Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Cell-penetrating Peptides as Keys to Endosomal Escape and Intracellular Trafficking in Nanomedicine Delivery

Author(s): Sakshi Soni, Shivam K. Kori, Priyanshu Nema, Arun K. Iyer, Vandana Soni* and Sushil K. Kashaw*

Volume 32, Issue 7, 2025

Published on: 15 February, 2024

Page: [1288 - 1312] Pages: 25

DOI: 10.2174/0109298673278936240107121907

Price: $65

TIMBC 2025
Abstract

This review article discusses the challenges of delivering cargoes to the cytoplasm, for example, proteins, peptides, and nucleic acids, and the mechanisms involved in endosomal escape. Endocytosis, endosomal maturation, and exocytosis pose significant barriers to effective cytoplasmic delivery. The article explores various endosomal escape mechanisms, such as the proton sponge effect, osmotic lysis, membrane fusion, pore formation, membrane destabilization/ disruption, and vesicle budding and collapse. Additionally, it discusses the role of lysosomes, glycocalyx, and molecular crowding in the cytoplasmic delivery process. Despite the recent advances in nonviral delivery systems, there is still a need to improve cytoplasmic delivery. Strategies such as fusogenic peptides, endosomolytic polymers, and cell-penetrating peptides have shown promise in improving endosomal escape and cytoplasmic delivery. More research is needed to refine these strategies and make them safer and more effective. In conclusion, the article highlights the challenges associated with cytoplasmic delivery and the importance of understanding the mechanisms involved in endosomal escape. A better understanding of these processes could result in the creation of greater effectiveness and safe delivery systems for various cargoes, including proteins, peptides, and nucleic acids.

Keywords: Endosomal escape, nanoparticle delivery, cytoplasmic trafficking, siRNA, nonviral vectors, membrane fusion, lysosome.

« Previous Next »
[1]
Adler, M.; Mayo, A.; Zhou, X.; Franklin, R.A.; Jacox, J.B.; Medzhitov, R.; Alon, U. Endocytosis as a stabilizing mechanism for tissue homeostasis. Proc. Natl. Acad. Sci., 2018, 115(8), E1926-E1935.
[http://dx.doi.org/10.1073/pnas.1714377115] [PMID: 29429964]
[2]
Sahay, G.; Alakhova, D.Y.; Kabanov, A.V. Endocytosis of nanomedicines. J. Control. Release, 2010, 145(3), 182-195.
[http://dx.doi.org/10.1016/j.jconrel.2010.01.036] [PMID: 20226220]
[3]
Akinc, A.; Battaglia, G. Exploiting endocytosis for nanomedicines. Cold Spring Harb. Perspect. Biol., 2013, 5(11), a016980.
[http://dx.doi.org/10.1101/cshperspect.a016980] [PMID: 24186069]
[4]
Mosquera, J.; García, I.; Liz-Marzán, L.M. Cellular uptake of nanoparticles versus small molecules: A matter of size. Acc. Chem. Res., 2018, 51(9), 2305-2313.
[http://dx.doi.org/10.1021/acs.accounts.8b00292] [PMID: 30156826]
[5]
Prior, I.A.; Harding, A.; Yan, J.; Sluimer, J.; Parton, R.G.; Hancock, J.F. GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nat. Cell Biol., 2001, 3(4), 368-375.
[http://dx.doi.org/10.1038/35070050] [PMID: 11283610]
[6]
Denzer, K.; Kleijmeer, M.J.; Heijnen, H.F.G.; Stoorvogel, W.; Geuze, H.J. Exosome: From internal vesicle of the multivesicular body to intercellular signaling device. J. Cell Sci., 2000, 113(19), 3365-3374.
[http://dx.doi.org/10.1242/jcs.113.19.3365] [PMID: 10984428]
[7]
Sousa de Almeida, M.; Susnik, E.; Drasler, B.; Taladriz-Blanco, P.; Petri-Fink, A.; Rothen-Rutishauser, B. Understanding nanoparticle endocytosis to improve targeting strategies in nanomedicine. Chem. Soc. Rev., 2021, 50(9), 5397-5434.
[http://dx.doi.org/10.1039/D0CS01127D] [PMID: 33666625]
[8]
Sabnis, S.; Kumarasinghe, E.S.; Salerno, T.; Mihai, C.; Ketova, T.; Senn, J.J.; Lynn, A.; Bulychev, A.; McFadyen, I.; Chan, J.; Almarsson, Ö.; Stanton, M.G.; Benenato, K.E. A novel amino lipid series for mRNA delivery: Improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther., 2018, 26(6), 1509-1519.
[http://dx.doi.org/10.1016/j.ymthe.2018.03.010] [PMID: 29653760]
[9]
Patel, S.; Kim, J.; Herrera, M.; Mukherjee, A.; Kabanov, A.V.; Sahay, G. Brief update on endocytosis of nanomedicines. Adv. Drug Deliv. Rev., 2019, 144, 90-111.
[http://dx.doi.org/10.1016/j.addr.2019.08.004] [PMID: 31419450]
[10]
Zhang, J.; Wang, X.; Wen, J.; Su, X.; Weng, L.; Wang, C.; Tian, Y.; Zhang, Y.; Tao, J.; Xu, P.; Lu, G.; Teng, Z.; Wang, L. Size effect of mesoporous organosilica nanoparticles on tumor penetration and accumulation. Biomater. Sci., 2019, 7(11), 4790-4799.
[http://dx.doi.org/10.1039/C9BM01164A] [PMID: 31524909]
[11]
Ballabio, A. The awesome lysosome. EMBO Mol. Med., 2016, 8(2), 73-76.
[http://dx.doi.org/10.15252/emmm.201505966] [PMID: 26787653]
[12]
Wittrup, A.; Ai, A.; Liu, X.; Hamar, P.; Trifonova, R.; Charisse, K.; Manoharan, M.; Kirchhausen, T.; Lieberman, J. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol., 2015, 33(8), 870-876.
