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Pegylation of Mrna by Hybridization of Complementary PEG-RNA Oligonucleotides Stabilizes Mrna Without Using Cationic Materials

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Pegylation of Mrna by Hybridization of Complementary PEG-RNA Oligonucleotides Stabilizes Mrna Without Using Cationic Materials pharmaceutics Communication PEGylation of mRNA by Hybridization of Complementary PEG-RNA Oligonucleotides Stabilizes mRNA without Using Cationic Materials Naoto Yoshinaga 1,2,† , Mitsuru Naito 3,† , Yoshihiro Tachihara 1, Eger Boonstra 1 , Kensuke Osada 4, Horacio Cabral 1,* and Satoshi Uchida 1,5,6,* 1 Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan; [email protected] (N.Y.); [email protected] (Y.T.); [email protected] (E.B.) 2 RIKEN Center for Sustainable Resource Science, Wako 351-0198, Saitama, Japan 3 Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; [email protected] 4 National Institute of Radiological Science, 4-9-1 Anagawa, Inage-ku, Chiba-shi 263-8555, Chiba, Japan; [email protected] 5 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Inamori Memorial Building, 1-5 Shimogamohangi-cho, Sakyo-ku, Kyoto 606-0823, Japan 6 Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan * Correspondence: [email protected] (H.C.); [email protected] (S.U.); Tel.: +81-3-5841-7138 (H.C.); +81-75-703-4938 (S.U.) † These authors contributed equally to this work. Citation: Yoshinaga, N.; Naito, M.; Abstract: Messenger RNA (mRNA) delivery strategies are required to protect biologically fragile Tachihara, Y.; Boonstra, E.; Osada, K.; mRNA from ribonuclease (RNase) attacks to achieve efficient therapeutic protein expression. To tackle Cabral, H.; Uchida, S. PEGylation of this issue, most mRNA delivery systems have used cationic components, which form electrostatically mRNA by Hybridization of driven complexes with mRNA and shield encapsulated mRNA strands. However, cationic materials Complementary PEG-RNA Oligonucleotides Stabilizes mRNA interact with anionic biomacromolecules in physiological environments, which leads to unspecific without Using Cationic Materials. reactions and toxicities. To circumvent this issue of cation-based approaches, herein, we propose a Pharmaceutics 2021, 13, 800. cation-free delivery strategy by hybridization of PEGylated RNA oligonucleotides with mRNA. The https://doi.org/10.3390/ PEG strands on the mRNA sterically and electrostatically shielded the mRNA, improving mRNA pharmaceutics13060800 nuclease stability 15-fold after serum incubation compared with unhybridized mRNA. Eventually, the PEGylated mRNA induced nearly 20-fold higher efficiency of reporter protein expression than Academic Editor: Gabriele Grassi unhybridized mRNA in cultured cells. This study provides a platform to establish a safe and efficient cation-free mRNA delivery system. Received: 10 April 2021 Accepted: 24 May 2021 Keywords: mRNA therapeutics; RNA engineering; mRNA delivery Published: 27 May 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- iations. In recent years, messenger RNA (mRNA) has been widely used for medical applica- tions, supplying therapeutic proteins at proper timing in a safe manner [1–3]. Nevertheless, the biological fragility of mRNA against ribonuclease (RNase) attacks impedes the devel- opment of mRNA applications for in vivo use. In addition, exogenous mRNA strands are recognized by pattern recognition receptors (PRRs) [4,5], such as Toll-like receptor and Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. retinoic acid-inducible gene I (RIG-I), causing a strong immune response. To solve this This article is an open access article problem, mRNA is usually complexed with cationic lipids or polymers to avoid enzymatic distributed under the terms and degradation and PRR recognition en route to the target sites [6–9]. Cationic materials conditions of the Creative Commons can also be designed to modulate the intracellular processes, for example, by facilitating Attribution (CC BY) license (https:// endosomal escape [10] and preventing intracellular mRNA degradation [11]. Furthermore, creativecommons.org/licenses/by/ pharmacological functionalities, such as adjuvanticity in vaccination, can be integrated 4.0/). to the cationic materials [12,13]. The complexation strategy exhibits potent outcomes in Pharmaceutics 2021, 13, 800. https://doi.org/10.3390/pharmaceutics13060800 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, x 2 of 10 itating endosomal escape [10] and preventing intracellular mRNA degradation [11]. Fur- Pharmaceutics 2021, 13, 800 thermore, pharmacological functionalities, such as adjuvanticity in vaccination, can be2 of in- 10 tegrated to the cationic materials [12,13]. The complexation strategy exhibits potent out- comes in efficient mRNA