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Volume 22, Issue 4
  • ISSN: 1567-2018
  • E-ISSN: 1875-5704

Abstract

Cell-penetrating peptides (CPPs) comprise short peptides of fewer than 30 amino acids, which are rich in arginine (Arg) or lysine (Lys). CPPs have attracted interest in the delivery of various cargos, such as drugs, nucleic acids, and other macromolecules over the last 30 years. Among all types of CPPs, arginine-rich CPPs exhibit higher transmembrane efficiency due to bidentate bonding between their guanidinium groups and negatively charged cellular components. Besides, endosome escape can be induced by arginine-rich CPPs to protect cargo from lysosome-dependent degradation. Here we summarize the function, design principles, and penetrating mechanisms of arginine-rich CPPs, and outline their biomedical applications in drug delivery and biosensing in tumors.

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2025-05-04

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References

  1. GrovesJ.T. Membrane mechanics in living cells.Dev. Cell2019481151610.1016/j.devcel.2018.12.011 30620900
     [Google Scholar]
  2. BeltingM. SandgrenS. WittrupA. Nuclear delivery of macromolecules: Barriers and carriers.Adv. Drug Deliv. Rev.200557450552710.1016/j.addr.2004.10.004 15722161
     [Google Scholar]
  3. LangelU. Cell-penetrating peptides in design, synthesis and applications of oligonucleotide delivery.Amino Acids20093739
     [Google Scholar]
  4. CopoloviciD.M. LangelK. EristeE. LangelÜ. Cell-penetrating peptides: Design, synthesis, and applications.ACS Nano2014831972199410.1021/nn4057269 24559246
     [Google Scholar]
  5. GuidottiG. BrambillaL. RossiD. Cell-penetrating peptides: From basic research to clinics.Trends Pharmacol. Sci.201738440642410.1016/j.tips.2017.01.003 28209404
     [Google Scholar]
  6. KhalilI.A. KogureK. FutakiS. HarashimaH. High density of octaarginine stimulates macropinocytosis leading to efficient intracellular trafficking for gene expression.J. Biol. Chem.200628163544355110.1074/jbc.M503202200 16326716
     [Google Scholar]
  7. MäeM. LangelU. Cell-penetrating peptides as vectors for peptide, protein and oligonucleotide delivery.Curr. Opin. Pharmacol.20066550951410.1016/j.coph.2006.04.004 16860608
     [Google Scholar]
  8. VasconcelosL. PärnK. LangelÜ. Therapeutic potential of cell-penetrating peptides.Ther. Deliv.20134557359110.4155/tde.13.22 23647276
     [Google Scholar]
  9. CaoG. PeiW. GeH. LiangQ. LuoY. SharpF.R. LuA. RanR. GrahamS.H. ChenJ. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis.J. Neurosci.200222135423543110.1523/JNEUROSCI.22‑13‑05423.2002 12097494
     [Google Scholar]
  10. WarsoM.A. RichardsJ.M. MehtaD. ChristovK. SchaefferC. Rae BresslerL. YamadaT. MajumdarD. KennedyS.A. BeattieC.W. Das GuptaT.K. A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours.Br. J. Cancer201310851061107010.1038/bjc.2013.74 23449360
     [Google Scholar]
  11. YangD. SunY.Y. LinX. BaumannJ.M. DunnR.S. LindquistD.M. KuanC.Y. Intranasal delivery of cell-penetrating anti-NF-κB peptides (Tat-NBD) alleviates infection-sensitized hypoxic–ischemic brain injury.Exp. Neurol.201324744745510.1016/j.expneurol.2013.01.015 23353638
     [Google Scholar]
  12. XuJ. KhanA.R. FuM. WangR. JiJ. ZhaiG. Cell-penetrating peptide: A means of breaking through the physiological barriers of different tissues and organs.J. Control. Release201930910612410.1016/j.jconrel.2019.07.020 31323244
     [Google Scholar]
  13. KimS.W. KimN.Y. ChoiY.B. ParkS.H. YangJ.M. ShinS. RNA interference in vitro and in vivo using an arginine peptide/siRNA complex system.J. Control. Release2010143333534310.1016/j.jconrel.2010.01.009 20079391
     [Google Scholar]
  14. JafariM. ChenP. Peptide mediated siRNA delivery.Curr. Top. Med. Chem.20099121088109710.2174/156802609789630839 19860709
     [Google Scholar]
  15. El-SayedA. FutakiS. HarashimaH. Delivery of macromolecules using arginine-rich cell-penetrating peptides: Ways to overcome endosomal entrapment.AAPS J.2009111132210.1208/s12248‑008‑9071‑2 19125334
     [Google Scholar]
  16. WenderP.A. GalliherW.C. GounE.A. JonesL.R. PillowT.H. The design of guanidinium-rich transporters and their internalization mechanisms.Adv. Drug Deliv. Rev.2008604-545247210.1016/j.addr.2007.10.016 18164781
     [Google Scholar]
  17. FutakiS. NakaseI. Cell-surface interactions on arginine-rich cell-penetrating peptides allow for multiplex modes of internalization.Acc. Chem. Res.201750102449245610.1021/acs.accounts.7b00221 28910080
     [Google Scholar]
  18. FawellS. SeeryJ. DaikhY. MooreC. ChenL.L. PepinskyB. BarsoumJ. Tat-mediated delivery of heterologous proteins into cells.Proc. Natl. Acad. Sci. USA199491266466810.1073/pnas.91.2.664
     [Google Scholar]
  19. KadkhodayanS. BolhassaniA. SadatS.M. IraniS. FotouhiF. The efficiency of tat cell penetrating peptide for intracellular uptake of HIV-1 nef expressed in E. coli and mammalian cell.Curr. Drug Deliv.2017144536542 27719633
     [Google Scholar]