[http://dx.doi.org/10.1038/nbt.3298] [PMID: 26192320]
[13]
Smith, S.A.; Selby, L.I.; Johnston, A.P.R.; Such, G.K. The endosomal escape of nanoparticles: Toward more efficient cellular delivery. Bioconjug. Chem., 2019, 30(2), 263-272.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00732] [PMID: 30452233]
[14]
Selby, L.I.; Cortez-Jugo, C.M.; Such, G.K.; Johnston, A.P.R. Nanoescapology: Progress toward understanding the endosomal escape of polymeric nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2017, 9(5), e1452.
[http://dx.doi.org/10.1002/wnan.1452] [PMID: 28160452]
[15]
Perera, R.M.; Zoncu, R. The lysosome as a regulatory hub. Annu. Rev. Cell Dev. Biol., 2016, 32(1), 223-253.
[http://dx.doi.org/10.1146/annurev-cellbio-111315-125125] [PMID: 27501449]
[16]
Lim, C.Y.; Zoncu, R. The lysosome as a command-and-control center for cellular metabolism. J. Cell Biol., 2016, 214(6), 653-664.
[http://dx.doi.org/10.1083/jcb.201607005] [PMID: 27621362]
[17]
Rabanal-Ruiz, Y.; Korolchuk, V. mTORC1 and nutrient homeostasis: The central role of the lysosome. Int. J. Mol. Sci., 2018, 19(3), 818.
[http://dx.doi.org/10.3390/ijms19030818] [PMID: 29534520]
[18]
Saha, S.; Panigrahi, D.P.; Patil, S.; Bhutia, S.K. Autophagy in health and disease: A comprehensive review. Biomed. Pharmacother., 2018, 104, 485-495.
[http://dx.doi.org/10.1016/j.biopha.2018.05.007] [PMID: 29800913]
[19]
Maxfield, F.R. Role of endosomes and lysosomes in human disease. Cold Spring Harb. Perspect. Biol., 2014, 6(5), a016931.
[http://dx.doi.org/10.1101/cshperspect.a016931] [PMID: 24789821]
[20]
Boustany, R.M.N. Lysosomal storage diseases—the horizon expands. Nat. Rev. Neurol., 2013, 9(10), 583-598.
[http://dx.doi.org/10.1038/nrneurol.2013.163] [PMID: 23938739]
[21]
Castanheira, S.; García-del Portillo, F. Salmonella populations inside host cells. Front. Cell. Infect. Microbiol., 2017, 7, 432.
[http://dx.doi.org/10.3389/fcimb.2017.00432] [PMID: 29046870]
[22]
Leung, K.; Chakraborty, K.; Saminathan, A.; Krishnan, Y. A DNA nanomachine chemically resolves lysosomes in live cells. Nat. Nanotechnol., 2019, 14(2), 176-183.
[http://dx.doi.org/10.1038/s41565-018-0318-5] [PMID: 30510277]
[23]
Wang, C.; Zhao, T.; Li, Y.; Huang, G.; White, M.A.; Gao, J. Investigation of endosome and lysosome biology by ultra pH-sensitive nanoprobes. Adv. Drug Deliv. Rev., 2017, 113, 87-96.
[http://dx.doi.org/10.1016/j.addr.2016.08.014] [PMID: 27612550]
[24]
Batrakova, E.V.; Kim, M.S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J. Control. Release, 2015, 219, 396-405.
[http://dx.doi.org/10.1016/j.jconrel.2015.07.030] [PMID: 26241750]
[25]
Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol., 2019, 21(1), 9-17.
[http://dx.doi.org/10.1038/s41556-018-0250-9] [PMID: 30602770]
[26]
Jiang, X.C.; Gao, J.Q. Exosomes as novel bio-carriers for gene and drug delivery. Int. J. Pharm., 2017, 521(1-2), 167-175.
[http://dx.doi.org/10.1016/j.ijpharm.2017.02.038] [PMID: 28216464]
[27]
Haney, M.J.; Klyachko, N.L.; Harrison, E.B.; Zhao, Y.; Kabanov, A.V.; Batrakova, E.V. TPP1 delivery to lysosomes with extracellular vesicles and their enhanced brain distribution in the animal model of batten disease. Adv. Healthc. Mater., 2019, 8(11), 1801271.
[http://dx.doi.org/10.1002/adhm.201801271] [PMID: 30997751]
[28]
Chen, W.H.; Luo, G.F.; Zhang, X.Z. Recent advances in subcellular targeted cancer therapy based on functional materials. Adv. Mater., 2019, 31(3), 1802725.
[http://dx.doi.org/10.1002/adma.201802725] [PMID: 30260521]
[29]
Donahue, N.D.; Acar, H.; Wilhelm, S. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Adv. Drug Deliv. Rev., 2019, 143, 68-96.
[http://dx.doi.org/10.1016/j.addr.2019.04.008] [PMID: 31022434]
[30]
Xu, X.; Zhu, L.; Xue, K.; Liu, J.; Wang, J.; Wang, G.; Gu, J.; Zhang, Y.; Li, X. Ultrastructural studies of the neurovascular unit reveal enhanced endothelial transcytosis in hyperglycemia-enhanced hemorrhagic transformation after stroke. CNS Neurosci. Ther., 2021, 27(1), 123-133.
[http://dx.doi.org/10.1111/cns.13571]
[31]
Gundu, C.; Arruri, V.K.; Yadav, P.; Navik, U.; Kumar, A.; Amalkar, V.S.; Vikram, A.; Gaddam, R.R. Dynamin-independent mechanisms of endocytosis and receptor trafficking. Cells, 2022, 11(16), 2557.
[http://dx.doi.org/10.3390/cells11162557] [PMID: 36010634]
[32]
Cheng, X.; Chen, K.; Dong, B.; Yang, M.; Filbrun, S.L.; Myoung, Y.; Huang, T.X.; Gu, Y.; Wang, G.; Fang, N. Dynamin-dependent vesicle twist at the final stage of clathrin- mediated endocytosis. Nat. Cell Biol., 2021, 23(8), 859-869.
