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Recent Advances in Mrna Vaccine Delivery Nano Research 2018, 11(10): 5338–5354 https://doi.org/10.1007/s12274-018-2091-z Recent advances in mRNA vaccine delivery Lu Tan and Xun Sun () Key Laboratory of Drug Targeting and Novel Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China Received: 14 March 2018 ABSTRACT Revised: 30 April 2018 In recent years, messenger RNA (mRNA) vaccines have been intensively studied Accepted: 4 May 2018 in the fields of cancer immunotherapy and infectious diseases because of their excellent efficacy and safety profile. Despite significant progress in the rational © Tsinghua University Press design of mRNA vaccines and elucidation of their mechanism of action, their and Springer-Verlag GmbH widespread application is limited by the development of safe and effective Germany, part of Springer delivery systems that protect them from ubiquitous ribonucleases (RNases), Nature 2018 facilitate their entry into cells and subsequent escape from endosomes, and target them to lymphoid organs or particular cells. Some mRNA vaccines based KEYWORDS on lipid carriers have entered clinical trials. Vaccines based on polymers, while messenger RNA (mRNA) not as clinically advanced as lipid vectors, show considerable potentials. In this vaccines, review, we discuss the necessity of formulating mRNA vaccines with delivery delivery systems, systems, and we provide an overview of reported delivery systems. polymer, lipid 1 Introduction and their complex composition can trigger adverse effects [3]. In contrast, mRNA vaccines express well- Messenger RNA (mRNA) vaccines carry transcripts defined antigens that induce focused immune responses encoding antigens, and use the host cell translational specifically against the encoded antigens [4]. Inactivated machinery to produce the antigens, which then stimulates pathogens or subunit vaccines are generally safer an immune response [1]. In 1993, liposome-delivered than live attenuated vaccines, but they are considered mRNA encoding influenza virus nucleoprotein was to elicit primarily humoral immunity. In contrast, shown to induce a virus-specific T cell response in mRNA vaccines can induce both humoral and cellular mice [2], and since then these vaccines have been the immune responses, including responses mediated subject of intense research. Their popularity reflects by cytotoxic T lymphocytes (CTLs), which are essential their numerous advantages over other vaccine platforms. for cancer immunotherapy and for eradicating Live attenuated vaccines carry the risk that the pathogens “hidden” within host cells [5]. In addition, attenuated organism will revert to a virulent form, these vaccines can be constructed simply and inex- Address correspondence to [email protected] Nano Res. 2018, 11(10): 5338–5354 5339 pensively in a similar way with high purity and delivery systems that have been reported in the stability [4, 6]. literature. Finally, we will provide an overview of These advantages of mRNA vaccines mentioned preclinical and clinical applications of mRNA vaccines. above are shared by DNA vaccines and viral vectors. However, mRNA vaccines have advantages over these 2 From production to function other nucleic acid vaccines. DNA vaccines must be delivered into the nucleus, where antigen transcripts Synthetic mRNA can be produced in a cell-free in are generated for subsequent translation in the vitro transcription system containing a DNA template cytoplasm. Ensuring entry of DNA vaccines into the encoding all the structural elements of a functional nucleus brings technical challenges and carries risk mRNA, ribonucleotides, bacteriophage RNA poly- of insertional mutagenesis [3, 7]. The application of merase, and normally a synthetic cap analogue [7, 12]. viral vectors can be severely limited by anti-vector In some cases, total RNA extracted from tumor cells immunity resulting from live infection or previous can also be used as vaccines [13]. The antigen-encoding immunization [3]. In contrast, mRNA vaccines are mRNA, whether in vitro-transcribed or extracted, is usually delivered by non-viral systems and are required administered nakedly or complexed with an appro- only to reach the cytoplasm, eliminating risk of priate vector. In all cases, the mRNA induces an integration into the host genome [5]. In addition, immune response via a similar process (Fig. 1). mRNA vaccines can transfect cells that divide slowly At first, target cells internalize the mRNA vaccine; or not at all, such as dendritic cells (DCs) [5]. DNA these target cells may be DCs in the case of intranodal vaccines cross the nuclear membranes of such injection [14] or non-immune cells at the administration cells much less efficiently than they cross the nuclear site in the case of intramuscular