;17(1):95-103. doi:10.1038/mt.2008.215
  52. Elmquist A, Hansen M, Langel U. Structure-activity relationship study of the cell-penetrating peptide pVEC. Biochim Biophys Acta. 2006;1758(6):721-729. doi:10.1016/j.bbamem.2006.05.013
  53. Schmidt S, Adjobo-Hermans MJW, Kohze R, Enderle T, Brock R, Milletti F. Identification of Short Hydrophobic Cell-Penetrating Peptides for Cytosolic Peptide Delivery by Rational Design. Bioconjug Chem. 2017;28(2):382-389. doi:10.1021/acs.bioconjchem.6b00535
  54. Soomets U, Lindgren M, Gallet X, et al. Deletion analogues of transportan. Biochim Biophys Acta. 2000;1467(1):165-176. doi:10.1016/s0005-2736(00)00216-9
  55. Kamide K, Nakakubo H, Uno S, Fukamizu A. Isolation of novel cell-penetrating peptides from a random peptide library using in vitro virus and their modifications. Int J Mol Med. 2010;25(1):41-51.
  56. Sandgren S, Cheng F, Belting M. Nuclear targeting of macromolecular polyanions by an HIV-Tat derived peptide. Role for cell-surface proteoglycans. J Biol Chem. 2002;277(41):38877-38883. doi:10.1074/jbc.M205395200
  57. Ziegler A, Seelig J. Interaction of the protein transduction domain of HIV-1 TAT with heparan sulfate: binding mechanism and thermodynamic parameters. Biophys J. 2004;86(1 Pt 1):254-263. doi:10.1016/S0006-3495(04)74101-6
  58. Gandhi NS, Mancera RL. The structure of glycosaminoglycans and their interactions with proteins. Chem Biol Drug Des. 2008;72(6):455-482. doi:10.1111/j.1747-0285.2008.00741.x
  59. Ghibaudi E, Boscolo B, Inserra G, et al. The interaction of the cell-penetrating peptide penetratin with heparin, heparansulfates and phospholipid vesicles investigated by ESR spectroscopy. J Pept Sci. 2005;11(7):401-409. doi:10.1002/psc.633
  60. Gonçalves E, Kitas E, Seelig J. Binding of oligoarginine to membrane lipids and heparan sulfate: structural and thermodynamic characterization of a cell-penetrating peptide. Biochemistry. 2005;44(7):2692-2702. doi:10.1021/bi048046i
  61. Ponnappan N, Budagavi DP, Chugh A. CyLoP-1: Membrane-active peptide with cell-penetrating and antimicrobial properties. Biochim Biophys Acta Biomembr. 2017;1859(2):167-176. doi:10.1016/j.bbamem.2016.11.002
  62. Console S, Marty C, García-Echeverría C, Schwendener R, Ballmer-Hofer K. Antennapedia and HIV transactivator of transcription (TAT) “protein transduction domains” promote endocytosis of high molecular weight cargo upon binding to cell surface glycosaminoglycans. J Biol Chem. 2003;278(37):35109-35114. doi:10.1074/jbc.M301726200
  63. Fuchs SM, Raines RT. Pathway for polyarginine entry into mammalian cells. Biochemistry. 2004;43(9):2438-2444. doi:10.1021/bi035933x
  64. Lin L, Chi J, Yan Y, et al. Membrane-disruptive peptides/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era. Acta Pharm Sin B. 2021;11(9):2609-2644. doi:10.1016/j.apsb.2021.07.014
  65. Mäler L. Solution NMR studies of cell-penetrating peptides in model membrane systems. Adv Drug Deliv Rev. 2013;65(8):1002-1011. doi:10.1016/j.addr.2012.10.011
  66. Marion D, Zasloff M, Bax A. A two-dimensional NMR study of the antimicrobial peptide magainin 2. FEBS Lett. 1988;227(1):21-26. doi:10.1016/0014-5793(88)81405-4