  20. FrankelA.D. PaboC.O. Cellular uptake of the tat protein from human immunodeficiency virus.Cell19885561189119310.1016/0092‑8674(88)90263‑2 2849510
     [Google Scholar]
  21. GreenM. LoewensteinP.M. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein.Cell19885561179118810.1016/0092‑8674(88)90262‑0 2849509
     [Google Scholar]
  22. ParkJ. RyuJ. KimK.A. LeeH.J. BahnJ.H. HanK. ChoiE.Y. LeeK.S. KwonH.Y. ChoiS.Y. 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.20028351173118110.1099/0022‑1317‑83‑5‑1173 11961273
     [Google Scholar]
  23. MitchellD.J. SteinmanL. KimD.T. FathmanC.G. RothbardJ.B. Polyarginine enters cells more efficiently than other polycationic homopolymers.J. Pept. Res.200056531832510.1034/j.1399‑3011.2000.00723.x 11095185
     [Google Scholar]
  24. NajjarK. Erazo-OliverasA. MosiorJ.W. WhitlockM.J. RostaneI. CinclairJ.M. PelloisJ.P. Unlocking endosomal entrapment with supercharged arginine-rich peptides.Bioconjug. Chem.201728122932294110.1021/acs.bioconjchem.7b00560 29065262
     [Google Scholar]
  25. ChuD. XuW. PanR. DingY. SuiW. ChenP. Rational modification of oligoarginine for highly efficient siRNA delivery: structure–activity relationship and mechanism of intracellular trafficking of siRNA.Nanomedicine201511243544610.1016/j.nano.2014.08.007 25193363
     [Google Scholar]
  26. VerdurmenW.P.R. BrockR. Biological responses towards cationic peptides and drug carriers.Trends Pharmacol. Sci.201132211612410.1016/j.tips.2010.11.005 21167610
     [Google Scholar]
  27. GounE.A. PillowT.H. JonesL.R. RothbardJ.B. WenderP.A. Molecular transporters: Synthesis of oligoguanidinium transporters and their application to drug delivery and real-time imaging.ChemBioChem20067101497151510.1002/cbic.200600171 16972294
     [Google Scholar]
  28. KosugeM. TakeuchiT. NakaseI. JonesA.T. FutakiS. Cellular internalization and distribution of arginine-rich peptides as a function of extracellular peptide concentration, serum, and plasma membrane associated proteoglycans.Bioconjug. Chem.200819365666410.1021/bc700289w 18269225
     [Google Scholar]
  29. NakaseI. NoguchiK. AokiA. Takatani-NakaseT. FujiiI. FutakiS. Arginine-rich cell-penetrating peptide-modified extracellular vesicles for active macropinocytosis induction and efficient intracellular deliverySci. Rep.-Uk20177
     [Google Scholar]
  30. BrockR. The uptake of arginine-rich cell-penetrating peptides: putting the puzzle together.Bioconjug. Chem.201425586386810.1021/bc500017t 24679171
     [Google Scholar]
  31. TashimaT. Intelligent substance delivery into cells using cell-penetrating peptides.Bioorg. Med. Chem. Lett.201727212113010.1016/j.bmcl.2016.11.083 27956345
     [Google Scholar]
  32. YangJ. LuoY. ShibuM.A. TothI. SkwarczynskiaM. Cell-penetrating Peptides: Efficient vectors for vaccine delivery.Curr. Drug Deliv.201916543044310.2174/1567201816666190123120915 30760185
     [Google Scholar]
  33. LiuB.R. ChiouS.H. HuangY.W. LeeH.J. Bio-membrane internalization mechanisms of arginine-rich cell-penetrating peptides in various species.Membranes20221218810.3390/membranes12010088 35054614
     [Google Scholar]
  34. RothbardJ.B. JessopT.C. LewisR.S. MurrayB.A. WenderP.A. Role of membrane potential and hydrogen bonding in the mechanism of translocation of guanidinium-rich peptides into cells.J. Am. Chem. Soc.2004126319506950710.1021/ja0482536 15291531
     [Google Scholar]
  35. KorenE. TorchilinV.P. Cell-penetrating peptides: Breaking through to the other side.Trends Mol. Med.201218738539310.1016/j.molmed.2012.04.012 22682515
     [Google Scholar]
  36. El-SayedA. KhalilI.A. KogureK. FutakiS. HarashimaH. Octaarginine- and octalysine-modified nanoparticles have different modes of endosomal escape.J. Biol. Chem.200828334234502346110.1074/jbc.M709387200 18550548
     [Google Scholar]
  37. KonateK. JosseE. TasicM. RedjattiK. AldrianG. DeshayesS. BoisguerinP. VivesE. WRAP-based nanoparticles for siRNA delivery: A SAR study and a comparison with lipid-based transfection reagents;J. Nanobiotechnol20211918
     [Google Scholar]
  38. FuselierT. WimleyW.C. Spontaneous membrane translocating peptides: the role of leucine-arginine consensus motifs.Biophys. J.2017113483584610.1016/j.bpj.2017.06.070 28834720
     [Google Scholar]
  39. PanR. XuW. DingY. LuS. ChenP. Uptake mechanism and direct translocation of a new CPP for siRNA delivery.Mol. Pharm.20161341366137410.1021/acs.molpharmaceut.6b00030 26937821
     [Google Scholar]
  40. PurijjalaP.W.C.M. RathnayakeP.V.G.M. KumaraB.T. GunathungeB.C.M. RanasingheR.A.A.P. KarunaratneD.N. RanatungaR.J.K.U. Multiscale modeling of the cellular uptake of C6 peptide-siRNA complexes.Comput. Biol. Chem.20229810767910.1016/j.compbiolchem.2022.107679 35462199
     [Google Scholar]
  41. TraboulsiH. LarkinH. BoninM.A. VolkovL. LavoieC.L. MarsaultÉ. Macrocyclic cell penetrating peptides: A study of structure-penetration properties.Bioconjug. Chem.201526340541110.1021/acs.bioconjchem.5b00023 25654426
     [Google Scholar]
