ESTONIAN ACADEMY
PUBLISHERS
eesti teaduste
akadeemia kirjastus
PUBLISHED
SINCE 1952
 
Proceeding cover
proceedings
of the estonian academy of sciences
ISSN 1736-7530 (Electronic)
ISSN 1736-6046 (Print)
Impact Factor (2022): 0.9
Nucleic acid delivery by cell-penetrating peptides; pp. 361–370
PDF | https://doi.org/10.3176/proc.2023.4.01

Author
Ülo Langel
Abstract

Establishment of multiple novel mechanisms and applications of cell-penetrating peptides (CPP) has been demonstrated, leading to novel drug delivery systems. Here, I present a brief introduction to the CPP area together with the selected recent achievements in the delivery of nucleic acids.

References

Abdelhamid, H. N., Dowaidar, M., Hallbrink, M. and Langel, U. 2020a. Gene delivery using cell penetrating peptides-zeolitic imidazolate frameworks. Microporous Mesoporous Mater.300, 110173.
https://doi.org/10.1016/j.micromeso.2020.110173

Abdelhamid, H. N., Dowaidar, M. and Langel, U. 2020b. Carbonized chitosan encapsulated hierarchical porous zeolitic imidazolate frameworks nanoparticles for gene delivery. Microporous Mesoporous Mater.302, 110200.
https://doi.org/10.1016/j.micromeso.2020.110200

Allinquant, B., Hantraye, P., Mailleux, P., Moya, K., Bouillot, C. and Prochiantz, A. 1995. Downregulation of amyloid precursor protein inhibits neurite outgrowth in vitro. J. Cell Biol.128, 919–927.
https://doi.org/10.1083/jcb.128.5.919

Alvarez, M. J., Subramaniam, P. S., Tang, L. H., Grunn, A., Aburi, M., Rieckhof, G. et al. 2018. A precision oncology approach to the pharmacological targeting of mechanistic dependencies in neuroendocrine tumors. Nat. Genet.50, 979–989. 
https://doi.org/10.1038/s41588-018-0138-4

Anderson, B. R., Muramatsu, H., Nallagatla, S. R., Bevilacqua, P. C., Sansing, L. H., Weissman, D. et al. 2010. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic Acids Res.38(17), 5884–5892.
https://doi.org/10.1093/nar/gkq347

Bendifallah, N., Rasmussen, F. W., Zachar, V., Ebbesen, P., Nielsen, P. E. and Koppelhus, U. 2006. Evaluation of cell-penetrating peptides (CPPs) as vehicles for intracellular delivery of antisense peptide nucleic acid (PNA). Bioconjugate Chem.,17(3), 750–758. 
https://doi.org/10.1021/bc050283q

Boisguérin, P., Konate, K., Josse, E., Vivès, E. and Deshayes, S. 2021. Peptide-based nanoparticles for therapeutic nucleic acid delivery. Biomedicines9(5), 583. 
https://doi.org/10.3390/biomedicines9050583

Buss, C. G. and Bhatia, S. N. 2020. Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics. Proc. Natl. Acad. Sci. U. S. A.117(24), 13428–13436. 
https://doi.org/10.1073/pnas.2001569117

Carreras-Badosa, G., Maslovskaja, J., Periyasamy, K., Urgard, E., Padari, K., Vaher, H. et al. 2020. NickFect type of cell-penetrating peptides present enhanced efficiency for microRNA-146a delivery into dendritic cells and during skin inflammation. Biomaterials262, 120316. 
https://doi.org/10.1016/j.biomaterials.2020.120316

Carruthers, J. D., Fagien, S., Joseph, J. H., Humphrey, S. D., Biesman, B. S., Gallagher, C. J. et al. 2020. DaxibotulinumtoxinA for injection for the treatment of glabellar lines: results from each of two multicenter, randomized, double-blind, placebo-controlled, phase 3 studies (SAKURA 1 and SAKURA 2). Plast. Reconstr. Surg.145(1), 45–58.
https://doi.org/10.1097/PRS.0000000000006327

Cerrato, C. P., Kivijärvi, T., Tozzi, R., Lehto, T., Gestin, M. and Langel, Ü. 2020. Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides. J. Mater. Chem. B.8, 10825–10836. 
https://doi.org/10.1039/D0TB01106A

Chugh, A. and Eudes, F. 2008. Study of uptake of cell penetrating peptides and their cargoes in permeabilized wheat immature embryos. FEBS J.275(10), 2403–2414. 
https://doi.org/10.1111/j.1742-4658.2008.06384.x