  67. Williamson JA, Loria JP, Miranker AD. Helix stabilization precedes aqueous and bilayer-catalyzed fiber formation in islet amyloid polypeptide. J Mol Biol. 2009;393(2):383-396. doi:10.1016/j.jmb.2009.07.077
  68. Butterfield SM, Lashuel HA. Amyloidogenic Protein-Membrane Interactions: Mechanistic Insight from Model Systems. Angewandte Chemie International Edition. 2010;49(33):5628-5654. doi:10.1002/anie.200906670
  69. Epand RM, Vogel HJ. Diversity of antimicrobial peptides and their mechanisms of action. Biochim Biophys Acta. 1999;1462(1-2):11-28. doi:10.1016/s0005-2736(99)00198-4
  70. Huang HW. Molecular mechanism of antimicrobial peptides: the origin of cooperativity. Biochim Biophys Acta. 2006;1758(9):1292-1302. doi:10.1016/j.bbamem.2006.02.001
  71. Jao CC, Hegde BG, Chen J, Haworth IS, Langen R. Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement. Proc Natl Acad Sci U S A. 2008;105(50):19666-19671. doi:10.1073/pnas.0807826105
  72. Shin MC, Zhang J, Min KA, et al. Cell-penetrating peptides: achievements and challenges in application for cancer treatment. J Biomed Mater Res A. 2014;102(2):575-587. doi:10.1002/jbm.a.34859
  73. Cleal K, He L, Watson PD, Jones AT. Endocytosis, intracellular traffic and fate of cell penetrating peptide based conjugates and nanoparticles. Curr Pharm Des. 2013;19(16):2878-2894. doi:10.2174/13816128113199990297
  74. Säälik P, Padari K, Niinep A, et al. Protein delivery with transportans is mediated by caveolae rather than flotillin-dependent pathways. Bioconjug Chem. 2009;20(5):877-887. doi:10.1021/bc800416f
  75. Khan MA, Wu VM, Ghosh S, Uskoković V. Gene delivery using calcium phosphate nanoparticles: Optimization of the transfection process and the effects of citrate and poly(l-lysine) as additives. J Colloid Interface Sci. 2016;471:48-58. doi:10.1016/j.jcis.2016.03.007
  76. Ruseska I, Zimmer A. Internalization mechanisms of cell-penetrating peptides. Beilstein J Nanotechnol. 2020;11:101-123. doi:10.3762/bjnano.11.10
  77. Bevers EM, Comfurius P, Dekkers DW, Harmsma M, Zwaal RF. Regulatory mechanisms of transmembrane phospholipid distributions and pathophysiological implications of transbilayer lipid scrambling. Lupus. 1998;7 Suppl 2:S126-131. doi:10.1177/096120339800700228
  78. Gaspar D, Veiga AS, Castanho MARB. From antimicrobial to anticancer peptides. A review. Front Microbiol. 2013;4:294. doi:10.3389/fmicb.2013.00294
  79. Tan J, Tay J, Hedrick J, Yang YY. Synthetic macromolecules as therapeutics that overcome resistance in cancer and microbial infection. Biomaterials. 2020;252:120078. doi:10.1016/j.biomaterials.2020.120078
  80. Li X, Shen B, Chen Q, et al. Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells. BMC Cancer. 2016;16:251. doi:10.1186/s12885-016-2287-0
  81. Deslouches B, Di YP. Antimicrobial peptides with selective antitumor mechanisms: prospect for anticancer applications. Oncotarget. 2017;8(28):46635-46651. doi:10.18632/oncotarget.16743
  82. Duclohier H, Molle G, Spach G. Antimicrobial peptide magainin I from Xenopus skin forms anion-permeable channels in planar lipid bilayers. Biophys J. 1989;56(5):1017-1021. doi:10.1016/S0006-3495(89)82746-8
  83. Gallucci E, Meleleo D, Micelli S, Picciarelli V. Magainin 2 channel formation in planar lipid membranes: the role of lipid polar groups and ergosterol. Eur Biophys J. 2003;32(1):22-32. doi:10.1007/s00249-002-0262-y