  42. YamadaT. SignorelliS. CannistraroS. BeattieC.W. BizzarriA.R. Chirality switching within an anionic cell-penetrating peptide inhibits translocation without affecting preferential entry.Mol. Pharm.201512114014910.1021/mp500495u 25478723
     [Google Scholar]
  43. UedaY. WeiF.Y. HideT. MichiueH. TakayamaK. KaitsukaT. NakamuraH. MakinoK. KuratsuJ. FutakiS. TomizawaK. Induction of autophagic cell death of glioma-initiating cells by cell-penetrating d-isomer peptides consisting of Pas and the p53 C-terminus.Biomaterials201233359061906910.1016/j.biomaterials.2012.09.003 23006589
     [Google Scholar]
  44. TaiW. GaoX. Functional peptides for siRNA delivery.Adv. Drug Deliv. Rev.2017110-11115716810.1016/j.addr.2016.08.004 27530388
     [Google Scholar]
  45. MaY. GongC. MaY. FanF. LuoM. YangF. ZhangY.H. Direct cytosolic delivery of cargoes in vivo by a chimera consisting of D- and L-arginine residues.J. Control. Release2012162228629410.1016/j.jconrel.2012.07.022 22824782
     [Google Scholar]
  46. VerdurmenW.P.R. Bovee-GeurtsP.H. WadhwaniP. UlrichA.S. HällbrinkM. van KuppeveltT.H. BrockR. Preferential uptake of L- versus D-amino acid cell-penetrating peptides in a cell type-dependent manner.Chem. Biol.20111881000101010.1016/j.chembiol.2011.06.006 21867915
     [Google Scholar]
  47. ObaM. NaganoY. KatoT. TanakaM. Secondary structures and cell-penetrating abilities of arginine-rich peptide foldamers.Sci. Rep.2019911349
     [Google Scholar]
  48. AlmeidaP.F. LadokhinA.S. WhiteS.H. Hydrogen-bond energetics drive helix formation in membrane interfaces.Biochim. Biophys. Acta Biomembr.20121818217818210.1016/j.bbamem.2011.07.019 21802405
     [Google Scholar]
  49. KominA. BogoradM.I. LinR. CuiH. SearsonP.C. HristovaK. A peptide for transcellular cargo delivery: Structure-function relationship and mechanism of action.J. Control. Release202032463364310.1016/j.jconrel.2020.05.030 32474121
     [Google Scholar]
  50. PisaM.D. ChassaingG. SwiecickiJ.M. When cationic cell-penetrating peptides meet hydrocarbons to enhance in-cell cargo delivery.J. Pept. Sci.201521535636910.1002/psc.2755 25787823
     [Google Scholar]
  51. GuptaA. MandalD. AhmadibeniY. ParangK. BothunG. Hydrophobicity drives the cellular uptake of short cationic peptide ligands.Eur. Biophys. J.201140672773610.1007/s00249‑011‑0685‑4 21409455
     [Google Scholar]
  52. TakayamaK. HiroseH. TanakaG. PujalsS. KatayamaS. NakaseI. FutakiS. Effect of the attachment of a penetration accelerating sequence and the influence of hydrophobicity on octaarginine-mediated intracellular delivery.Mol. Pharm.2012951222123010.1021/mp200518n 22486588
     [Google Scholar]
  53. SwiecickiJ.M. Di PisaM. LippiF. ChwetzoffS. MansuyC. TrugnanG. ChassaingG. LavielleS. BurlinaF. Unsaturated acyl chains dramatically enhanced cellular uptake by direct translocation of a minimalist oligo-arginine lipopeptide.Chem. Commun.20155178146561465910.1039/C5CC06116D 26291669
     [Google Scholar]
  54. OhD. Nasrolahi ShiraziA. NorthupK. SullivanB. TiwariR.K. BisoffiM. ParangK. Enhanced cellular uptake of short polyarginine peptides through fatty acylation and cyclization.Mol. Pharm.20141182845285410.1021/mp500203e 24978295
     [Google Scholar]
  55. KatayamaS. HiroseH. TakayamaK. NakaseI. FutakiS. Acylation of octaarginine: Implication to the use of intracellular delivery vectors.J. Control. Release20111491293510.1016/j.jconrel.2010.02.004 20144669
     [Google Scholar]
  56. SchneiderA.F.L. KithilM. CardosoM.C. LehmannM. HackenbergerC.P.R. Cellular uptake of large biomolecules enabled by cell-surface-reactive cell-penetrating peptide additives.Nat. Chem.202113653053910.1038/s41557‑021‑00661‑x 33859390
     [Google Scholar]
  57. MuellerJ. KretzschmarI. VolkmerR. BoisguerinP. Comparison of cellular uptake using 22 CPPs in 4 different cell lines.Bioconjug. Chem.200819122363237410.1021/bc800194e 19053306
     [Google Scholar]
  58. FretzM.M. PenningN.A. Al-TaeiS. FutakiS. TakeuchiT. NakaseI. StormG. JonesA.T. Temperature-, concentration- and cholesterol-dependent translocation of L - and D -octa-arginine across the plasma and nuclear membrane of CD34+ leukaemia cells.Biochem. J.2007403233534210.1042/BJ20061808 17217340
     [Google Scholar]
  59. ChughA. EudesF. ShimY.S. Cell-penetrating peptides: Nanocarrier for macromolecule delivery in living cells.IUBMB Life201062318319310.1002/iub.297 20101631
     [Google Scholar]
  60. ZhuP. JinL. Cell penetrating peptides: A promising tool for the cellular uptake of macromolecular drugs.Curr. Protein Pept. Sci.2018192211220 28699510
     [Google Scholar]
  61. LundbergM. WikströmS. JohanssonM. Cell surface adherence and endocytosis of protein transduction domains.Mol. Ther.20038114315010.1016/S1525‑0016(03)00135‑7 12842437
     [Google Scholar]
  62. HiroseH. TakeuchiT. OsakadaH. PujalsS. KatayamaS. NakaseI. KobayashiS. HaraguchiT. FutakiS. Transient focal membrane deformation induced by arginine-rich peptides leads to their direct penetration into cells.Mol. Ther.201220598499310.1038/mt.2011.313 22334015
     [Google Scholar]
