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Pharmaceutics
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Advances in the Development of mRNA Medicines and mRNA Vaccines
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Advances in the Development of mRNA Medicines and mRNA Vaccines

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 13993

Special Issue Editor

Prof. Dr. Keiji Itaka

E-Mail Website
Guest Editor
1. Department of Biofunction Research, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Tokyo 101-0062, Japan
2. Clinical Biotechnology Team, Center for Infectious Disease Education and Research (CiDER), Osaka University, 1-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Interests: mRNA therapeutics; regenerative medicine; synthetic biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Synthetic mRNA is attracting much attention as a new drug modality, with significant interest in the next applications of mRNA medicines and vaccines. This Special Issue of Pharmaceutics will address new ideas for developing mRNA medicines and vaccines, including mRNA design (e.g., modified nucleotides, self-amplified mRNA), delivery systems (e.g., lipid nanoparticle (LNP), polyplex carrier, injection device), refinements to improve safety, and proof-of-concept studies using animal models. Original research papers or review articles on any of these aspects are welcomed in this Special Issue.

Prof. Dr. Keiji Itaka
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • messenger RNA (mRNA)
  • mRNA medicine
  • mRNA vaccine
  • nucleic acid medicine
  • LNP
  • polyplex
  • mRNA therapeutics

Published Papers (7 papers)