  84. Zhang L, Rozek A, Hancock RE. Interaction of cationic antimicrobial peptides with model membranes. J Biol Chem. 2001;276(38):35714-35722. doi:10.1074/jbc.M104925200
  85. Bimbo LM, Peltonen L, Hirvonen J, Santos HA. Toxicological profile of therapeutic nanodelivery systems. Curr Drug Metab. 2012;13(8):1068-1086. doi:10.2174/138920012802850047
  86. Ma N, Ma C, Li C, et al. Influence of nanoparticle shape, size, and surface functionalization on cellular uptake. J Nanosci Nanotechnol. 2013;13(10):6485-6498. doi:10.1166/jnn.2013.7525
  87. Nakase I, Akita H, Kogure K, et al. Efficient intracellular delivery of nucleic acid pharmaceuticals using cell-penetrating peptides. Acc Chem Res. 2012;45(7):1132-1139. doi:10.1021/ar200256e
  88. Treuel L, Jiang X, Nienhaus GU. New views on cellular uptake and trafficking of manufactured nanoparticles. J R Soc Interface. 2013;10(82):20120939. doi:10.1098/rsif.2012.0939
  89. Erazo-Oliveras A, Muthukrishnan N, Baker R, Wang TY, Pellois JP. Improving the endosomal escape of cell-penetrating peptides and their cargos: strategies and challenges. Pharmaceuticals (Basel). 2012;5(11):1177-1209. doi:10.3390/ph5111177
  90. Yang ST, Zaitseva E, Chernomordik LV, Melikov K. Cell-penetrating peptide induces leaky fusion of liposomes containing late endosome-specific anionic lipid. Biophys J. 2010;99(8):2525-2533. doi:10.1016/j.bpj.2010.08.029
  91. El-Sayed A, Futaki S, Harashima H. Delivery of macromolecules using arginine-rich cell-penetrating peptides: ways to overcome endosomal entrapment. AAPS J. 2009;11(1):13-22. doi:10.1208/s12248-008-9071-2
  92. Ladokhin AS, White SH. “Detergent-like” permeabilization of anionic lipid vesicles by melittin. Biochim Biophys Acta. 2001;1514(2):253-260. doi:10.1016/s0005-2736(01)00382-0
  93. Lee MT, Chen FY, Huang HW. Energetics of pore formation induced by membrane active peptides. Biochemistry. 2004;43(12):3590-3599. doi:10.1021/bi036153r
  94. Naito A, Nagao T, Norisada K, Mizuno T, Tuzi S, Saitô H. Conformation and dynamics of melittin bound to magnetically oriented lipid bilayers by solid-state (31)P and (13)C NMR spectroscopy. Biophys J. 2000;78(5):2405-2417. doi:10.1016/S0006-3495(00)76784-1
  95. Vogel H, Jähnig F. The structure of melittin in membranes. Biophys J. 1986;50(4):573-582. doi:10.1016/S0006-3495(86)83497-X
  96. Meyer M, Zintchenko A, Ogris M, Wagner E. A dimethylmaleic acid-melittin-polylysine conjugate with reduced toxicity, pH-triggered endosomolytic activity and enhanced gene transfer potential. J Gene Med. 2007;9(9):797-805. doi:10.1002/jgm.1075
  97. Jones CH, Chen CK, Ravikrishnan A, Rane S, Pfeifer BA. Overcoming nonviral gene delivery barriers: perspective and future. Mol Pharm. 2013;10(11):4082-4098. doi:10.1021/mp400467x
  98. Juliano R, Bauman J, Kang H, Ming X. Biological barriers to therapy with antisense and siRNA oligonucleotides. Mol Pharm. 2009;6(3):686-695. doi:10.1021/mp900093r
  99. Khalil IA, Harashima H. An efficient PEGylated gene delivery system with improved targeting: Synergism between octaarginine and a fusogenic peptide. Int J Pharm. 2018;538(1-2):179-187. doi:10.1016/j.ijpharm.2018.01.007