  63. Palm-ApergiC. LönnP. DowdyS.F. Do cell-penetrating peptides actually “penetrate” cellular membranes?Mol. Ther.201220469569710.1038/mt.2012.40 22472979
     [Google Scholar]
  64. NakaseI. KawaguchiY. NomizuM. FutakiS. Cellular uptake of arginine-rich cell-penetrating peptides and the contribution of membrane-associated proteoglycans.Trends Glycosci. Glycotechnol.201527155818810.4052/tigg.1420.1
     [Google Scholar]
  65. StanzlE.G. TrantowB.M. VargasJ.R. WenderP.A. Fifteen years of cell-penetrating, guanidinium-rich molecular transporters: Basic science, research tools, and clinical applications.Acc. Chem. Res.201346122944295410.1021/ar4000554 23697862
     [Google Scholar]
  66. JobinM.L. VamparysL. DeniauR. GrélardA. MackerethC. FuchsP. AlvesI. Biophysical insight on the membrane insertion of an arginine-rich cell-penetrating peptide.Int. J. Mol. Sci.20192018444110.3390/ijms20184441 31505894
     [Google Scholar]
  67. HerceH.D. GarciaA.E. CardosoM.C. Fundamental molecular mechanism for the cellular uptake of guanidinium-rich molecules.J. Am. Chem. Soc.201413650174591746710.1021/ja507790z 25405895
     [Google Scholar]
  68. Takechi-HarayaY. AkiK. TohyamaY. HaranoY. KawakamiT. SaitoH. OkamuraE. Glycosaminoglycan binding and non-endocytic membrane translocation of cell-permeable octaarginine monitored by real-time in-cell NMR spectroscopy.Pharmaceuticals20171044210.3390/ph10020042 28420127
     [Google Scholar]
  69. Takechi-HarayaY. SaitoH. Current understanding of physicochemical mechanisms for cell membrane penetration of Arginine-rich cell penetrating peptides: Role of glycosaminoglycan interactions.Curr. Protein Pept. Sci.201819662363010.2174/1389203719666180112100747 29332576
     [Google Scholar]
  70. Rádis-BaptistaG. CampeloI.S. MorlighemJ.É.R.L. MeloL.M. FreitasV.J.F. Cell-penetrating peptides (CPPs): From delivery of nucleic acids and antigens to transduction of engineered nucleases for application in transgenesis.J. Biotechnol.2017252152610.1016/j.jbiotec.2017.05.002 28479163
     [Google Scholar]
  71. Takechi-HarayaY. NadaiR. KimuraH. NishitsujiK. UchimuraK. Sakai-KatoK. KawakamiK. ShigenagaA. KawakamiT. OtakaA. HojoH. SakashitaN. SaitoH. Enthalpy-driven interactions with sulfated glycosaminoglycans promote cell membrane penetration of arginine peptides.Biochim. Biophys. Acta Biomembr.2016185861339134910.1016/j.bbamem.2016.03.021 27003128
     [Google Scholar]
  72. Gerbal-ChaloinS. GondeauC. Aldrian-HerradaG. HeitzF. Gauthier-RouvièreC. DivitaG. First step of the cell-penetrating peptide mechanism involves Rac1 GTPase-dependent actin-network remodelling.Biol. Cell200799422323810.1042/BC20060123 17233629
     [Google Scholar]
  73. KawaguchiY. TakeuchiT. KuwataK. ChibaJ. HatanakaY. NakaseI. FutakiS. Syndecan-4 is a receptor for clathrin-mediated endocytosis of arginine-rich cell-penetrating peptides.Bioconjug. Chem.20162741119113010.1021/acs.bioconjchem.6b00082 27019270
     [Google Scholar]
  74. WallbrecherR. VerdurmenW.P.R. SchmidtS. Bovee-GeurtsP.H. BroeckerF. ReinhardtA. van KuppeveltT.H. SeebergerP.H. BrockR. The stoichiometry of peptide-heparan sulfate binding as a determinant of uptake efficiency of cell-penetrating peptides.Cell. Mol. Life Sci.2014711427172729 24270856
     [Google Scholar]
  75. NakaseI. Biofunctional peptide-modified extracellular vesicles enable effective intracellular delivery via the induction of macropinocytosis.Processes20219222410.3390/pr9020224
     [Google Scholar]
  76. PujalsS. GiraltE. Proline-rich, amphipathic cell-penetrating peptides.Adv. Drug Deliv. Rev.2008604-547348410.1016/j.addr.2007.09.012 18187229
     [Google Scholar]
  77. KhandiaR. MunjalA. KumarA. SinghG. KarthikK. DhamaK. Cell penetrating peptides: Biomedical/therapeutic applications with emphasis as promising futuristic hope for treating cancer.Int. J. Pharmacol.201713767768910.3923/ijp.2017.677.689
     [Google Scholar]
  78. JärverP. MägerI. LangelÜ. In vivo biodistribution and efficacy of peptide mediated delivery.Trends Pharmacol. Sci.2010311152853510.1016/j.tips.2010.07.006 20828841
     [Google Scholar]
  79. PounyY. RapaportD. MorA. NicolasP. ShaiY. Interaction of antimicrobial dermaseptin and its fluorescently labeled analogs with phospholipid membranes.Biochemistry19923149124161242310.1021/bi00164a017 1463728
     [Google Scholar]
  80. ThennarasuS. TanA. PenumatchuR. ShelburneC.E. HeylD.L. RamamoorthyA. Antimicrobial and membrane disrupting activities of a peptide derived from the human cathelicidin antimicrobial peptide LL37.Biophys. J.201098224825710.1016/j.bpj.2009.09.060 20338846
     [Google Scholar]
  81. AlvesI. GoasdouéN. CorreiaI. AubryS. GalanthC. SaganS. LavielleS. ChassaingG. Membrane interaction and perturbation mechanisms induced by two cationic cell penetrating peptides with distinct charge distribution.Biochim. Biophys. Acta, Gen. Subj.200817807-894895910.1016/j.bbagen.2008.04.004 18498774
     [Google Scholar]