[http://dx.doi.org/10.1038/s41556-021-00713-x] [PMID: 34253896]
[33]
Rennick, J.J.; Johnston, A.P.R.; Parton, R.G. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat. Nanotechnol., 2021, 16(3), 266-276.
[http://dx.doi.org/10.1038/s41565-021-00858-8] [PMID: 33712737]
[34]
Dheer, D.; Nicolas, J.; Shankar, R. Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases. Adv. Drug Deliv. Rev., 2019, 151-152, 130-151.
[http://dx.doi.org/10.1016/j.addr.2019.01.010] [PMID: 30690054]
[35]
Liu, C.G.; Han, Y.H.; Kankala, R.K.; Wang, S.B.; Chen, A.Z. Subcellular performance of nanoparticles in cancer therapy. Int. J. Nanomedicine, 2020, 15, 675-704.
[http://dx.doi.org/10.2147/IJN.S226186] [PMID: 32103936]
[36]
Makvandi, P.; Chen, M.; Sartorius, R.; Zarrabi, A.; Ashrafizadeh, M.; Dabbagh, M.F.; Ma, J.; Mattoli, V.; Tay, F.R. Endocytosis of abiotic nanomaterials and nanobiovectors: Inhibition of membrane trafficking. Nano Today, 2021, 40, 101279.
[http://dx.doi.org/10.1016/j.nantod.2021.101279] [PMID: 34518771]
[37]
Cheng, J.P.X.; Nichols, B.J. Caveolae: One function or many? Trends Cell Biol., 2016, 26(3), 177-189.
[http://dx.doi.org/10.1016/j.tcb.2015.10.010] [PMID: 26653791]
[38]
Mehta, D.; Malik, A.B. Signaling mechanisms regulating endothelial permeability. Physiol. Rev., 2006, 86(1), 279-367.
[http://dx.doi.org/10.1152/physrev.00012.2005] [PMID: 16371600]
[39]
Cardarelli, F.; Pozzi, D.; Bifone, A.; Marchini, C.; Caracciolo, G. Cholesterol-dependent macropinocytosis and endosomal escape control the transfection efficiency of lipoplexes in CHO living cells. Mol. Pharm., 2012, 9(2), 334-340.
[http://dx.doi.org/10.1021/mp200374e] [PMID: 22196199]
[40]
Bloomfield, G.; Kay, R.R. Uses and abuses of macropinocytosis. J. Cell Sci., 2016, 129(14), 2697-2705.
[PMID: 27352861]
[41]
Hu, Q.; Li, H.; Wang, L.; Gu, H.; Fan, C. DNA nanotechnology-enabled drug delivery systems. Chem. Rev., 2019, 119(10), 6459-6506.
[http://dx.doi.org/10.1021/acs.chemrev.7b00663] [PMID: 29465222]
[42]
Murray, D.H.; Jahnel, M.; Lauer, J.; Avellaneda, M.J.; Brouilly, N.; Cezanne, A.; Morales-Navarrete, H.; Perini, E.D.; Ferguson, C.; Lupas, A.N.; Kalaidzidis, Y.; Parton, R.G.; Grill, S.W.; Zerial, M. An endosomal tether undergoes an entropic collapse to bring vesicles together. Nature, 2016, 537(7618), 107-111.
[http://dx.doi.org/10.1038/nature19326] [PMID: 27556945]
[43]
Shimizu, Y.; Takagi, J.; Ito, E.; Ito, Y.; Ebine, K.; Komatsu, Y.; Goto, Y.; Sato, M.; Toyooka, K.; Ueda, T.; Kurokawa, K.; Uemura, T.; Nakano, A. Cargo sorting zones in the trans-golgi network visualized by super-resolution confocal live imaging microscopy in plants. Nat. Commun., 2021, 12(1), 1901.
[http://dx.doi.org/10.1038/s41467-021-22267-0] [PMID: 33772008]
[44]
Huotari, J.; Helenius, A. Endosome maturation. EMBO J., 2011, 30(17), 3481-3500.
[http://dx.doi.org/10.1038/emboj.2011.286] [PMID: 21878991]
[45]
Bakhtiar, A; Chowdhury, EH PH-responsive strontium nanoparticles for targeted gene therapy against mammary carcinoma cells. Asian J. Pharm. Sci., 2021, 16(2), 236-252.
[46]
Dahiya, U.R.; Ganguli, M. Exocytosis - a putative road-block in nanoparticle and nanocomplex mediated gene delivery. J. Control. Release, 2019, 303, 67-76.
[http://dx.doi.org/10.1016/j.jconrel.2019.04.012] [PMID: 30980852]
[47]
Mahmood, A. Investigating Spatiotemporal Kinetics, Dynamics, and Mechanism of Exosome Release. Electronic Theses and Dissertations, 2022, 126
[48]
Pei, D.; Buyanova, M. Overcoming endosomal entrapment in drug delivery. Bioconjug. Chem., 2019, 30(2), 273-283.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00778] [PMID: 30525488]
[49]
Behr, J.P. The proton sponge: A trick to enter cells the viruses did not exploit. Chimia, 1997, 51(1-2), 34-36.
[http://dx.doi.org/10.2533/chimia.1997.34]
[50]
Sonawane, N.D.; Szoka, F.C., Jr; Verkman, A.S. Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J. Biol. Chem., 2003, 278(45), 44826-44831.
[http://dx.doi.org/10.1074/jbc.M308643200] [PMID: 12944394]
[51]
He, J.; Xu, S.; Mixson, A.J. The multifaceted histidine-based carriers for nucleic acid delivery: advances and challenges. Pharmaceutics, 2020, 12(8), 774.
[http://dx.doi.org/10.3390/pharmaceutics12080774] [PMID: 32823960]
[52]
Cheng, Y. Polymeric Gene Delivery Systems; Springer, 2018, p. 358.