  100. Whitehead KA, Langer R, Anderson DG. Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov. 2009;8(2):129-138. doi:10.1038/nrd2742
  101. Tarvirdipour S, Huang X, Mihali V, Schoenenberger CA, Palivan CG. Peptide-Based Nanoassemblies in Gene Therapy and Diagnosis: Paving the Way for Clinical Application. Molecules. 2020;25(15):3482. doi:10.3390/molecules25153482
  102. Luan L, Meng Q, Xu L, Meng Z, Yan H, Liu K. Peptide amphiphiles with multifunctional fragments promoting cellular uptake and endosomal escape as efficient gene vectors. J Mater Chem B. 2015;3(6):1068-1078. doi:10.1039/c4tb01353k
  103. Meng Z, Kang Z, Sun C, et al. Enhanced gene transfection efficiency by use of peptide vectors containing laminin receptor-targeting sequence YIGSR. Nanoscale. 2018;10(3):1215-1227. doi:10.1039/c7nr05843h
  104. Meng Z, Luan L, Kang Z, Feng S, Meng Q, Liu K. Histidine-enriched multifunctional peptide vectors with enhanced cellular uptake and endosomal escape for gene delivery. J Mater Chem B. 2017;5(1):74-84. doi:10.1039/c6tb02862d
  105. Wang T, Zou C, Wen N, et al. The effect of structural modification of antimicrobial peptides on their antimicrobial activity, hemolytic activity, and plasma stability. J Pept Sci. 2021;27(5):e3306. doi:10.1002/psc.3306
  106. Yang S, Meng Z, Kang Z, et al. The structure and configuration changes of multifunctional peptide vectors enhance gene delivery efficiency. RSC Adv. 2018;8(50):28356-28366. doi:10.1039/c8ra04101f
  107. Mishra S, Webster P, Davis ME. PEGylation significantly affects cellular uptake and intracellular trafficking of non-viral gene delivery particles. Eur J Cell Biol. 2004;83(3):97-111. doi:10.1078/0171-9335-00363
  108. Kang Z, Meng Q, Liu K. Peptide-based gene delivery vectors. J Mater Chem B. 2019;7(11):1824-1841. doi:10.1039/c8tb03124j
  109. Alhakamy NA, Nigatu AS, Berkland CJ, Ramsey JD. Noncovalently associated cell-penetrating peptides for gene delivery applications. Ther Deliv. 2013;4(6):741-757. doi:10.4155/tde.13.44
  110. Pack DW, Hoffman AS, Pun S, Stayton PS. Design and development of polymers for gene delivery. Nat Rev Drug Discov. 2005;4(7):581-593. doi:10.1038/nrd1775
  111. Avila LA, Aps LRMM, Sukthankar P, et al. Branched amphiphilic cationic oligopeptides form peptiplexes with DNA: a study of their biophysical properties and transfection efficiency. Mol Pharm. 2015;12(3):706-715. doi:10.1021/mp500524s
  112. Mandal H, Katiyar SS, Swami R, et al. ε-Poly-l-Lysine/plasmid DNA nanoplexes for efficient gene delivery in vivo. Int J Pharm. 2018;542(1-2):142-152. doi:10.1016/j.ijpharm.2018.03.021
  113. Walsh DP, Raftery RM, Castaño IM, et al. Transfection of autologous host cells in vivo using gene activated collagen scaffolds incorporating star-polypeptides. J Control Release. 2019;304:191-203. doi:10.1016/j.jconrel.2019.05.009
  114. Ziady AG, Gedeon CR, Miller T, et al. Transfection of airway epithelium by stable PEGylated poly-L-lysine DNA nanoparticles in vivo. Mol Ther. 2003;8(6):936-947. doi:10.1016/j.ymthe.2003.07.007
  115. Wang G, Gao X, Gu G, et al. Polyethylene glycol-poly(ε-benzyloxycarbonyl-l-lysine)-conjugated VEGF siRNA for antiangiogenic gene therapy in hepatocellular carcinoma. Int J Nanomedicine. 2017;12:3591-3603. doi:10.2147/IJN.S131078