Dominski, Z. and Kole, R. 1993. Restoration of correct splicing in thalassemic pre-mRNA by antisense oligonucleotides. Proc. Natl. Acad. Sci. U. S. A.90(18), 8673–8677. 
https://doi.org/10.1073/pnas.90.18.8673

Dowaidar, M., Abdelhamid, H., Hällbrink, M., Zou, X. and Langel, Ü. 2017a. Graphene oxide nanosheets in complex with cell penetrating peptides for oligonucleotides delivery. Biochim. Biophys. Acta Gen. Subj.1861(9), 2334–2341. 
https://doi.org/10.1016/j.bbagen.2017.07.002

Dowaidar, M., Abdelhamid, H., Hällbrink, M., Freimann, K., Kurrikoff, K., Zou, X. et al. 2017b. Magnetic nanoparticles assisted self-assembly of cell penetrating peptides–oligonucleotides complexes for gene delivery. Sci. Rep., 7, 9159. 
https://doi.org/10.1038/s41598-017-09803-z

Dowaidar, M., Gestin, M., Cerrato, C. P., Jafferali, M. H., Margus, H., Kivistik, P. A. et al. 2017c. Role of autophagy in cell-penetrating peptide transfection model. Sci. Rep.7, 12635. 
https://doi.org/10.1038/s41598-017-12747-z

Eguchi, A., Meade, B. R., Chang, Y. C., Fredrickson, C. T., Willert, K., Puri, N. et al. 2009. Efficient siRNA delivery into primary cells by a peptide transduction domain-dsRNA binding domain fusion protein. Nat. Biotechnol.27, 567–571. 
https://doi.org/10.1038/nbt.1541

El-Andaloussi, S., Johansson, H. J., Lundberg, P. and Langel, Ü. 2006. Induction of splice correction by cell-penetrating peptide nucleic acids. J. Gene. Med.8(10), 1262–1273. 
https://doi.org/10.1002/jgm.950

El-Andaloussi, S., Lehto, T., Mäger, I., Rosenthal-Aizman, K., Oprea, I. I., Simonson, O. E. et al. 2011. Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo. Nucleic Acids Res.39(9),3972–3987. 
https://doi.org/10.1093/nar/gkq1299

Falato, L., Gestin, M. and Langel, Ü. 2022. PepFect14 signaling and transfection. Methods Mol. Biol.2383, 229–246.
https://doi.org/10.1007/978-1-0716-1752-6_15

Fisher, L., Samuelsson, M., Jiang, Y., Ramberg, V., Figueroa, R., Hallberg, E. et al. 2007. Targeting cytokine expression in glial cells by cellular delivery of an NF-kappaB decoy. J. Mol. Neurosci.31, 209–219. 
https://doi.org/10.1385/JMN:31:03:209

Fisher, L., Soomets, U., Cortés Toro, V., Chilton, L., Jiang, Y., Langel, Ü. et al. 2004. Cellular delivery of a double-stranded oligonucleotide NFkappaB decoy by hybridization to complementary PNA linked to a cell-penetrating peptide. Gene Ther.11,1264–1272. 
https://doi.org/10.1038/sj.gt.3302291

Fossat, P., Dobremez, E., Bouali-Benazzouz, R., Favereaux, A., Bertrand, S. S., Kilk, K. et al. 2010. Knockdown of L calcium channel subtypes: differential effects in neuropathic pain. J.  Neurosci.30(3), 1073–1085. 
https://doi.org/10.1523/JNEUROSCI.3145-09.2010

Freimann, K., Arukuusk, P., Kurrikoff, K., Vasconcelos, L. D. F., Veiman, K. L., Uusna, J. et al. 2016. Optimization of in vivoDNA delivery with NickFect peptide vectors. J. Control. Release241, 135–143. 
https://doi.org/10.1016/j.jconrel.2016.09.022

Futaki, S., Ohashi, W., Suzuki, T., Niwa, M., Tanaka, S., Ueda, K. et al. 2001. Stearylated arginine-rich peptides:  a new class of transfection systems. Bioconjug. Chem.12(6), 1005–1011. 
https://doi.org/10.1021/bc015508l

Hällbrink, M. and Karelson, M. 2015. Prediction of cell-penetrating peptides. Methods Mol. Biol.1324, 39–58.
https://doi.org/10.1007/978-1-4939-2806-4_3

Hoy, S. M. 2018. Patisiran: first global approval. Drugs78, 1625–1631. 
https://doi.org/10.1007/s40265-018-0983-6