[http://dx.doi.org/10.1007/978-3-319-77866-2]
[53]
Funhoff, A.M.; van Nostrum, C.F.; Koning, G.A.; Schuurmans-Nieuwenbroek, N.M.E.; Crommelin, D.J.A.; Hennink, W.E. Endosomal escape of polymeric gene delivery complexes is not always enhanced by polymers buffering at low pH. Biomacromolecules, 2004, 5(1), 32-39.
[http://dx.doi.org/10.1021/bm034041+] [PMID: 14715005]
[54]
Rangasamy, L.; Chelvam, V.; Kanduluru, A.K.; Srinivasarao, M.; Bandara, N.A.; You, F.; Orellana, E.A.; Kasinski, A.L.; Low, P.S. New mechanism for release of endosomal contents: Osmotic lysis via nigericin-mediated K+/H+ exchange. Bioconjug. Chem., 2018, 29(4), 1047-1059.
[http://dx.doi.org/10.1021/acs.bioconjchem.7b00714] [PMID: 29446616]
[55]
Benjaminsen, R.V.; Mattebjerg, M.A.; Henriksen, J.R.; Moghimi, S.M.; Andresen, T.L. The possible “proton sponge” effect of polyethylenimine (PEI) does not include change in lysosomal pH. Mol. Ther., 2013, 21(1), 149-157.
[http://dx.doi.org/10.1038/mt.2012.185] [PMID: 23032976]
[56]
Wang, C.; Wang, Y.; Li, Y.; Bodemann, B.; Zhao, T.; Ma, X.; Huang, G.; Hu, Z.; DeBerardinis, R.J.; White, M.A.; Gao, J. A nanobuffer reporter library for fine-scale imaging and perturbation of endocytic organelles. Nat. Commun., 2015, 6(1), 8524.
[http://dx.doi.org/10.1038/ncomms9524] [PMID: 26437053]
[57]
Rehman, Z.; Hoekstra, D.; Zuhorn, I.S. Mechanism of polyplex- and lipoplex-mediated delivery of nucleic acids: real-time visualization of transient membrane destabilization without endosomal lysis. ACS Nano, 2013, 7(5), 3767-3777.
[http://dx.doi.org/10.1021/nn3049494] [PMID: 23597090]
[58]
Yang, M.M.; Yarragudi, S.B.; Jamieson, S.M.F.; Tang, M.; Wilson, W.R.; Wu, Z. Calcium enabled remote loading of a weak acid into pH-sensitive liposomes and augmented cytosolic delivery to cancer cells via the proton sponge effect. Pharm. Res., 2022, 39(6), 1181-1195.
[http://dx.doi.org/10.1007/s11095-022-03206-0] [PMID: 35229237]
[59]
White, J.M.; Whittaker, G.R. Fusion of enveloped viruses in endosomes. Traffic, 2016, 17(6), 593-614.
[http://dx.doi.org/10.1111/tra.12389] [PMID: 26935856]
[60]
Wang, C.; Wang, X.; Du, L.; Dong, Y.; Hu, B.; Zhou, J.; Shi, Y.; Bai, S.; Huang, Y.; Cao, H.; Liang, Z.; Dong, A. Harnessing pH-sensitive polycation vehicles for the efficient siRNA delivery. ACS Appl. Mater. Interfaces, 2021, 13(2), 2218-2229.
[http://dx.doi.org/10.1021/acsami.0c17866] [PMID: 33406826]
[61]
Han, X.; Bushweller, J.H.; Cafiso, D.S.; Tamm, L.K. Membrane structure and fusion-triggering conformational change of the fusion domain from influenza hemagglutinin. Nat. Struct. Biol., 2001, 8(8), 715-720.
[http://dx.doi.org/10.1038/90434] [PMID: 11473264]
[62]
Smrt, S.T.; Draney, A.W.; Lorieau, J.L. The influenza hemagglutinin fusion domain is an amphipathic helical hairpin that functions by inducing membrane curvature. J. Biol. Chem., 2015, 290(1), 228-238.
[http://dx.doi.org/10.1074/jbc.M114.611657] [PMID: 25398882]
[63]
Murphy, J.R.; Harrison, R.J. Mechanisms of bacterial protein toxin entry into the target cell cytosol. Drug Discov. Today Dis. Mech., 2006, 3(2), 267-272.
[http://dx.doi.org/10.1016/j.ddmec.2006.05.005]
[64]
Tilley, S.J.; Saibil, H.R. The mechanism of pore formation by bacterial toxins. Curr. Opin. Struct. Biol., 2006, 16(2), 230-236.
[http://dx.doi.org/10.1016/j.sbi.2006.03.008] [PMID: 16563740]
[65]
Kordus, S.L.; Thomas, A.K.; Lacy, D.B. Clostridioides difficile toxins: Mechanisms of action and antitoxin therapeutics. Nat. Rev. Microbiol., 2022, 20(5), 285-298.
[http://dx.doi.org/10.1038/s41579-021-00660-2] [PMID: 34837014]
[66]
Herce, H.D.; Garcia, A.E.; Litt, J.; Kane, R.S.; Martín, P.; Enrique, N.; Rebolledo, A.; Milesi, V. Arginine-rich peptides destabilize the plasma membrane, consistent with a pore formation translocation mechanism of cell-penetrating peptides. Biophys. J., 2009, 97(7), 1917-1925.
[http://dx.doi.org/10.1016/j.bpj.2009.05.066] [PMID: 19804722]
[67]
Nadal-Bufí, F.; Henriques, S.T. How to overcome endosomal entrapment of cell-penetrating peptides to release the therapeutic potential of peptides? Pept. Sci., 2020, 112(6), e24168.
[http://dx.doi.org/10.1002/pep2.24168]
[68]
Shai, Y. Mode of action of membrane active antimicrobial peptides. Biopolymers, 2002, 66(4), 236-248.