  116. Midoux P, Breuzard G, Gomez JP, Pichon C. Polymer-based gene delivery: a current review on the uptake and intracellular trafficking of polyplexes. Curr Gene Ther. 2008;8(5):335-352. doi:10.2174/156652308786071014
  117. Loughran SP, McCrudden CM, McCarthy HO. Designer peptide delivery systems for gene therapy. European Journal of Nanomedicine. 2015;7(2):85-96. doi:10.1515/ejnm-2014-0037
  118. van Rossenberg SMW, van Keulen ACI, Drijfhout JW, et al. Stable polyplexes based on arginine-containing oligopeptides for in vivo gene delivery. Gene Ther. 2004;11(5):457-464. doi:10.1038/sj.gt.3302183
  119. Kim HH, Choi HS, Yang JM, Shin S. Characterization of gene delivery in vitro and in vivo by the arginine peptide system. Int J Pharm. 2007;335(1-2):70-78. doi:10.1016/j.ijpharm.2006.11.017
  120. Ul Ain Q, Chung H, Chung JY, Choi JH, Kim YH. Amelioration of atherosclerotic inflammation and plaques via endothelial adrenoceptor-targeted eNOS gene delivery using redox-sensitive polymer bearing l-arginine. J Control Release. 2017;262:72-86. doi:10.1016/j.jconrel.2017.07.019
  121. Won YW, Kim HA, Lee M, Kim YH. Reducible poly(oligo-D-arginine) for enhanced gene expression in mouse lung by intratracheal injection. Mol Ther. 2010;18(4):734-742. doi:10.1038/mt.2009.297
  122. Woo J, Bae SH, Kim B, et al. Cardiac Usage of Reducible Poly(oligo-D-arginine) As a Gene Carrier for Vascular Endothelial Growth Factor Expression. PLoS One. 2015;10(12):e0144491. doi:10.1371/journal.pone.0144491
  123. Johnson LN, Cashman SM, Kumar-Singh R. Cell-penetrating peptide for enhanced delivery of nucleic acids and drugs to ocular tissues including retina and cornea. Mol Ther. 2008;16(1):107-114. doi:10.1038/sj.mt.6300324
  124. Kesharwani P, Iyer AK. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery. Drug Discov Today. 2015;20(5):536-547. doi:10.1016/j.drudis.2014.12.012
  125. Torchilin VP. Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery. Biopolymers. 2008;90(5):604-610. doi:10.1002/bip.20989
  126. Luo K, Li C, Li L, She W, Wang G, Gu Z. Arginine functionalized peptide dendrimers as potential gene delivery vehicles. Biomaterials. 2012;33(19):4917-4927. doi:10.1016/j.biomaterials.2012.03.030
  127. Kozhikhova KV, Andreev SM, Shilovskiy IP, et al. A novel peptide dendrimer LTP efficiently facilitates transfection of mammalian cells. Org Biomol Chem. 2018;16(43):8181-8190. doi:10.1039/c8ob02039f
  128. Yoo J, Lee D, Gujrati V, et al. Bioreducible branched poly(modified nona-arginine) cell-penetrating peptide as a novel gene delivery platform. J Control Release. 2017;246:142-154. doi:10.1016/j.jconrel.2016.04.040
  129. Tang M, Dong H, Li Y, Ren T. Harnessing the PEG-cleavable strategy to balance cytotoxicity, intracellular release and the therapeutic effect of dendrigraft poly-l-lysine for cancer gene therapy. J Mater Chem B. 2016;4(7):1284-1295. doi:10.1039/c5tb02224j
  130. Lehto T, Simonson OE, Mäger I, et al. A peptide-based vector for efficient gene transfer in vitro and in vivo. Mol Ther. 2011;19(8):1457-1467. doi:10.1038/mt.2011.10