  82. HabaultJ. PoyetJ.L. Recent advances in cell penetrating peptide-based anticancer therapies.Molecules201924592710.3390/molecules24050927 30866424
     [Google Scholar]
  83. KauffmanW.B. FuselierT. HeJ. WimleyW.C. Mechanism Matters: A taxonomy of cell penetrating peptides.Trends Biochem. Sci.2015401274976410.1016/j.tibs.2015.10.004 26545486
     [Google Scholar]
  84. FutakiS. NakaseI. TadokoroA. TakeuchiT. JonesA.T. Arginine-rich peptides and their internalization mechanisms.Biochem. Soc. Trans.200735478478710.1042/BST0350784 17635148
     [Google Scholar]
  85. YeJ. LiuE. YuZ. PeiX. ChenS. ZhangP. ShinM.C. GongJ. HeH. YangV. CPP-assisted intracellular drug delivery, what is next?Int. J. Mol. Sci.20161711189210.3390/ijms17111892 27854260
     [Google Scholar]
  86. WangF. WangY. ZhangX. ZhangW. GuoS. JinF. Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery.J. Control. Release201417412613610.1016/j.jconrel.2013.11.020 24291335
     [Google Scholar]
  87. IslamM.Z. SharminS. MoniruzzamanM. YamazakiM. Elementary processes for the entry of cell-penetrating peptides into lipid bilayer vesicles and bacterial cells.Appl. Microbiol. Biotechnol.201810293879389210.1007/s00253‑018‑8889‑5 29523934
     [Google Scholar]
  88. CardosoA.M.S. TrabuloS. CardosoA.L. LorentsA. MoraisC.M. GomesP. NunesC. LúcioM. ReisS. PadariK. PoogaM. Pedroso de LimaM.C. JuradoA.S. S4(13)-PV cell-penetrating peptide induces physical and morphological changes in membrane-mimetic lipid systems and cell membranes: Implications for cell internalization.Biochim. Biophys. Acta Biomembr.20121818387788810.1016/j.bbamem.2011.12.022 22230348
     [Google Scholar]
  89. JiaoC.Y. DelarocheD. BurlinaF. AlvesI.D. ChassaingG. SaganS. Translocation and endocytosis for cell-penetrating peptide internalization.J. Biol. Chem.200928449339573396510.1074/jbc.M109.056309 19833724
     [Google Scholar]
  90. DuchardtF. Fotin-MleczekM. SchwarzH. FischerR. BrockR. A comprehensive model for the cellular uptake of cationic cell-penetrating peptides.Traffic20078784886610.1111/j.1600‑0854.2007.00572.x 17587406
     [Google Scholar]
  91. TünnemannG. MartinR.M. HauptS. PatschC. EdenhoferF. CardosoM.C. Cargo-dependent mode of uptake and bioavailability of TAT-containing proteins and peptides in living cells.FASEB J.200620111775178410.1096/fj.05‑5523com 16940149
     [Google Scholar]
  92. AllolioC. MagarkarA. JurkiewiczP. BaxováK. JavanainenM. MasonP.E. ŠachlR. CebecauerM. HofM. HorinekD. HeinzV. RachelR. ZieglerC.M. SchröfelA. JungwirthP. Arginine-rich cell-penetrating peptides induce membrane multilamellarity and subsequently enter via formation of a fusion pore.Proc. Natl. Acad. Sci. USA201811547119231192810.1073/pnas.1811520115 30397112
     [Google Scholar]
  93. BorrelliA. TorneselloA. TorneselloM. BuonaguroF. Cell penetrating peptides as molecular carriers for anti-cancer agents.Molecules201823229510.3390/molecules23020295 29385037
     [Google Scholar]
  94. RichardJ.P. MelikovK. VivesE. RamosC. VerbeureB. GaitM.J. ChernomordikL.V. LebleuB. Cell-penetrating peptides.J. Biol. Chem.2003278158559010.1074/jbc.M209548200 12411431
     [Google Scholar]
  95. LimJ.P. GleesonP.A. Macropinocytosis: An endocytic pathway for internalising large gulps.Immunol. Cell Biol.201189883684310.1038/icb.2011.20 21423264
     [Google Scholar]
  96. WadiaJ.S. StanR.V. DowdyS.F. Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis.Nat. Med.200410331031510.1038/nm996 14770178
     [Google Scholar]
  97. NakaseI. NiwaM. TakeuchiT. SonomuraK. KawabataN. KoikeY. TakehashiM. TanakaS. UedaK. SimpsonJ.C. JonesA.T. SugiuraY. FutakiS. Cellular uptake of arginine-rich peptides: roles for macropinocytosis and actin rearrangement.Mol. Ther.20041061011102210.1016/j.ymthe.2004.08.010 15564133
     [Google Scholar]
  98. RichardJ.P. MelikovK. BrooksH. PrevotP. LebleuB. ChernomordikL.V. Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis and heparan sulfate receptors.J. Biol. Chem.200528015153001530610.1074/jbc.M401604200 15687490
     [Google Scholar]
  99. MousaviS.A. MalerødL. BergT. KjekenR. Clathrin-dependent endocytosis.Biochem. J.2004377111610.1042/bj20031000 14505490
     [Google Scholar]
  100. PelkmansL. HeleniusA. Endocytosis via caveolae.Traffic20023531132010.1034/j.1600‑0854.2002.30501.x 11967125
     [Google Scholar]
  101. MaioloJ.R. FerrerM. OttingerE.A. Effects of cargo molecules on the cellular uptake of arginine-rich cell-penetrating peptides.Biochim. Biophys. Acta Biomembr.20051712216117210.1016/j.bbamem.2005.04.010 15935328
     [Google Scholar]
  102. ZhaoX. ChenB. HanJ. WeiL. PanX. Delivery of cell-penetrating peptide-peptide nucleic acid conjugates by assembly on an oligonucleotide scaffold.Sci. Rep.-Uk20155
     [Google Scholar]
  103. McCloreyG. BanerjeeS. Cell-Penetrating peptides to enhance delivery of oligonucleotide-based therapeutics.Biomedicines2018625110.3390/biomedicines6020051 29734750
     [Google Scholar]