[http://dx.doi.org/10.1002/bip.10260] [PMID: 12491537]
[69]
Lei, J.; Sun, L.; Huang, S.; Zhu, C.; Li, P.; He, J.; Mackey, V.; Coy, D.H.; He, Q. The antimicrobial peptides and their potential clinical applications. Am. J. Transl. Res., 2019, 11(7), 3919-3931.
[PMID: 31396309]
[70]
Tuerkova, A.; Kabelka, I.; Králová, T.; Sukeník, L.; Pokorná, Š.; Hof, M.; Vácha, R. Effect of helical kink in antimicrobial peptides on membrane pore formation. eLife, 2020, 9, e47946.
[http://dx.doi.org/10.7554/eLife.47946] [PMID: 32167466]
[71]
Bus, T.; Traeger, A.; Schubert, U.S. The great escape: How cationic polyplexes overcome the endosomal barrier. J. Mater. Chem. B Mater. Biol. Med., 2018, 6(43), 6904-6918.
[http://dx.doi.org/10.1039/C8TB00967H] [PMID: 32254575]
[72]
Wang, J.; Zhu, M.; Nie, G. Biomembrane-based nanostructures for cancer targeting and therapy: From synthetic liposomes to natural biomembranes and membrane-vesicles. Adv. Drug Deliv. Rev., 2021, 178, 113974.
[http://dx.doi.org/10.1016/j.addr.2021.113974] [PMID: 34530015]
[73]
Sahni, A.; Qian, Z.; Pei, D. Cell-penetrating peptides escape the endosome by inducing vesicle budding and collapse. ACS Chem. Biol., 2020, 15(9), 2485-2492.
[http://dx.doi.org/10.1021/acschembio.0c00478] [PMID: 32786250]
[74]
Dougherty, P.G.; Sahni, A.; Pei, D. Understanding cell penetration of cyclic peptides. Chem. Rev., 2019, 119(17), 10241-10287.
[http://dx.doi.org/10.1021/acs.chemrev.9b00008] [PMID: 31083977]
[75]
Davidson, S.M.; Vander Heiden, M.G. Critical functions of the lysosome in cancer biology. Annu. Rev. Pharmacol. Toxicol., 2017, 57(1), 481-507.
[http://dx.doi.org/10.1146/annurev-pharmtox-010715-103101] [PMID: 27732799]
[76]
Griffiths, G.; Gruenberg, J.; Marsh, M.; Wohlmann, J.; Jones, A.T.; Parton, R.G. Nanoparticle entry into cells; the cell biology weak link. Adv. Drug Deliv. Rev., 2022, 188, 114403.
[http://dx.doi.org/10.1016/j.addr.2022.114403] [PMID: 35777667]
[77]
Reily, C.; Stewart, T.J.; Renfrow, M.B.; Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol., 2019, 15(6), 346-366.
[http://dx.doi.org/10.1038/s41581-019-0129-4] [PMID: 30858582]
[78]
Singh, T.; Murthy, A.S.N.; Yang, H.J.; Im, J. Versatility of cell-penetrating peptides for intracellular delivery of siRNA. Drug Deliv., 2018, 25(1), 1996-2006.
[http://dx.doi.org/10.1080/10717544.2018.1543366] [PMID: 30799658]
[79]
Chiper, M.; Niederreither, K.; Zuber, G. Transduction methods for cytosolic delivery of proteins and bioconjugates into living cells. Adv. Healthc. Mater., 2018, 7(6), 1701040.
[http://dx.doi.org/10.1002/adhm.201701040] [PMID: 29205903]
[80]
D’Astolfo, D.S.; Pagliero, R.J.; Pras, A.; Karthaus, W.R.; Clevers, H.; Prasad, V.; Lebbink, R.J.; Rehmann, H.; Geijsen, N. Efficient intracellular delivery of native proteins. Cell, 2015, 161(3), 674-690.
[http://dx.doi.org/10.1016/j.cell.2015.03.028] [PMID: 25910214]
[81]
Jerjes, W.; Theodossiou, T.A.; Hirschberg, H.; Høgset, A.; Weyergang, A.; Selbo, P.K.; Hamdoon, Z.; Hopper, C.; Berg, K. Photochemical internalization for intracellular drug delivery. From basic mechanisms to clinical research. J. Clin. Med., 2020, 9(2), 528.
[http://dx.doi.org/10.3390/jcm9020528] [PMID: 32075165]
[82]
Ohtsuki, T.; Miki, S.; Kobayashi, S.; Haraguchi, T.; Nakata, E.; Hirakawa, K.; Sumita, K.; Watanabe, K.; Okazaki, S. The molecular mechanism of photochemical internalization of cell penetrating peptide-cargo-photosensitizer conjugates. Sci. Rep., 2015, 5(1), 18577.
[http://dx.doi.org/10.1038/srep18577] [PMID: 26686907]
[83]
Lächelt, U.; Wagner, E. Nucleic acid therapeutics using polyplexes: A journey of 50 years (and beyond). Chem. Rev., 2015, 115(19), 11043-11078.
[http://dx.doi.org/10.1021/cr5006793] [PMID: 25872804]
[84]
Kermaniyan, S.S.; Chen, M.; Zhang, C.; Smith, S.A.; Johnston, A.P.R.; Such, C.; Such, G.K. Understanding the biological interactions of pH-swellable nanoparticles. Macromol. Biosci., 2022, 22(5), 2100445.
[http://dx.doi.org/10.1002/mabi.202100445] [PMID: 35182032]
[85]
Kumar, V.V.; Pichon, C.; Refregiers, M.; Guerin, B.; Midoux, P.; Chaudhuri, A. Single histidine residue in head-group region is sufficient to impart remarkable gene transfection properties to cationic lipids: Evidence for histidine-mediated membrane fusion at acidic pH. Gene Ther., 2003, 10(15), 1206-1215.
[http://dx.doi.org/10.1038/sj.gt.3301979] [PMID: 12858185]
[86]
Midoux, P.; Monsigny, M. Efficient gene transfer by histidylated polylysine/pDNA complexes. Bioconjug. Chem., 1999, 10(3), 406-411.