  131. Andaloussi SEL, Lehto T, Mäger I, et al. Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo. Nucleic Acids Res. 2011;39(9):3972-3987. doi:10.1093/nar/gkq1299
  132. Aldrian G, Vaissière A, Konate K, et al. PEGylation rate influences peptide-based nanoparticles mediated siRNA delivery in vitro and in vivo. J Control Release. 2017;256:79-91. doi:10.1016/j.jconrel.2017.04.012
  133. Rittner K, Benavente A, Bompard-Sorlet A, et al. New basic membrane-destabilizing peptides for plasmid-based gene delivery in vitro and in vivo. Mol Ther. 2002;5(2):104-114. doi:10.1006/mthe.2002.0523
  134. Liu Y, Song Z, Zheng N, Nagasaka K, Yin L, Cheng J. Systemic siRNA delivery to tumors by cell-penetrating α-helical polypeptide-based metastable nanoparticles. Nanoscale. 2018;10(32):15339-15349. doi:10.1039/c8nr03976c
  135. He H, Zheng N, Song Z, et al. Suppression of Hepatic Inflammation via Systemic siRNA Delivery by Membrane-Disruptive and Endosomolytic Helical Polypeptide Hybrid Nanoparticles. ACS Nano. 2016;10(2):1859-1870. doi:10.1021/acsnano.5b05470
  136. Xiang S, Tong H, Shi Q, et al. Uptake mechanisms of non-viral gene delivery. J Control Release. 2012;158(3):371-378. doi:10.1016/j.jconrel.2011.09.093
  137. Liu J, Guo N, Gao C, et al. Effective Gene Silencing Mediated by Polypeptide Nanoparticles LAH4-L1-siMDR1 in Multi-Drug Resistant Human Breast Cancer. J Biomed Nanotechnol. 2019;15(3):531-543. doi:10.1166/jbn.2019.2705
  138. Zhu H, Dong C, Dong H, et al. Cleavable PEGylation and hydrophobic histidylation of polylysine for siRNA delivery and tumor gene therapy. ACS Appl Mater Interfaces. 2014;6(13):10393-10407. doi:10.1021/am501928p
  139. Zhou J, Zhao Y, Simonenko V, et al. Simultaneous silencing of TGF-β1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis. Oncotarget. 2017;8(46):80651-80665. doi:10.18632/oncotarget.20869
  140. Tai Z, Wang X, Tian J, et al. Biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo. Biomacromolecules. 2015;16(4):1119-1130. doi:10.1021/bm501777a
  141. Yao C, Liu J, Wu X, et al. Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy. J Control Release. 2016;232:203-214. doi:10.1016/j.jconrel.2016.04.034
  142. Khatibi S, Modaresi M, Kazemi Oskuee R, Salehi M, Aghaee-Bakhtiari SH. Genetic modification of cystic fibrosis with ΔF508 mutation of CFTR gene using the CRISPR system in peripheral blood mononuclear cells. Iran J Basic Med Sci. 2021;24(1):73-78. doi:10.22038/ijbms.2020.50051.11415
  143. Zhou Y, Han S, Liang Z, Zhao M, Liu G, Wu J. Progress in arginine-based gene delivery systems. J Mater Chem B. 2020;8(26):5564-5577. doi:10.1039/d0tb00498g
  144. Yong SB, Kim HJ, Kim JK, Chung JY, Kim YH. Human CD64-targeted non-viral siRNA delivery system for blood monocyte gene modulation. Sci Rep. 2017;7:42171. doi:10.1038/srep42171
  145. Manunta MDI, Tagalakis AD, Attwood M, et al. Delivery of ENaC siRNA to epithelial cells mediated by a targeted nanocomplex: a therapeutic strategy for cystic fibrosis. Sci Rep. 2017;7(1):700. doi:10.1038/s41598-017-00662-2
  146. Amin M, Mansourian M, Koning GA, Badiee A, Jaafari MR, Ten Hagen TLM. Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region. J Control Release. 2015;220(Pt A):308-315. doi:10.1016/j.jconrel.2015.10.039