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Research

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16 pages, 6938 KiB  
Article
The Effect of Cholesterol Content on the Adjuvant Activity of Nucleic-Acid-Free Lipid Nanoparticles
by Jessica Anindita, Hiroki Tanaka, Takuma Yamakawa, Yuka Sato, Chika Matsumoto, Kota Ishizaki, Taiji Oyama, Satoko Suzuki, Keisuke Ueda, Kenjirou Higashi, Kunikazu Moribe, Kasumi Sasaki, Yumika Ogura, Etsuo Yonemochi, Yu Sakurai, Hiroto Hatakeyama and Hidetaka Akita
Pharmaceutics 2024, 16(2), 181; https://doi.org/10.3390/pharmaceutics16020181 - 26 Jan 2024
Viewed by 2066
Abstract
RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug [...] Read more.
RNA vaccines are applicable to the treatment of various infectious diseases via the inducement of robust immune responses against target antigens by expressing antigen proteins in the human body. The delivery of messenger RNA by lipid nanoparticles (LNPs) has become a versatile drug delivery system used in the administration of RNA vaccines. LNPs are widely considered to possess adjuvant activity that induces a strong immune response. However, the properties of LNPs that contribute to their adjuvant activity continue to require clarification. To characterize the relationships between the lipid composition, particle morphology, and adjuvant activity of LNPs, the nanostructures of LNPs and their antibody production were evaluated. To simply compare the adjuvant activity of LNPs, empty LNPs were subcutaneously injected with recombinant proteins. Consistent with previous research, the presence of ionizable lipids was one of the determinant factors. Adjuvant activity was induced when a tiny cholesterol assembly (cholesterol-induced phase, ChiP) was formed according to the amount of cholesterol present. Moreover, adjuvant activity was diminished when the content of cholesterol was excessive. Thus, it is plausible that an intermediate structure of cholesterol (not in a crystalline-like state) in an intra-particle space could be closely related to the immunogenicity of LNPs. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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20 pages, 2758 KiB  
Article
Development of a Ready-to-Use-Type RNA Vaccine Carrier Based on an Intracellular Environment-Responsive Lipid-like Material with Immune-Activating Vitamin E Scaffolds
by Jessica Anindita, Hiroki Tanaka, Ryotaro Oyama, Shinya Hagiwara, Daiki Shirane, Sakura Taneichi, Yuta Nakai, Kota Tange, Hiroto Hatakeyama, Yu Sakurai and Hidetaka Akita
Pharmaceutics 2023, 15(12), 2702; https://doi.org/10.3390/pharmaceutics15122702 - 29 Nov 2023
Viewed by 1802
Abstract
Because of its efficient and robust gene transfer capability, messenger RNA (mRNA) has become a promising tool in various research fields. The lipid nanoparticle (LNP) is considered to be a fundamental technology for an mRNA delivery system and has been used extensively for [...] Read more.
Because of its efficient and robust gene transfer capability, messenger RNA (mRNA) has become a promising tool in various research fields. The lipid nanoparticle (LNP) is considered to be a fundamental technology for an mRNA delivery system and has been used extensively for the development of RNA vaccines against SARS-CoV-2. We recently developed ssPalm, an environmentally responsive lipid-like material, as a component of LNP for mRNA delivery. In this study, a self-degradable unit (phenyl ester) that confers high transfection activity and an immune stimulating unit (vitamin E scaffold) for high immune activation were combined to design a material, namely, ssPalmE-Phe-P4C2, for vaccine use. To design a simple and user-friendly form of an RNA vaccine based on this material, a freeze-drying-based preparation method for producing a ready-to-use-type LNP (LNP(RtoU)) was used to prepare the LNPssPalmE-Phe. The optimization of the preparation method and the lipid composition of the LNPssPalmE-Phe(RtoU) revealed that dioleoyl-sn-glycero phosphatidylethanolamine (DOPE) was a suitable helper lipid for achieving a high vaccination activity of the LNPssPalmE-Phe(RtoU). Other findings indicated that to maintain particle properties and vaccination activity, a 40% cholesterol content was necessary. A single administration of the LNPssPalmE-Phe(RtoU) that contained mRNA-encoding Ovalbumin (mOVA-LNPssPalmE-Phe(RtoU)) demonstrated a significant suppression of tumor progression in a tumor-bearing mouse OVA-expressing cell line (E.G7-OVA). In summary, the LNPssPalmE-Phe(RtoU) is an easy-to-handle drug delivery system (DDS) for delivering mRNA antigens in immunotherapy. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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14 pages, 4568 KiB  
Article
Comprehensive Evaluation of Lipid Nanoparticles and Polyplex Nanomicelles for Muscle-Targeted mRNA Delivery
by Xuan Du, Erica Yada, Yuki Terai, Takuya Takahashi, Hideyuki Nakanishi, Hiroki Tanaka, Hidetaka Akita and Keiji Itaka
Pharmaceutics 2023, 15(9), 2291; https://doi.org/10.3390/pharmaceutics15092291 - 07 Sep 2023
Cited by 2 | Viewed by 2242
Abstract
The growing significance of messenger RNA (mRNA) therapeutics in diverse medical applications, such as cancer, infectious diseases, and genetic disorders, highlighted the need for efficient and safe delivery systems. Lipid nanoparticles (LNPs) have shown great promise for mRNA delivery, but challenges such as [...] Read more.
The growing significance of messenger RNA (mRNA) therapeutics in diverse medical applications, such as cancer, infectious diseases, and genetic disorders, highlighted the need for efficient and safe delivery systems. Lipid nanoparticles (LNPs) have shown great promise for mRNA delivery, but challenges such as toxicity and immunogenicity still remain to be addressed. In this study, we aimed to compare the performance of polyplex nanomicelles, our original cationic polymer-based carrier, and LNPs in various aspects, including delivery efficiency, organ toxicity, muscle damage, immune reaction, and pain. Our results showed that nanomicelles (PEG-PAsp(DET)) and LNPs (SM-102) exhibited distinct characteristics, with the former demonstrating relatively sustained protein production and reduced inflammation, making them suitable for therapeutic purposes. On the other hand, LNPs displayed desirable properties for vaccines, such as rapid mRNA expression and potent immune response. Taken together, these results suggest the different potentials of nanomicelles and LNPs, supporting further optimization of mRNA delivery systems tailored for specific purposes. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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15 pages, 7520 KiB  
Article
Administration of mRNA-Nanomedicine-Augmented Calvarial Defect Healing via Endochondral Ossification
by Hsi-Kai Tsou, Cheng-Hsin Wu, Long Yi Chan, Kazunori Kataoka, Nanae Itokazu, Minoru Tsuzuki, Hsuan Hu, Guan-Yu Zhuo, Keiji Itaka and Chin-Yu Lin
Pharmaceutics 2023, 15(7), 1965; https://doi.org/10.3390/pharmaceutics15071965 - 17 Jul 2023