Ishihara, T., Goto, M., Kodera, K., Kanazawa, H., Murakami, Y., Mizushima, Y. et al. 2009. Intracellular delivery of siRNA by cell-penetrating peptides modified with cationic oligopeptides. Drug Deliv.16(3), 153–159. 
https://doi.org/10.1080/10717540902722774

Jain, P. K., Lo, J. H., Rananaware, S., Downing, M., Panda, A., Tai, M. et al. 2019. Non-viral delivery of CRISPR/Cas9 complex using CRISPR-GPS nanocomplexes. Nanoscale11(44), 21317–21323. 
https://doi.org/10.1039/C9NR01786K

Kaushik, N., Basu, A., Palumbo, P., Myers, R. L. and Pandey, V. N. 2002. Anti-TAR polyamide nucleotide analog conjugated with a membrane-permeating peptide inhibits human immunodeficiency virus type 1 production. J. Virol.76(8), 3881–3891. 
https://doi.org/10.1128/jvi.76.8.3881-3891.2002

Kilk, K., El-Andaloussi, S., Järver, P., Meikas, A., Valkna, A., Bartfai, T. et al. 2005. Evaluation of transportan 10 in PEI mediated plasmid delivery assay. J. Control. Release103(2), 511–523. 
https://doi.org/10.1016/j.jconrel.2004.12.006

Kilk, K., Mahlapuu, R., Soomets, U. and Langel, Ü. 2009. Analysis of in vitro toxicity of five cell-penetrating peptides by metabolic profiling. Toxicology265(3), 87–95. 
https://doi.org/10.1016/j.tox.2009.09.016

Kim, H. B., Morris, J., Miyashiro, K., Lehto, T., Langel, Ü., Eberwine, J. et al. 2021. Astrocytes promote ethanol-induced enhancement of intracellular Ca2+ signals through intercellular communication with neurons. iScience24(5), 102436. 
https://doi.org/10.1016/j.isci.2021.102436

Kulkarni, J. A., Witzigmann, D., Thomson, S. B., Chen, S., Leavitt, B. R., Cullis, P. R. et al. 2021. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol.16, 630–643.
https://doi.org/10.1038/s41565-021-00898-0

Künnapuu, K., Veiman, K. L., Porosk, L., Rammul, E., Kiisholts, K., Langel, Ü. et al. 2019. Tumor gene therapy by systemic delivery of plasmid DNA with cell-penetrating peptides. FASEB bioAdvances1(2), 105–114. 
https://doi.org/10.1096/fba.1026

Kurrikoff, K., Freimann, K., Veiman, K. L., Peets, E. M., Piirsoo, A. and Langel, Ü. 2019. Effective lung-targeted RNAi in mice with peptide-based delivery of nucleic acid. Sci. Rep.9, 19926.
https://doi.org/10.1038/s41598-019-56455-2

Langel, Ü. 2019. CPP, Cell-Penetrating Peptides. Springer, Singapore. 
https://doi.org/10.1007/978-981-13-8747-0

Langel, Ü. 2021. Cell-penetrating peptides and transportan. Pharmaceutics, 13(7), 987.
https://doi.org/10.3390/pharmaceutics13070987

Langel, Ü. (ed.). 2022. Cell-penetrating peptidesMethods and protocols3rd ed. Methods Mol. Biol.2383. Humana, New York.
https://doi.org/10.1007/978-1-0716-1752-6

Lehto, T., Ezzat, K. and Langel, Ü. 2011. Peptide nanoparticles for oligonucleotide delivery. Prog. Mol. Biol. Transl. Sci.104,397–426.
https://doi.org/10.1016/B978-0-12-416020-0.00010-3

Michiue, H., Eguchi, A., Scadeng, M. and Dowdy, S. F. 2009. Induction of in vivo synthetic lethal RNAi responses to treat glioblastoma. Cancer Biol. Ther.8(23), 2306–2313.
https://doi.org/10.4161/cbt.8.23.10271

Morris, M. C., Vidal, P., Chaloin, L., Heitz, F. and Divita, G. 1997. A new peptide vector for efficient delivery of oligonucleotides into mammalian cells. Nucleic Acids Res.25(14), 2730–2736.
https://doi.org/10.1093/nar/25.14.2730

Muratovska, A. and Eccles, M. R. 2004. Conjugate for efficient delivery of short interfering RNA (siRNA) into mammalian cells. FEBS Lett.558(1–3), 63–68.
https://doi.org/10.1016/S0014-5793(03)01505-9