  147. Adil MM, Erdman ZS, Kokkoli E. Transfection mechanisms of polyplexes, lipoplexes, and stealth liposomes in α₅β₁ integrin bearing DLD-1 colorectal cancer cells. Langmuir. 2014;30(13):3802-3810. doi:10.1021/la5001396
  148. Byrne JD, Betancourt T, Brannon-Peppas L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv Drug Deliv Rev. 2008;60(15):1615-1626. doi:10.1016/j.addr.2008.08.005
  149. Yang H, Li Y, Li T, et al. Multifunctional core/shell nanoparticles cross-linked polyetherimide-folic acid as efficient Notch-1 siRNA carrier for targeted killing of breast cancer. Sci Rep. 2014;4:7072. doi:10.1038/srep07072
  150. Komin A, Russell LM, Hristova KA, Searson PC. Peptide-based strategies for enhanced cell uptake, transcellular transport, and circulation: Mechanisms and challenges. Adv Drug Deliv Rev. 2017;110-111:52-64. doi:10.1016/j.addr.2016.06.002
  151. Kumar P, Wu H, McBride JL, et al. Transvascular delivery of small interfering RNA to the central nervous system. Nature. 2007;448(7149):39-43. doi:10.1038/nature05901
  152. Georgieva JV, Hoekstra D, Zuhorn IS. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier. Pharmaceutics. 2014;6(4):557-583. doi:10.3390/pharmaceutics6040557
  153. Huang S, Li J, Han L, et al. Dual targeting effect of Angiopep-2-modified, DNA-loaded nanoparticles for glioma. Biomaterials. 2011;32(28):6832-6838. doi:10.1016/j.biomaterials.2011.05.064
  154. Somani S, Blatchford DR, Millington O, Stevenson ML, Dufès C. Transferrin-bearing polypropylenimine dendrimer for targeted gene delivery to the brain. J Control Release. 2014;188:78-86. doi:10.1016/j.jconrel.2014.06.006
  155. Vadevoo SMP, Gurung S, Khan F, et al. Peptide-based targeted therapeutics and apoptosis imaging probes for cancer therapy. Arch Pharm Res. 2019;42(2):150-158. doi:10.1007/s12272-019-01125-0
  156. de Araujo CB, Heimann AS, Remer RA, et al. Intracellular Peptides in Cell Biology and Pharmacology. Biomolecules. 2019;9(4):150. doi:10.3390/biom9040150
  157. de Araujo CB, Russo LC, Castro LM, et al. A novel intracellular peptide derived from g1/s cyclin d2 induces cell death. J Biol Chem. 2014;289(24):16711-16726. doi:10.1074/jbc.M113.537118
  158. Wh L, D S. Role of the p16 tumor suppressor gene in cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1998;16(3). doi:10.1200/JCO.1998.16.3.1197
  159. Snyder EL, Meade BR, Saenz CC, Dowdy SF. Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. PLoS Biol. 2004;2(2):E36. doi:10.1371/journal.pbio.0020036
  160. Hosotani R, Miyamoto Y, Fujimoto K, et al. Trojan p16 peptide suppresses pancreatic cancer growth and prolongs survival in mice. Clin Cancer Res. 2002;8(4):1271-1276.
  161. Fulda S, Wick W, Weller M, Debatin KM. Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med. 2002;8(8):808-815. doi:10.1038/nm735
  162. Vucic D, Deshayes K, Ackerly H, et al. SMAC negatively regulates the anti-apoptotic activity of melanoma inhibitor of apoptosis (ML-IAP). J Biol Chem. 2002;277(14):12275-12279. doi:10.1074/jbc.M112045200
  163. Stirpe F, Olsnes S, Pihl A. Gelonin, a new inhibitor of protein synthesis, nontoxic to intact cells. Isolation, characterization, and preparation of cytotoxic complexes with concanavalin A. J Biol Chem. 1980;255(14):6947-6953.