Viewed by 1265
Abstract
Large-area craniofacial defects remain a challenge for orthopaedists, hastening the need to develop a facile and safe tissue engineering strategy; osteoconductive material and a combination of optimal growth factors and microenvironment should be considered. Faced with the unmet need, we propose that abundant [...] Read more.
Large-area craniofacial defects remain a challenge for orthopaedists, hastening the need to develop a facile and safe tissue engineering strategy; osteoconductive material and a combination of optimal growth factors and microenvironment should be considered. Faced with the unmet need, we propose that abundant cytokines and chemokines can be secreted from the bone defect, provoking the infiltration of endogenous stem cells to assist bone regeneration. We can provide a potent mRNA medicine cocktail to promptly initiate the formation of bone templates, osteogenesis, and subsequent bone matrix deposition via endochondral ossification, which may retard rapid fibroblast infiltration and prevent the formation of atrophic non-union. We explored the mutual interaction of BMP2 and TGFβ3 mRNA, both potent chondrogenic factors, on inducing endochondral ossification; examined the influence of in vitro the transcribed polyA tail length on mRNA stability; prepared mRNA nanomedicine using a PEGylated polyaspartamide block copolymer loaded in a gelatin sponge and grafted in a critical-sized calvarial defect; and evaluated bone regeneration using histological and μCT examination. The BMP2 and TGFβ3 composite mRNA nanomedicine resulted in over 10-fold new bone volume (BV) regeneration in 8 weeks than the BMP2 mRNA nanomedicine administration alone, demonstrating that the TGFβ3 mRNA nanomedicine synergistically enhances the bone’s formation capability, which is induced by BMP2 mRNA nanomedicine. Our data demonstrated that mRNA-medicine-mediated endochondral ossification provides an alternative cell-free tissue engineering methodology for guiding craniofacial defect healing. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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17 pages, 2505 KiB  
Article
An mRNA-Based Multiple Antigenic Gene Expression System Delivered by Engineered Salmonella for Severe Fever with Thrombocytopenia Syndrome and Assessment of Its Immunogenicity and Protection Using a Human DC-SIGN-Transduced Mouse Model
by Ji-Young Park, Chamith Hewawaduge, Chandran Sivasankar, Khristine Kaith S. Lloren, Byungkwan Oh, Mi Young So and John Hwa Lee
Pharmaceutics 2023, 15(5), 1339; https://doi.org/10.3390/pharmaceutics15051339 - 26 Apr 2023
Cited by 3 | Viewed by 1687
Abstract
Currently, there are no commercial vaccines or therapeutics against severe fever with thrombocytopenia syndrome (SFTS) virus. This study explored an engineered Salmonella as a vaccine carrier to deliver a eukaryotic self-mRNA replicating vector, pJHL204. This vector expresses multiple SFTS virus antigenic genes for [...] Read more.
Currently, there are no commercial vaccines or therapeutics against severe fever with thrombocytopenia syndrome (SFTS) virus. This study explored an engineered Salmonella as a vaccine carrier to deliver a eukaryotic self-mRNA replicating vector, pJHL204. This vector expresses multiple SFTS virus antigenic genes for the nucleocapsid protein (NP), glycoprotein precursor (Gn/Gc), and nonstructural protein (NS) to induce host immune responses. The engineered constructs were designed and validated through 3D structure modeling. Western blot and qRT-PCR analyses of transformed HEK293T cells confirmed the delivery and expression of the vaccine antigens. Significantly, mice immunized with these constructs demonstrated a cell-mediated and humoral response as balanced Th1/Th2 immunity. The JOL2424 and JOL2425 delivering NP and Gn/Gc generated strong immunoglobulin IgG and IgM antibodies and high neutralizing titers. To further examine the immunogenicity and protection, we utilized a human DC-SIGN receptor transduced mouse model for SFTS virus infection by an adeno-associated viral vector system. Among the SFTSV antigen constructs, the construct with full-length NP and Gn/Gc and the construct with NP and selected Gn/Gc epitopes induced robust cellular and humoral immune responses. These were followed by adequate protection based on viral titer reduction and reduced histopathological lesions in the spleen and liver. In conclusion, these data indicate that recombinant attenuated Salmonella JOL2424 and JOL2425 delivering NP and Gn/Gc antigens of SFTSV are promising vaccine candidates that induce strong humoral and cellular immune responses and protection against SFTSV. Moreover, the data proved that the hDC-SIGN transduced mice as a worthy tool for immunogenicity study for SFTSV. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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14 pages, 5007 KiB  
Article
Anti-Inflammatory Therapy for Temporomandibular Joint Osteoarthritis Using mRNA Medicine Encoding Interleukin-1 Receptor Antagonist
by Jia Deng, Yuta Fukushima, Kosuke Nozaki, Hideyuki Nakanishi, Erica Yada, Yuki Terai, Kenji Fueki and Keiji Itaka
Pharmaceutics 2022, 14(9), 1785; https://doi.org/10.3390/pharmaceutics14091785 - 26 Aug 2022
Cited by 5 | Viewed by 2517
Abstract
Messenger RNA (mRNA) is an emerging drug modality for protein replacement therapy. As mRNA efficiently provides protein expression in post-mitotic cells without the risk of insertional mutagenesis, direct delivery of mRNA can be applied, not only as an alternative to gene therapy, but [...] Read more.
Messenger RNA (mRNA) is an emerging drug modality for protein replacement therapy. As mRNA efficiently provides protein expression in post-mitotic cells without the risk of insertional mutagenesis, direct delivery of mRNA can be applied, not only as an alternative to gene therapy, but also for various common diseases such as osteoarthritis (OA). In this study, using an mRNA-encoding interleukin-1 receptor antagonist (IL-1Ra), we attempted anti-inflammatory therapy in a rat model of the temporomandibular joint (TMJ) OA, which causes long-lasting joint pain with chronic inflammation. For the intra-articular injection of mRNA, a polyplex nanomicelle, our original polymer-based carrier, was used to offer the advantage of excellent tissue penetration with few immunogenic responses. While the protein expression was transient, a single administration of IL-1Ra mRNA provided sustained pain relief and an inhibitory effect on OA progression for 4 weeks. The mRNA-loaded nanomicelles provided the encoded protein diffusely in the disc and articular cartilage without upregulation of the expression levels of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α). This proof-of-concept study demonstrates how anti-inflammatory proteins delivered by mRNA delivery using a polyplex nanomicelle could act to alleviate OA, stimulating the development of mRNA therapeutics. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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Review