  104. WallbrecherR. AckelsT. OleaR.A. KleinM.J. CaillonL. SchillerJ. Bovée-GeurtsP.H. van KuppeveltT.H. UlrichA.S. SpehrM. Adjobo-HermansM.J.W. BrockR. Membrane permeation of arginine-rich cell-penetrating peptides independent of transmembrane potential as a function of lipid composition and membrane fluidity.J. Control. Release2017256687810.1016/j.jconrel.2017.04.013 28411183
     [Google Scholar]
  105. van den BergA. DowdyS.F. Protein transduction domain delivery of therapeutic macromolecules.Curr. Opin. Biotechnol.201122688889310.1016/j.copbio.2011.03.008 21489777
     [Google Scholar]
  106. HitzT. ItenR. GardinerJ. NamotoK. WaldeP. SeebachD. Interaction of alpha-and beta-oligoarginine-acids and amides with anionic lipid vesicles: A mechanistic and thermodynamic study.Biochemistry200645185817582910.1021/bi060285d 16669625
     [Google Scholar]
  107. LundbergP. El-AndaloussiS. SütlüT. JohanssonH. LangelÜ. Delivery of short interfering RNA using endosomolytic cell-penetrating peptides.FASEB J.200721112664267110.1096/fj.06‑6502com 17463227
     [Google Scholar]
  108. LoS.L. WangS. An endosomolytic Tat peptide produced by incorporation of histidine and cysteine residues as a nonviral vector for DNA transfection.Biomaterials200829152408241410.1016/j.biomaterials.2008.01.031 18295328
     [Google Scholar]
  109. BeloorJ. ZellerS. ChoiC.S. LeeS.K. KumarP. Cationic cell-penetrating peptides as vehicles for siRNA delivery.Ther. Deliv.20156449150710.4155/tde.15.2 25996046
     [Google Scholar]
  110. XiaM.C. CaiL. YangY. ZhangS. ZhangX. Tuning the p Ka of carboxyfluorescein with arginine-rich cell-penetrating peptides for intracellular pH imaging.Anal. Chem.201991149168917310.1021/acs.analchem.9b01864 31251035
     [Google Scholar]
  111. OhE. DelehantyJ.B. SapsfordK.E. SusumuK. GoswamiR. Blanco-CanosaJ.B. DawsonP.E. GranekJ. ShoffM. ZhangQ. GoeringP.L. HustonA. MedintzI.L. Cellular uptake and fate of PEGylated gold nanoparticles is dependent on both cell-penetration peptides and particle size.ACS Nano2011586434644810.1021/nn201624c 21774456
     [Google Scholar]
  112. PanL. HeQ. LiuJ. ChenY. MaM. ZhangL. ShiJ. Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nanoparticles.J. Am. Chem. Soc.2012134135722572510.1021/ja211035w 22420312
     [Google Scholar]
  113. MartinR.M. HerceH.D. LudwigA.K. CardosoM.C. Visualization of the Nucleolus in Living Cells with Cell-Penetrating Fluorescent Peptides; In: The Nucleolus Methods and Protocals. NemethA. New YorkHumans Press2016Vol. 145510.1007/978‑1‑4939‑3792‑9_6
     [Google Scholar]
  114. HowlJ. JonesS. Cell penetrating peptide-mediated transport enables the regulated secretion of accumulated cargoes from mast cells.J. Control. Release201520210811710.1016/j.jconrel.2015.02.005 25660072
     [Google Scholar]
  115. TanX. ZhangY. WangQ. RenT. GouJ. GuoW. YinT. HeH. ZhangY. TangX. Cell-penetrating peptide together with PEG-modified mesostructured silica nanoparticles promotes mucous permeation and oral delivery of therapeutic proteins and peptides.Biomater. Sci.2019729342950
     [Google Scholar]
  116. ZhangP. ZhangH. ZhengB. WangH. QiX. WangS. LiuZ. SunL. LiuY. QinX. FanW. MaM. LaiW.F. ZhangD. Combined self-assembled hendeca-arginine nanocarriers for effective targeted gene delivery to bladder cancer.Int. J. Nanomedicine2022174433444810.2147/IJN.S379356 36172006
     [Google Scholar]
  117. DingY. JiangZ. SahaK. KimC.S. KimS.T. LandisR.F. RotelloV.M. Gold nanoparticles for nucleic acid delivery.Mol. Ther.20142261075108310.1038/mt.2014.30 24599278
     [Google Scholar]
  118. DuanL. XuL. XuX. QinZ. ZhouX. XiaoY. LiangY. XiaJ. Exosome-mediated delivery of gene vectors for gene therapy.Nanoscale20211331387139710.1039/D0NR07622H 33350419
     [Google Scholar]
  119. van den BergA.I.S. YunC.O. SchiffelersR.M. HenninkW.E. Polymeric delivery systems for nucleic acid therapeutics: Approaching the clinic.J. Control. Release202133112114110.1016/j.jconrel.2021.01.014 33453339
     [Google Scholar]
  120. SadeghianI. HeidariR. SadeghianS. RaeeM.J. NegahdaripourM. Potential of cell-penetrating peptides (CPPs) in delivery of antiviral therapeutics and vaccines.Eur. J. Pharm. Sci.202216910609410.1016/j.ejps.2021.106094 34896590
     [Google Scholar]
  121. BoisguérinP. DeshayesS. GaitM.J. O’DonovanL. GodfreyC. BettsC.A. WoodM.J.A. LebleuB. Delivery of therapeutic oligonucleotides with cell penetrating peptides.Adv. Drug Deliv. Rev.201587526710.1016/j.addr.2015.02.008 25747758
     [Google Scholar]
  122. NakaseI. TanakaG. FutakiS. Cell-penetrating peptides (CPPs) as a vector for the delivery of siRNAs into cells.Mol. Biosyst.20139585586110.1039/c2mb25467k 23306408
     [Google Scholar]
  123. LiuL. LuH. ShiR. PengX.X. XiangQ. WangB. WanQ.Q. SunY. YangF. ZhangG.J. Synergy of peptide–nucleic acid and spherical nucleic acid enabled quantitative and specific detection of tumor exosomal MicroRNA.Anal. Chem.20199120131981320510.1021/acs.analchem.9b03622 31553171
     [Google Scholar]
  124. LiuB.R. LinM.D. ChiangH.J. LeeH.J. Arginine-rich cell-penetrating peptides deliver gene into living human cells.Gene20125051374510.1016/j.gene.2012.05.053 22669044
     [Google Scholar]