[http://dx.doi.org/10.1021/bc9801070] [PMID: 10346871]
[87]
Peeler, D.J.; Sellers, D.L.; Pun, S.H. pH-sensitive polymers as dynamic mediators of barriers to nucleic acid delivery. Bioconjug. Chem., 2019, 30(2), 350-365.
[http://dx.doi.org/10.1021/acs.bioconjchem.8b00695] [PMID: 30398844]
[88]
Zhou, Y.N.; Li, J.J.; Wu, Y.Y.; Luo, Z.H. Role of external field in polymerization: Mechanism and kinetics. Chem. Rev., 2020, 120(5), 2950-3048.
[http://dx.doi.org/10.1021/acs.chemrev.9b00744] [PMID: 32083844]
[89]
Tejeda-Muñoz, N.; Albrecht, L.V.; Bui, M.H.; De Robertis, E.M. Wnt canonical pathway activates macropinocytosis and lysosomal degradation of extracellular proteins. Proc. Natl. Acad. Sci., 2019, 116(21), 10402-10411.
[http://dx.doi.org/10.1073/pnas.1903506116] [PMID: 31061124]
[90]
Zahaf, N.I.; Schmidt, G. Bacterial toxins for cancer therapy. Toxins, 2017, 9(8), 236.
[http://dx.doi.org/10.3390/toxins9080236] [PMID: 28788054]
[91]
Yu, Y.; Wang, X.; Fan, G.C. Versatile effects of bacterium-released membrane vesicles on mammalian cells and infectious/inflammatory diseases. Acta Pharmacol. Sin., 2018, 39(4), 514-533.
[http://dx.doi.org/10.1038/aps.2017.82] [PMID: 28858295]
[92]
Rabideau, A.E.; Pentelute, B.L. Delivery of non-native cargo into mammalian cells using anthrax lethal toxin. ACS Chem. Biol., 2016, 11(6), 1490-1501.
[http://dx.doi.org/10.1021/acschembio.6b00169] [PMID: 27055654]
[93]
Kakimoto, S.; Hamada, T.; Komatsu, Y.; Takagi, M.; Tanabe, T.; Azuma, H.; Shinkai, S.; Nagasaki, T. The conjugation of diphtheria toxin T domain to poly(ethylenimine) based vectors for enhanced endosomal escape during gene transfection. Biomaterials, 2009, 30(3), 402-408.
[http://dx.doi.org/10.1016/j.biomaterials.2008.09.042] [PMID: 18930314]
[94]
Orellana, E.A.; Abdelaal, A.M.; Rangasamy, L.; Tenneti, S.; Myoung, S.; Low, P.S.; Kasinski, A.L. Enhancing microRNA activity through increased endosomal release mediated by nigericin. Mol. Ther. Nucleic Acids, 2019, 16, 505-518.
[http://dx.doi.org/10.1016/j.omtn.2019.04.003] [PMID: 31071527]
[95]
Oliveira, S.; Vanrooy, I.; Kranenburg, O.; Storm, G.; Schiffelers, R. Fusogenic peptides enhance endosomal escape improving siRNA-induced silencing of oncogenes. Int. J. Pharm., 2007, 331(2), 211-214.
[http://dx.doi.org/10.1016/j.ijpharm.2006.11.050] [PMID: 17187949]
[96]
Hatakeyama, H.; Ito, E.; Akita, H.; Oishi, M.; Nagasaki, Y.; Futaki, S.; Harashima, H. A pH-sensitive fusogenic peptide facilitates endosomal escape and greatly enhances the gene silencing of siRNA-containing nanoparticles in vitro and in vivo. J. Control. Release, 2009, 139(2), 127-132.
[http://dx.doi.org/10.1016/j.jconrel.2009.06.008] [PMID: 19540888]
[97]
Subhan, M.A.; Torchilin, V.P. siRNA based drug design, quality, delivery and clinical translation. Nanomedicine, 2020, 29, 102239.
[http://dx.doi.org/10.1016/j.nano.2020.102239] [PMID: 32544449]
[98]
Alipour, M.; Hosseinkhani, S.; Sheikhnejad, R.; Cheraghi, R. Nano-biomimetic carriers are implicated in mechanistic evaluation of intracellular gene delivery. Sci. Rep., 2017, 7(1), 41507.
[http://dx.doi.org/10.1038/srep41507] [PMID: 28128339]
[99]
Gonzalez, M.E.; Carrasco, L. Viroporins. FEBS Lett., 2003, 552(1), 28-34.
[http://dx.doi.org/10.1016/S0014-5793(03)00780-4] [PMID: 12972148]
[100]
Costin, J.M.; Rausch, J.M.; Garry, R.F.; Wimley, W.C. Viroporin potential of the lentivirus lytic peptide (LLP) domains of the HIV-1 gp41 protein. Virol. J., 2007, 4(1), 123.
[http://dx.doi.org/10.1186/1743-422X-4-123] [PMID: 18028545]
[101]
Memariani, H.; Memariani, M.; Shahidi-Dadras, M.; Nasiri, S.; Akhavan, M.M.; Moravvej, H. Melittin: From honeybees to superbugs. Appl. Microbiol. Biotechnol., 2019, 103(8), 3265-3276.
[http://dx.doi.org/10.1007/s00253-019-09698-y] [PMID: 30824944]
[102]
Rozema, D.B.; Ekena, K.; Lewis, D.L.; Loomis, A.G.; Wolff, J.A. Endosomolysis by masking of a membrane-active agent (EMMA) for cytoplasmic release of macromolecules. Bioconjug. Chem., 2003, 14(1), 51-57.
[http://dx.doi.org/10.1021/bc0255945] [PMID: 12526692]
[103]
Chen, S.; Wang, S.; Kopytynski, M.; Bachelet, M.; Chen, R. Membrane-anchoring, comb-like pseudopeptides for efficient, pH-mediated membrane destabilization and intracellular delivery. ACS Appl. Mater. Interfaces, 2017, 9(9), 8021-8029.