  164. Park YJ, Chang LC, Liang JF, Moon C, Chung CP, Yang VC. Nontoxic membrane translocation peptide from protamine, low molecular weight protamine (LMWP), for enhanced intracellular protein delivery: in vitro and in vivo study. FASEB J. 2005;19(11):1555-1557. doi:10.1096/fj.04-2322fje
  165. Kim HY, Kim S, Youn H, Chung JK, Shin DH, Lee K. The cell penetrating ability of the proapoptotic peptide, KLAKLAKKLAKLAK fused to the N-terminal protein transduction domain of translationally controlled tumor protein, MIIYRDLISH. Biomaterials. 2011;32(22):5262-5268. doi:10.1016/j.biomaterials.2011.03.074
  166. Yin J, Liu D, Bao L, et al. Tumor targeting and microenvironment-responsive multifunctional fusion protein for pro-apoptotic peptide delivery. Cancer Lett. 2019;452:38-50. doi:10.1016/j.canlet.2019.03.016
  167. Diener C, Garza Ramos Martínez G, Moreno Blas D, et al. Effective Design of Multifunctional Peptides by Combining Compatible Functions. PLoS Comput Biol. 2016;12(4):e1004786. doi:10.1371/journal.pcbi.1004786
  168. Gronewold A, Horn M, Ranđelović I, et al. Characterization of a Cell-Penetrating Peptide with Potential Anticancer Activity. ChemMedChem. 2017;12(1):42-49. doi:10.1002/cmdc.201600498
  169. Wang K rong, Yan J xi, Zhang B zhi, Song J jing, Jia P fei, Wang R. Novel mode of action of polybia-MPI, a novel antimicrobial peptide, in multi-drug resistant leukemic cells. Cancer Lett. 2009;278(1):65-72. doi:10.1016/j.canlet.2008.12.027
  170. Wang K rong, Zhang B zhi, Zhang W, Yan J xi, Li J, Wang R. Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides. 2008;29(6):963-968. doi:10.1016/j.peptides.2008.01.015
  171. Fázio MA, Jouvensal L, Vovelle F, et al. Biological and structural characterization of new linear gomesin analogues with improved therapeutic indices. Biopolymers. 2007;88(3):386-400. doi:10.1002/bip.20660
  172. Sinthuvanich C, Veiga AS, Gupta K, Gaspar D, Blumenthal R, Schneider JP. Anticancer β-hairpin peptides: membrane-induced folding triggers activity. J Am Chem Soc. 2012;134(14):6210-6217. doi:10.1021/ja210569f
  173. Liu S, Yang H, Wan L, Cheng J, Lu X. Penetratin-mediated delivery enhances the antitumor activity of the cationic antimicrobial peptide Magainin II. Cancer Biother Radiopharm. 2013;28(4):289-297. doi:10.1089/cbr.2012.1328
  174. Thankappan B, Sivakumar J, Asokan S, et al. Dual antimicrobial and anticancer activity of a novel synthetic α-helical antimicrobial peptide. Eur J Pharm Sci. 2021;161:105784. doi:10.1016/j.ejps.2021.105784
  175. Wang C, Zhou Y, Li S, et al. Anticancer mechanisms of temporin-1CEa, an amphipathic α-helical antimicrobial peptide, in Bcap-37 human breast cancer cells. Life Sci. 2013;92(20-21):1004-1014. doi:10.1016/j.lfs.2013.03.016
  176. Xu H, Chen CX, Hu J, et al. Dual modes of antitumor action of an amphiphilic peptide A(9)K. Biomaterials. 2013;34(11):2731-2737. doi:10.1016/j.biomaterials.2012.12.039
  177. Eliassen LT, Berge G, Leknessund A, et al. The antimicrobial peptide, lactoferricin B, is cytotoxic to neuroblastoma cells in vitro and inhibits xenograft growth in vivo. Int J Cancer. 2006;119(3):493-500. doi:10.1002/ijc.21886
  178. Yoo YC, Watanabe S, Watanabe R, Hata K, Shimazaki K, Azuma I. Bovine lactoferrin and lactoferricin, a peptide derived from bovine lactoferrin, inhibit tumor metastasis in mice. Jpn J Cancer Res. 1997;88(2):184-190. doi:10.1111/j.1349-7006.1997.tb00364.x