  125. KumarP. WuH. McBrideJ.L. JungK.E. Hee KimM. DavidsonB.L. Kyung LeeS. ShankarP. ManjunathN. Transvascular delivery of small interfering RNA to the central nervous system.Nature20074487149394310.1038/nature05901 17572664
     [Google Scholar]
  126. LangJ. ZhaoX. QiY. ZhangY. HanX. DingY. GuanJ. JiT. ZhaoY. NieG. Reshaping prostate tumor microenvironment to suppress metastasis via cancer-associated fibroblast inactivation with peptide-assembly-based nanosystem.ACS Nano20191311123571237110.1021/acsnano.9b04857 31545587
     [Google Scholar]
  127. MartinM.E. RiceK.G. Peptide-guided gene delivery.AAPS J.200791E18E2910.1208/aapsj0901003 17408236
     [Google Scholar]
  128. ZhangL. BennettW.F.D. ZhengT. OuyangP.K. OuyangX. QiuX. LuoA. KarttunenM. ChenP. Effect of cholesterol on cellular uptake of cancer drugs pirarubicin and ellipticine.J. Phys. Chem. B2016120123148315610.1021/acs.jpcb.5b12337 26937690
     [Google Scholar]
  129. DubikovskayaE.A. ThorneS.H. PillowT.H. ContagC.H. WenderP.A. Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters.Proc. Natl. Acad. Sci.200810534121281213310.1073/pnas.0805374105 18713866
     [Google Scholar]
  130. ArouiS. BrahimS. De WaardM. BréardJ. KenaniA. Efficient induction of apoptosis by doxorubicin coupled to cell-penetrating peptides compared to unconjugated doxorubicin in the human breast cancer cell line MDA-MB 231.Cancer Lett.20092851283810.1016/j.canlet.2009.04.044 19523755
     [Google Scholar]
  131. LindgrenM. Rosenthal-AizmanK. SaarK. EiríksdóttirE. JiangY. SassianM. ÖstlundP. HällbrinkM. LangelÜ. Overcoming methotrexate resistance in breast cancer tumour cells by the use of a new cell-penetrating peptide.Biochem. Pharmacol.200671441642510.1016/j.bcp.2005.10.048 16376307
     [Google Scholar]
  132. DeshpandeP. JhaveriA. PattniB. BiswasS. TorchilinV. Transferrin and octaarginine modified dual-functional liposomes with improved cancer cell targeting and enhanced intracellular delivery for the treatment of ovarian cancer.Drug Deliv.201825151753210.1080/10717544.2018.1435747 29433357
     [Google Scholar]
  133. TakaraK. HatakeyamaH. KibriaG. OhgaN. HidaK. HarashimaH. Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise for use in drug-resistant cancer therapy.J. Control. Release2012162122523210.1016/j.jconrel.2012.06.019 22728515
     [Google Scholar]
  134. LiuY. LuZ. MeiL. YuQ. TaiX. WangY. ShiK. ZhangZ. HeQ. Tandem peptide based on structural modification of poly-arginine for enhancing tumor targeting efficiency and therapeutic effect.ACS Appl. Mater. Interfaces2017932083209210.1021/acsami.6b12611 28025892
     [Google Scholar]
  135. PengY.Y. HuH. Diaz-DussanD. ZhaoJ. HaoX. NarainR. Glycopolymer–Cell-Penetrating Peptide (CPP) conjugates for efficient epidermal growth factor receptor (EGFR) silencing.ACS Macro Lett.202211458058710.1021/acsmacrolett.2c00046 35575337
     [Google Scholar]
  136. SerJ. LeeJ.Y. KimY.H. ChoH. Enhanced efficacy of photodynamic therapy by coupling a cell-penetrating peptide with methylene blue.Int. J. Nanomedicine2020155803581110.2147/IJN.S254881 32821102
     [Google Scholar]
  137. BiswasS. DeshpandeP.P. PercheF. DodwadkarN.S. SaneS.D. TorchilinV.P. Octa-arginine-modified pegylated liposomal doxorubicin: An effective treatment strategy for non-small cell lung cancer.Cancer Lett.2013335119120010.1016/j.canlet.2013.02.020 23419527
     [Google Scholar]
  138. YueG. WangC. LiuB. WuM. HuangY. GuoY. MaQ. Liposomes co-delivery system of doxorubicin and astragaloside IV co-modified by folate ligand and octa-arginine polypeptide for anti-breast cancer.RSC Advances20201020115731158110.1039/C9RA09040A 35496626
     [Google Scholar]
  139. CheungC.H.A. SunX. KanwarJ.R. BaiJ. ChengL. KrissansenG.W. A cell-permeable dominant-negative survivin protein induces apoptosis and sensitizes prostate cancer cells to TNF-alpha therapy.Cancer Cell Int.20101036
     [Google Scholar]
  140. ZhongG. XuZ. YangR. ZhangS. LiL. WuM. LiuH. ZhenY. An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDM fusion protein shows potent antitumor efficacy in pancreatic cancer.J. Cancer20189467468210.7150/jca.22277 29556325
     [Google Scholar]
  141. XiaoD. HuangY. HuangS. ZhuangJ. ChenP. WangY. ZhangL. Targeted delivery of cancer drug paclitaxel to chordomas tumor cells via an RNA nanoparticle harboring an EGFR aptamer.Colloids Surf. B Biointerfaces202221211236610.1016/j.colsurfb.2022.112366 35144131
     [Google Scholar]
  142. OkudaA. FutakiS. Protein delivery to cytosol by cell-penetrating peptide bearing tandem repeat penetration-accelerating sequence.Methods Mol. Biol.2022238326527310.1007/978‑1‑0716‑1752‑6_18 34766296
     [Google Scholar]
  143. ChenJ.X. XuX.D. YangS. YangJ. ZhuoR.X. ZhangX.Z. Self-assembled BolA-like amphiphilic peptides as viral-mimetic gene vectors for cancer cell targeted gene delivery.Macromol. Biosci.2013131849210.1002/mabi.201200283 23281275
     [Google Scholar]