Ostenson, C. G., Sandberg-Nordqvist, A. C., Chen, J., Hällbrink, M., Rotin, D., Langel, U. et al. 2002. Overexpression of protein-tyrosine phosphatase PTP sigma is linked to impaired glucose-induced insulin secretion in hereditary diabetic Goto-Kakizaki rats. Biochem. Biophys. Res. Commun.291(4), 945–950.
https://doi.org/10.1006/bbrc.2002.6536

Oyama, S., Yamamoto, T. and Yamayoshi, A. 2021. Recent advances in the delivery carriers and chemical conjugation strategies for nucleic acid drugs. Cancers13.
https://doi.org/10.3390/cancers13153881

Pae, J. and Pooga, M. 2014. Peptide-mediated delivery: an overview of pathways for efficient internalization. Ther. Deliv.,5(11), 1203–1222. 
https://doi.org/10.4155/tde.14.72

Park, K. 2016. In vivo DNA delivery with NickFect peptide vectors. J. Control. Release, 241, 242. 
https://doi.org/10.1016/j.jconrel.2016.10.005

Pooga, M., Hällbrink, M., Zorko, M. and Langel, U. 1998a. Cell penetration by transportan. FASEB J. 12(1), 67–77.
https://doi.org/10.1096/fsb2fasebj.12.1.67

Pooga, M., Soomets, U., Hällbrink, M., Valkna, A., Saar, K., Rezaei, K. et al. 1998b. Cell penetrating PNA constructs regulate galanin receptor levels and modify pain transmission in vivo. Nat. Biotechnol.16, 857–861.
https://doi.org/10.1038/nbt0998-857

Premeaux, T. A., Yeung, S. T., Bukhari, Z., Bowler, S., Alpan, O., Gupta, R. et al. 2022. Emerging insights on caspases in COVID-19 pathogenesis, sequelae, and directed therapies. Front. Immunol.13, 842740.
https://doi.org/10.3389/fimmu.2022.842740

Regberg, J., Srimanee, A., Erlandsson, M., Sillard, R., Dobchev, D. A., Karelson, M. et al. 2014. Rational design of a series of novel amphipathic cell-penetrating peptides. Int. J. Pharm.464, 111–116. 
https://doi.org/10.1016/j.ijpharm.2014.01.018

Regberg, J., Vasconcelos, L., Madani, F., Langel, Ü. and Hällbrink, M. 2016. pH-responsive PepFect cell-penetrating peptides. Int. J. Pharm.501(1–2), 32–38. 
https://doi.org/10.1016/j.ijpharm.2016.01.055

Ruczynski, J., Rusiecka, I., Turecka, K., Kozlowska, A., Alenowicz, M., Gagalo, I. et al. 2019. Transportan 10 improves the pharmacokinetics and pharmacodynamics of vancomycin. Sci. Rep.9(1), 3247.
https://doi.org/10.1038/s41598-019-40103-w

Shadid, M., Badawi, M. and Abulrob, A. 2021. Antisense oligonucleotides: absorption, distribution, metabolism, and excretion. Expert Opin. Drug Metab. Toxicol.17(11), 1281–1292. 
https://doi.org/10.1080/17425255.2021.1992382

Simeoni, F., Morris, M. C., Heitz, F. and Divita, G. 2003. Insight into the mechanism of the peptide-based gene delivery system MPG: implications for delivery of siRNA into mammalian cells. Nucleic Acids Res.31(11), 2717–2724. 
https://doi.org/10.1093/nar/gkg385

Soomets, U., Lindgren, M., Gallet, X., Hällbrink, M., Elmquist, A., Balaspiri, L. et al. 2000. Deletion analogues of transportan. Biochim. Biophys. Acta1467(1), 165–176. 
https://doi.org/10.1016/S0005-2736(00)00216-9

Srimanee, A., Arvanitidou, M., Kim, K., Hällbrink, M. and Langel, Ü. 2018. Cell-penetrating peptides for siRNA delivery to glioblastomas. Peptides104, 62–69. 
https://doi.org/10.1016/j.peptides.2018.04.015

Srimanee, A., Regberg, J., Hällbrink, M., Vajragupta, O. and Langel, Ü. 2016. Role of scavenger receptors in peptide-based delivery of plasmid DNA across a blood-brain barrier model. Int. J. Pharm.500(1–2), 128–135. 
https://doi.org/10.1016/j.ijpharm.2016.01.014