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17 pages, 656 KiB  
Review
Intradermal Delivery of Naked mRNA Vaccines via Iontophoresis
by Mahadi Hasan, Anowara Khatun and Kentaro Kogure
Pharmaceutics 2023, 15(12), 2678; https://doi.org/10.3390/pharmaceutics15122678 - 26 Nov 2023
Viewed by 1640
Abstract
Messenger RNA (mRNA) vaccines against infectious diseases and for anticancer immunotherapy have garnered considerable attention. Currently, mRNA vaccines encapsulated in lipid nanoparticles are administrated via intramuscular injection using a needle. However, such administration is associated with pain, needle phobia, and lack of patient [...] Read more.
Messenger RNA (mRNA) vaccines against infectious diseases and for anticancer immunotherapy have garnered considerable attention. Currently, mRNA vaccines encapsulated in lipid nanoparticles are administrated via intramuscular injection using a needle. However, such administration is associated with pain, needle phobia, and lack of patient compliance. Furthermore, side effects such as fever and anaphylaxis associated with the lipid nanoparticle components are also serious problems. Therefore, noninvasive, painless administration of mRNA vaccines that do not contain other problematic components is highly desirable. Antigen-presenting cells reside in the epidermis and dermis, making the skin an attractive vaccination site. Iontophoresis (ItP) uses weak electric current applied to the skin surface and offers a noninvasive permeation technology that enables intradermal delivery of hydrophilic and ionic substances. ItP-mediated intradermal delivery of biological macromolecules has also been studied. Herein, we review the literature on the use of ItP technology for intradermal delivery of naked mRNA vaccines which is expected to overcome the challenges associated with mRNA vaccination. In addition to the physical mechanism, we discuss novel biological mechanisms of iontophoresis, particularly ItP-mediated opening of the skin barriers and the intracellular uptake pathway, and how the combined mechanisms can allow for effective intradermal delivery of mRNA vaccines. Full article
(This article belongs to the Special Issue Advances in the Development of mRNA Medicines and mRNA Vaccines)
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