  144. JiT. DingY. ZhaoY. WangJ. QinH. LiuX. LangJ. ZhaoR. ZhangY. ShiJ. TaoN. QinZ. NieG. Peptide assembly integration of fibroblast-targeting and cell-penetration features for enhanced antitumor drug delivery.Adv. Mater.201527111865187310.1002/adma.201404715 25651789
     [Google Scholar]
  145. ZhangZ. MorsteinJ. EckerA.K. GuileyK.Z. ShokatK.M. Chemoselective covalent modification of K-Ras(G12R) with a small molecule electrophile.J. Am. Chem. Soc.202214435159161592110.1021/jacs.2c05377 36001446
     [Google Scholar]
  146. HsiehJ.T. ZhouJ. GoreC. ZimmernP. R11, a novel cell-permeable peptide, as an intravesical delivery vehicle.BJU Int.2011108101666167110.1111/j.1464‑410X.2011.10185.x 21453348
     [Google Scholar]
  147. DuY. WangL. WangW. GuoT. ZhangM. ZhangP. ZhangY. WuK. LiA. WangX. HeJ. FanJ. Novel application of cell penetrating r11 peptide for diagnosis of bladder cancer.J. Biomed. Nanotechnol.201814116116710.1166/jbn.2018.2499 29463373
     [Google Scholar]
  148. DingC. WuK. WangW. GuanZ. wang, L.; Wang, X.; Wang, R.; Liu, L.; Fan, J. Synthesis of a cell penetrating peptide modified superparamagnetic iron oxide and MRI detection of bladder cancer.Oncotarget2017834718472910.18632/oncotarget.13578 27902468
     [Google Scholar]
  149. ZhangT. WuK. DingC. SunK. GuanZ. WangX. HsiehJ.T. HeD. FanJ. Inhibiting bladder tumor growth with a cell penetrating R11 peptide derived from the p53 C-terminus.Oncotarget2015635377823779110.18632/oncotarget.5622 26462022
     [Google Scholar]
  150. ZhengB. LiuZ. WangH. SunL. LaiW.F. ZhangH. WangJ. LiuY. QinX. QiX. WangS. ShenY. ZhangP. ZhangD. R11 modified tumor cell membrane nanovesicle-camouflaged nanoparticles with enhanced targeting and mucus-penetrating efficiency for intravesical chemotherapy for bladder cancer.J. Control. Release202235183484610.1016/j.jconrel.2022.09.055 36191674
     [Google Scholar]
  151. UnkartJ.T. ChenS.L. WapnirI.L. GonzálezJ.E. HarootunianA. WallaceA.M. Intraoperative tumor detection using a ratiometric activatable fluorescent peptide: A first-in-human phase 1 study.Ann. Surg. Oncol.201724113167317310.1245/s10434‑017‑5991‑3 28699134
     [Google Scholar]
  152. ZhangZ. YuanY. LiuZ. ChenH. ChenD. FangX. ZhengJ. QinW. WuC. Brightness enhancement of near-infrared semiconducting polymer dots for in vivo whole-body cell tracking in deep organs.ACS Appl. Mater. Interfaces20181032269282693510.1021/acsami.8b08735 30033725
     [Google Scholar]
  153. LiuZ. XiongM. GongJ. ZhangY. BaiN. LuoY. LiL. WeiY. LiuY. TanX. XiangR. Legumain protease-activated TAT-liposome cargo for targeting tumours and their microenvironment.Nat. Commun.201451428010.1038/ncomms5280 24969588
     [Google Scholar]
  154. AguileraT. A. OlsonE. S. TimmersM. M. JiangT. TsienR. Y. Systemic in vivo distribution of activatable cell penetrating peptides is superior to that of cell penetrating peptides.Integr. Biol.-Uk2009137138110.1039/b904878b20023744
     [Google Scholar]
  155. HaoG. ZhouJ. GuoY. LongM.A. AnthonyT. StanfieldJ. HsiehJ.T. SunX. A cell permeable peptide analog as a potential-specific PET imaging probe for prostate cancer detection.Amino Acids20114151093110110.1007/s00726‑010‑0515‑5 20221650
     [Google Scholar]
  156. TanM. LanK.H. YaoJ. LuC.H. SunM. NealC.L. LuJ. YuD. Selective inhibition of ErbB2-overexpressing breast cancer in vivo by a novel TAT-based ErbB2-targeting signal transducers and activators of transcription 3-blocking peptide.Cancer Res.20066673764377210.1158/0008‑5472.CAN‑05‑2747 16585203
     [Google Scholar]
  157. ChenH.H. KhatunZ. WeiL. MekkaouiC. PatelD. KimS.J.W. BoukhalfaA. EnomaE. MengL. ChenY.I. KaikkonenL. LiG. CapenD.E. SahuP. KumarA.T.N. BlantonR.M. YuanH. DasS. JosephsonL. SosnovikD.E. A nanoparticle probe for the imaging of autophagic flux in live mice via magnetic resonance and near-infrared fluorescence.Nat. Biomed. Eng.2022691045105610.1038/s41551‑022‑00904‑3 35817962
     [Google Scholar]
  158. MaM. ZhangP. LiangX. CuiD. ShaoQ. ZhangH. ZhangM. YangT. WangL. ZhangN. JingM. ZhangL. DanW. SongR. LiuX. HaoJ. ChenY. GuL. WangL. FanJ. R11 peptides can promote the molecular imaging of spherical nucleic acids for bladder cancer margin identification.Nano Res.20221532278228710.1007/s12274‑021‑3807‑z
     [Google Scholar]
  159. WalrantA. CardonS. BurlinaF. SaganS. Membrane crossing and membranotropic activity of cell-penetrating peptides: Dangerous Liaisons?Acc. Chem. Res.201750122968297510.1021/acs.accounts.7b00455 29172443
     [Google Scholar]
/content/journals/cdd/10.2174/1567201820666230417083350
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Biological Properties of Arginine-rich Peptides and their Application in Cargo Delivery to Cancer
Curr. Drug Deliv. 22, 387 (2025); https://doi.org/10.2174/1567201820666230417083350
/content/journals/cdd/10.2174/1567201820666230417083350
/content/journals/cdd/10.2174/1567201820666230417083350
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  • Article Type:     Review Article
Keyword(s): Arginine-rich CPPs; lysine (Lys); phospholipids; polyarginines; PTDs; TAT

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