Stalmans, S., Bracke, N., Wynendaele, E., Gevaert, B., Peremans, K., Burvenich, C. et al. 2015. Cell-penetrating peptides selectively cross the blood-brain barrier in vivo. PLoS One, 10(10), e0139652.
https://doi.org/10.1371/journal.pone.0139652

Syed, Y. Y. 2021. Givosiran: a review in acute hepatic porphyria. Drugs81, 841–848. 
https://doi.org/10.1007/s40265-021-01511-3

Tripathi, S., Chaubey, B., Ganguly, S., Harris, D., Casale, R. A. and Pandey, V. N. 2005. Anti-HIV-1 activity of anti-TAR polyamide nucleic acid conjugated with various membrane transducing peptides. Nucleic Acids Res.33(13), 4345–4356. 
https://doi.org/10.1093/nar/gki743

Turner, J. J., Arzumanov, A. A. and Gait, M. J. 2005. Synthesis, cellular uptake and HIV-1 Tat-dependent trans-activation inhibition activity of oligonucleotide analogues disulphide-conjugated to cell-penetrating peptides. Nucleic Acids Res.33(1),27–42. 
https://doi.org/10.1093/nar/gki142

Turner, J. J., Jones, S., Fabani, M. M., Ivanova, G., Arzumanov, A. A. and Gait, M. J. 2007. RNA targeting with peptide conjugates of oligonucleotides, siRNA and PNA. Blood Cells Mol.  Dis.38(1), 1–7. 
https://doi.org/10.1016/j.bcmd.2006.10.003

van Asbeck, A. H., Dieker, J., Oude Egberink, R., van den Berg, L., van der Vlag, J. and Brock, R. 2021. Protein expression correlates linearly with mRNA dose over up to five orders of magnitude in vitro and in vivo. Biomedicines, 9(5), 511. 
https://doi.org/10.3390/biomedicines9050511

van den Brand, D., Gorris, M. A. J., van Asbeck, A. H., Palmen, E., Ebisch, I., Dolstra, H. et al. 2019. Peptide-mediated delivery of therapeutic mRNA in ovarian cancer. Eur. J. Pharm. Biopharm.141, 180–190. 
https://doi.org/10.1016/j.ejpb.2019.05.014

van der Bent, M. L., Paulino da Silva Filho, O., Willemse, M., Hällbrink, M., Wansink, D. G. and Brock, R. 2019. The nuclear concentration required for antisense oligonucleotide activity in myotonic dystrophy cells. FASEB J.33(10), 11314–11325. 
https://doi.org/10.1096/fj.201900263R

Veiman, K. L., Künnapuu, K., Lehto, T., Kiisholts, K., Pärn, K., Langel, Ü. et al. 2015. PEG shielded MMP sensitive CPPs for efficient and tumor specific gene delivery in vivo. J. Control. Release,  209, 238–247. 
https://doi.org/10.1016/j.jconrel.2015.04.038

Venit, T., Dowaidar, M., Gestin, M., Mahmood, S. R., Langel, Ü. and Percipalle, P. 2020. Transcriptional profiling reveals ribosome biogenesis, microtubule dynamics and expression of specific incRNAs to be part of a common response to cell-penetrating peptides. Biomolecules10(11), 1567. 
https://doi.org/10.3390/biom10111567

Wyman, T. B., Nicol, F., Zelphati, O., Scaria, P. V., Plank, C. and Szoka, F. C., Jr. 1997. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochem.36(10), 3008–3017. 
https://doi.org/10.1021/bi9618474

Yang, G., Zhao, Y., Gong, A., Miao, W., Yan, L., Nie, P. et al. 2021. Improved cellular delivery of antisense oligonucleotide for miRNA-21 imaging in vivo using cell-penetrating peptide-based nanoprobes. Mol. Pharm., 18(3), 787–795.
https://doi.org/10.1021/acs.molpharmaceut.0c00160

Youn, P., Chen, Y. and Furgeson, D. Y. 2014. A myristoylated cell-penetrating peptide bearing a transferrin receptor-targeting sequence for neuro-targeted siRNA delivery. Mol. Pharm.11(2), 486–495. 
https://doi.org/10.1021/mp400446v

Zielinski, J., Kilk, K., Peritz, T., Kannanayakal, T., Miyashiro, K. Y., Eiriksdottir, E. et al. 2006. In vivo identification of ribonucleoprotein-RNA interactions. Proc. Natl. Acad. Sci. U. S. A.103(5), 1557–1562.
https://doi.org/10.1073/pnas.0510611103

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