delivery. However, as cationic materials interact with anionic biomacromolecules,efficient mRNA delivery. such However,as glycosaminoglycans as cationic materials on the cell interact surface with [14] anionic, cationic biomacro- carrier componentsmolecules, such frequently as glycosaminoglycans damage cells and on tissues the cell [15 surface–17]. Further [14], cationicmore, carriercomplexed components mRNA canfrequently be kicked damage out by cells the andexchange tissues reaction [15–17 ].with Furthermore, anionic biomacromolecules, complexed mRNA leading can beto enzymatickicked out bydegradation the exchange of mRNA. reaction These with anionic issues derived biomacromolecules, from cationic leading materials to enzymatic have ac- celerateddegradation the ofdevelopment mRNA. These of cation issues-free derived delivery from strategies cationic materials in the field have of mRNA accelerated applica- the tionsdevelopment [18], and, of in cation-freefact, some clinical delivery trials strategies have used in thenaked field mRNA of mRNA in spite applications of the biological [18], fragilityand, in fact, and some immunogenicity clinical trials of have naked used mRNA naked [19,20] mRNA. The in spite increased of the momentum biological fragility of cat- ionand-free immunogenicity mRNA delivery of strategies naked mRNA motivated [19,20 us]. Theto design increased a safe momentum and efficient of system cation-free with- outmRNA using delivery cationic strategies materials. motivated us to design a safe and efficient system without using cationicChemical materials. modification of nucleotides in mRNA is an effective method to improve the bioavailabilityChemical modification of mRNA, of especially nucleotides to reduce in mRNA the immunogenicity is an effective method of mRNA to improve [21–23]. However,the bioavailability currently of used mRNA, chemi especiallycal modifications to reduce theprovide immunogenicity minimal protection of mRNA of [mRNA21–23]. againstHowever, RNases currently under used physiological chemical modificationsconditions [24] provide. Thus, additional minimal protection methods are of mRNAneeded toagainst modify RNases mRNA under without physiological using cationic conditions materials. [24]. Thus,Recently, additional we reported methods an areinnovative needed technologyto modify mRNAto functionalize without mR usingNA cationic through materials. hybridization Recently, with complementary we reported an RNA innova- oli- gonucleotidestive technology (OligoRNAs) to functionalize equipped mRNA with through a desired hybridization moiety [25 with–27 complementary]. Fine-tuning of RNA the complementaryoligonucleotides length (OligoRNAs) of OligoRNA equipped sequences, with a desired specifically moiety [2517– 27nt ].of Fine-tuning complementary of the length,complementary enables mRNA length ofmodification OligoRNA sequences,without decreasing specifically mRNA 17 nt oftranslational complementary activity length, and withoutenables mRNAinducing modification an immune without response decreasing caused by mRNA double translational strand RNA activity (dsRNA) and withoutregions. Ultimately,inducing an we immune demonstrated response the caused utility by of double this approach strand RNA to improve (dsRNA) the regions. functionalities Ultimately, of wepolycation demonstrated-based mRNA the utility delivery of this systems. approach In tothis improve study, we the employed functionalities this method of polycation- to im- provebased mRNARNase deliveryresistance systems. without In using this study, cationic we materials employed by this directly method PEGylating to improve mRNA RNase resistance without using cationic materials by directly PEGylating mRNA (PEG-mRNA) (PEG-mRNA) using 17 nt OligoRNAs possessing a PEG strand (PEG-OligoRNA) (Figure using 17 nt OligoRNAs possessing a PEG strand (PEG-OligoRNA) (Figure1). The PEG 1). The PEG strands surrounding the mRNA were expected to reduce non-specific inter- strands surrounding the mRNA were expected to reduce non-specific interaction with action with charged macromolecules in physiological conditions, leading the inhibition of charged macromolecules in physiological conditions, leading the inhibition of unpreferable unpreferable recognition by RNases for efficient mRNA delivery. Indeed, PEG-OligoRNA recognition by RNases for efficient mRNA delivery. Indeed, PEG-OligoRNA hybridiza- hybridization with mRNA enhanced the tolerability against RNases and eventually im- tion with mRNA enhanced the tolerability against RNases and eventually improved the proved the introduction efficiency of PEG-mRNA in cultured cells. For future clinical ap- introduction efficiency of PEG-mRNA in cultured cells. For future clinical application,
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