injection [15]. Many membranes of rapidly dividing cells [8]. The fact that cell types can take up naked mRNA spontaneously in mRNA does not replicate and is metabolically degraded a temperature- and dose-dependent manner [16]. within a few hours [9] means that the expression of Most mRNAs appear to enter cells via caveolae/lipid mRNA is rapid and transient. As a result, exposure rafts and involve scavenger-receptor(s) [16, 17], but to antigen is more controlled, minimizing the risk of they enter DCs primarily via macropinocytosis [18, tolerance induction [10]. Moreover, mRNA is not 19]. Uptake of mRNAs in vivo can be as efficient, or categorized by the US Food and Drug Administration even more so, as uptake in vitro [7, 15, 20]. Internalized as a genetically modified organism, whereas plasmid mRNA vaccines are usually trapped in endosomal DNA is [11]. vesicles, so they have to escape from the endosomes Despite all these advantages of mRNA vaccines, to reach the cytosol to be translated. The underlying their development has long been surpassed by that mechanism remains unclear [5]. of DNA vaccines because of uncertainties about RNA After escape into the cytoplasm, the mRNA is stability and large-scale manufacturing [3]. Technical translated to produce the encoded antigens, which in advances in RNA biology and chemistry have DCs are degraded by cytosolic proteasomes, in the eliminated these issues, but challenges remain, same way that endogenous proteins are degraded. including how to protect mRNA from degradation, The resulting epitope peptides are transported to the how to ensure its efficient arrival into the cytoplasm, endoplasmic reticulum, where they bind with major how to target it to desired cells and tissues in vivo, histocompatibility complex (MHC) I molecules. MHC and how to balance intrinsic adjuvant activity with I/epitope complexes are presented on the cell surface translation inhibition. In the present review, we will and induce antigen-specific CD8+ T cell responses [5, discuss these challenges and describe the rational 12, 21]. MHC II/antigen presentation, which leads to design of mRNA structure to ensure its stability and a CD4+ T helper cell response, is induced after DCs efficient translation. We will discuss the necessity of take up antigens released in the extracellular medium formulating mRNA vaccines with delivery systems, [21]. When an mRNA vaccine is internalized mainly and review lipid- and polymer-based as well as hybrid by non-immune cells, a CD8+ T cell response is also www.theNanoResearch.com∣www.Springer.com/journal/12274 | Nano Research 5340 Nano Res. 2018, 11(10): 5338–5354 Figure 1 Major steps involved for mRNA vaccines from production to function. (a) In vitro transcription: mRNA is transcribed from a DNA template in a cell-free system. (b) Cellular uptake: mRNA vaccine is internalized by DCs and trapped in endosomal vesicles. (c) Endosome escape: Entrapped mRNA is released into the cytoplasm. (d) Translation: Antigen proteins are synthesized using translational machinery of host cells. (e) MHC class I epitope processing pathway: Antigen proteins are degraded by proteasomes in the cytoplasm and generated epitopes are transported into the endoplasmic reticulum to bind with MHC class I molecules. (f) Presentation of MHC I/epitope complexes: MHC I/epitope complexes are presented on cell surface, leading to the induction of the antigen-specific CD8+ T cell response. (g) MHC class II epitope processing pathway: Exogenous antigens are taken up and degraded in endosomes. Generated epitopes bind with MHC class II molecules. (h) Presentation of MHC II/epitope complexes: MHC II/epitope complexes are presented on the cell surface, leading to the induction of antigen-specific CD4+ T cell response. observed, which might be partly obtained by cross- it may actually reduce this efficacy by destabilizing presentation of the translated antigens [22]. the antigen-encoding mRNA and inhibiting its In addition, in vitro-transcribed mRNA possesses translation [1, 5, 12]. Therefore, one challenge in strong immunostimulatory effects and intrinsic designing effective mRNA vaccines is how to deal adjuvant activity that may affect vaccine efficacy [23]. with the “doubled-edged” sword of innate immune Like viral RNA, synthetic mRNA is recognized by induction. specific pattern recognition receptors (PRRs) of the In order to arrive in the cytoplasm of target cells innate immune system, inducing the secretion of type I where it can be translated, naked mRNA faces several interferon (IFN) and establishing an antiviral response serious challenges. It is susceptible to ubiquitous [5]. These PRRs are mainly Toll-like receptors (TLRs) extracellular ribonucleases (RNases) [34], and its large localized
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