[http://dx.doi.org/10.1021/acsami.7b00498] [PMID: 28225250]
[104]
Cheng, J.; Zeidan, R.; Mishra, S.; Liu, A.; Pun, S.H.; Kulkarni, R.P.; Jensen, G.S.; Bellocq, N.C.; Davis, M.E. Structure-function correlation of chloroquine and analogues as transgene expression enhancers in nonviral gene delivery. J. Med. Chem., 2006, 49(22), 6522-6531.
[http://dx.doi.org/10.1021/jm060736s] [PMID: 17064070]
[105]
Ali Doosti, B.; Pezeshkian, W.; Bruhn, D.S.; Ipsen, J.H.; Khandelia, H.; Jeffries, G.D.M.; Lobovkina, T. Membrane tubulation in lipid vesicles triggered by the local application of calcium ions. Langmuir, 2017, 33(41), 11010-11017.
[http://dx.doi.org/10.1021/acs.langmuir.7b01461] [PMID: 28910109]
[106]
Xu, J.; Khan, A.R.; Fu, M.; Wang, R.; Ji, J.; Zhai, G. Cell-penetrating peptide: A means of breaking through the physiological barriers of different tissues and organs. J. Control. Release, 2019, 309, 106-124.
[http://dx.doi.org/10.1016/j.jconrel.2019.07.020] [PMID: 31323244]
[107]
Lönn, P.; Kacsinta, A.D.; Cui, X.S.; Hamil, A.S.; Kaulich, M.; Gogoi, K.; Dowdy, S.F. Enhancing endosomal escape for intracellular delivery of macromolecular biologic therapeutics. Sci. Rep., 2016, 6(1), 32301.
[http://dx.doi.org/10.1038/srep32301] [PMID: 27604151]
[108]
LeCher, J.C.; Nowak, S.J.; McMurry, J.L. Breaking in and busting out: Cell-penetrating peptides and the endosomal escape problem. Biomol. Concepts, 2017, 8(3-4), 131-141.
[http://dx.doi.org/10.1515/bmc-2017-0023] [PMID: 28841567]
[109]
Bhosle, G.S.; Fernandes, M. (R-X-R)4-motif peptides containing conformationally constrained cyclohexane-derived spacers: Effect on cellular uptake. ChemMedChem, 2017, 12(21), 1743-1747.
[http://dx.doi.org/10.1002/cmdc.201700498] [PMID: 28948715]
[110]
Valeur, E.; Guéret, S.M.; Adihou, H.; Gopalakrishnan, R.; Lemurell, M.; Waldmann, H.; Grossmann, T.N.; Plowright, A.T. New modalities for challenging targets in drug discovery. Angew. Chem. Int. Ed., 2017, 56(35), 10294-10323.
[http://dx.doi.org/10.1002/anie.201611914] [PMID: 28186380]
[111]
Zhang, K.; Du, Y.; Si, Z.; Liu, Y.; Turvey, M.E.; Raju, C.; Keogh, D.; Ruan, L.; Jothy, S.L.; Reghu, S.; Marimuthu, K.; De, P.P.; Ng, O.T.; Mediavilla, J.R.; Kreiswirth, B.N.; Chi, Y.R.; Ren, J.; Tam, K.C.; Liu, X.W.; Duan, H.; Zhu, Y.; Mu, Y.; Hammond, P.T.; Bazan, G.C.; Pethe, K.; Chan-Park, M.B. Enantiomeric glycosylated cationic block co-beta-peptides eradicate Staphylococcus aureus biofilms and antibiotic-tolerant persisters. Nat. Commun., 2019, 10(1), 4792.
[http://dx.doi.org/10.1038/s41467-019-12702-8] [PMID: 31636263]
[112]
Bolhassani, A.; Jafarzade, B.S.; Momeni, S. Cell-penetrating peptides: A concise review with emphasis on biomedical applications. Biopolymers, 2020, 111(11), e23437.
[113]
Maity, S.; Maity, S. Endosomal escape pathways for delivery of biologicals. Int. J. Biol. Macromol., 2020, 148, 740-749.
[114]
Kim, M.; Shin, J.M.; Kim, J.S. Thermo-triggered endosomal escape and intracellular delivery of CRISPR/Cas9 via a gold nanocage with a pH-responsive polymer coating. ACS Appl. Mater. Interfaces, 2019, 11(39), 35797-35807.
[115]
Murthy, N.; Xu, M.; Schuck, S.; Kunisawa, J.; Shastri, N.; Fréchet, J.M.J. A macromolecular delivery vehicle for protein-based vaccines: Acid-degradable protein-loaded microgels. Proc. Natl. Acad. Sci., 2003, 100(9), 4995-5000.
[http://dx.doi.org/10.1073/pnas.0930644100] [PMID: 12704236]
[116]
Wadia, J.S.; Stan, R.V.; Dowdy, S.F. Transducible TAT-HA fusogenic peptide enhances escape of TAT-fusion proteins after lipid raft macropinocytosis. Nat. Med., 2004, 10(3), 310-315.
[http://dx.doi.org/10.1038/nm996] [PMID: 14770178]
[117]
Morris, M.C.; Depollier, J.; Mery, J.; Heitz, F.; Divita, G. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat. Biotechnol., 2001, 19(12), 1173-1176.
[http://dx.doi.org/10.1038/nbt1201-1173] [PMID: 11731788]
[118]
Zhang, H.; Li, Y.; Huang, Y.; Wu, Y.; Zhang, X. Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly(lactic-co-glycolic acid) nanoparticles. J. Drug Target., 2010, 18(9), 662-670.
[PMID: 20222850]
[119]
Xiong, Y.; Xu, M.; Chen, S.; Wang, Y. Advances in targeting drug delivery system based on tumor-associated macrophages. J. Control. Release, 2017, 254, 1-10.
[120]
Zhou, J.; Neff, C.P.; Swiderski, P.; Li, H.; Smith, D.D.; Aboellail, T.; Remling-Mulder, L.; Akkina, R.; Rossi, J.J.; Kaminski, R. Functional in vivo delivery of multiplexed anti-HIV-1 siRNAs via a chemically synthesized aptamer with a sticky bridge. Mol. Ther., 2011, 19, 432-441.
[PMID: 23164935]
[121]
Liu, Y.; Zhang, X.; Yu, S.; Huang, Y.; Zhang, X.; Wang, Y.; Duan, Y. A robust in vitro assay for measuring cellular internalization using pH-sensitive fluorescent proteins. Anal. Biochem., 2018, 557, 1-7.
[PMID: 30291836]
[122]
Wang, P.; Natural and synthetic saponins as vaccine adjuvants. Vaccines, 2021, 9(3), 222.
[http://dx.doi.org/10.3390/vaccines9030222] [PMID: 33807582]
[123]
Berg, K.; Selbo, P.K.; Prasmickaite, L.; Tjelle, T.E.; Sandvig, K.; Moan, J.; Gaudernack, G.; Fodstad, O.; Kjølsrud, S.; Anholt, H.; Rodal, G.H.; Rodal, S.K.; Høgset, A. Photochemical internalization: A novel technology for delivery of macromolecules into cytosol. Cancer Res., 1999, 59(6), 1180-1183.
[PMID: 10096543]
[124]
Sun, Y.; Lau, S.Y.; Lim, Z.W.; Chang, S.C.; Ghadessy, F.; Partridge, A.; Miserez, A. Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics. Nat. Chem., 2022, 14(3), 274-283.
[http://dx.doi.org/10.1038/s41557-021-00854-4] [PMID: 35115657]
[125]
Chaudhuri, A.; Battaglia, G.; Golestanian, R. The effect of interactions on the cellular uptake of nanoparticles. Phys. Biol., 2011, 8(4), 046002.
[http://dx.doi.org/10.1088/1478-3975/8/4/046002] [PMID: 21508440]
[126]
Dirisala, A.; Uchida, S.; Li, J.; Van Guyse, J.F.R.; Hayashi, K.; Vummaleti, S.V.C.; Kaur, S.; Mochida, Y.; Fukushima, S.; Kataoka, K. Effective mRNA protection by poly( L -ornithine) synergizes with endosomal escape functionality of a charge-conversion polymer toward maximizing mRNA introduction efficiency. Macromol. Rapid Commun., 2022, 43(12), 2100754.
[http://dx.doi.org/10.1002/marc.202100754] [PMID: 35286740]
[127]
Sanjoh, M.; Hiki, S.; Lee, Y.; Oba, M.; Miyata, K.; Ishii, T.; Kataoka, K. pDNA/poly( L -lysine) polyplexes functionalized with a pH-sensitive charge-conversional poly(aspartamide) derivative for controlled gene delivery to human umbilical vein endothelial cells. Macromol. Rapid Commun., 2010, 31(13), 1181-1186.
[http://dx.doi.org/10.1002/marc.201000056] [PMID: 21590873]
[128]
Perche, F.; Yi, Y.; Hespel, L.; Mi, P.; Dirisala, A.; Cabral, H.; Miyata, K.; Kataoka, K. Hydroxychloroquine-conjugated gold nanoparticles for improved siRNA activity. Biomaterials, 2016, 90, 62-71.
[http://dx.doi.org/10.1016/j.biomaterials.2016.02.027] [PMID: 26986857]
[129]
Shen, X.; Dirisala, A.; Toyoda, M.; Xiao, Y.; Guo, H.; Honda, Y.; Nomoto, T.; Takemoto, H.; Miura, Y.; Nishiyama, N. pH-responsive polyzwitterion covered nanocarriers for DNA delivery. J. Control. Release, 2023, 360, 928-939.
[http://dx.doi.org/10.1016/j.jconrel.2023.07.038] [PMID: 37495117]
[130]
Mickler, F.M.; Vachutinsky, Y.; Oba, M.; Miyata, K.; Nishiyama, N.; Kataoka, K.; Bräuchle, C.; Ruthardt, N. Effect of integrin targeting and PEG shielding on polyplex micelle internalization studied by live-cell imaging. J. Control. Release, 2011, 156(3), 364-373.
[http://dx.doi.org/10.1016/j.jconrel.2011.08.003] [PMID: 21843561]
[131]
Li, J.; Ge, Z.; Liu, S. PEG-sheddable polyplex micelles as smart gene carriers based on MMP-cleavable peptide-linked block copolymers. Chem. Commun., 2013, 49(62), 6974-6976.
[http://dx.doi.org/10.1039/c3cc43576h] [PMID: 23802223]
[132]
Dirisala, A.; Osada, K.; Chen, Q.; Tockary, T.A.; Machitani, K.; Osawa, S.; Liu, X.; Ishii, T.; Miyata, K.; Oba, M.; Uchida, S.; Itaka, K.; Kataoka, K. Optimized rod length of polyplex micelles for maximizing transfection efficiency and their performance in systemic gene therapy against stroma-rich pancreatic tumors. Biomaterials, 2014, 35(20), 5359-5368.
[http://dx.doi.org/10.1016/j.biomaterials.2014.03.037] [PMID: 24720877]
[133]
Chen, Q.; Osada, K.; Ge, Z.; Uchida, S.; Tockary, T.A.; Dirisala, A.; Matsui, A.; Toh, K.; Takeda, K.M.; Liu, X.; Nomoto, T.; Ishii, T.; Oba, M.; Matsumoto, Y.; Kataoka, K. Polyplex micelle installing intracellular self-processing functionalities without free catiomers for safe and efficient systemic gene therapy through tumor vasculature targeting. Biomaterials, 2017, 113, 253-265.
[http://dx.doi.org/10.1016/j.biomaterials.2016.10.042] [PMID: 27835820]

Rights & Permissions Print Cite
Article Metrics
77
2
Wayfinder Image
TIMBC 2025
© 2025 Bentham Science Publishers | Privacy Policy