信使RNA药物修饰及其递送系统研究进展

Messenger RNA (mRNA) has shown tremendous potential in disease prevention and therapy. The clinical application requires mRNA with enhanced stability and high translation efficiency, ensuring it not to be degraded by nuclease and to target to specific tissues and cells. The mRNA immunogenicity can be reduced by nucleotide modification, and its translation efficiency can be enhanced by codon optimization. The 5´ capping structure and 3´ poly A increase mRNA stability, and the addition of 5' and 3' non-translational region regulates mRNA translation initiation and protein production. A nanoparticle delivery system protects mRNA from degradation by ubiquitous nuclease, enhances its circulation concentration and assists it entrancing cytoplasm for the purpose of treatment and prevention. In this article, we review the recent advances of mRNA technology, discuss the methods and principles to enhance mRNA stability and translation efficiency; summarize the requirements involved in designing mRNA delivery systems with the potential of industrial translation and biomedical application. Furthermore, we provide insights into future directions of mRNA therapeutics to meet the need for personalized precision medicine.

[1]  Y. Barenholz,et al.  Anti-PEG antibodies before and after a first dose of Comirnaty® (mRNA-LNP-based SARS-CoV-2 vaccine) , 2022, Journal of Controlled Release.

[2]  H. Cabral,et al.  Polymeric Micelles with pH-Responsive Cross-Linked Core Enhance In Vivo mRNA Delivery , 2022, Pharmaceutics.

[3]  Margaret M. Billingsley,et al.  Hydroxycholesterol substitution in Ionizable lipid nanoparticles for mRNA delivery to T cells. , 2022, Journal of controlled release : official journal of the Controlled Release Society.

[4]  Qiaobing Xu,et al.  Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis , 2022, Proceedings of the National Academy of Sciences.

[5]  D. Weissman,et al.  CAR T cells produced in vivo to treat cardiac injury , 2022, Science.

[6]  E. J. Chung,et al.  Targeted polyelectrolyte complex micelles treat vascular complications in vivo , 2021, Proceedings of the National Academy of Sciences.

[7]  M. Houston,et al.  Correction: Cap 1 Messenger RNA Synthesis with Co-transcriptional CleanCap® Analog by In Vitro Transcription. , 2021, Current protocols.

[8]  Rachel S. Riley,et al.  Added to pre-existing inflammation, mRNA-lipid nanoparticles induce inflammation exacerbation (IE) , 2021, Journal of Controlled Release.

[9]  Larissa B. Thackray,et al.  Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains , 2021, Science Translational Medicine.

[10]  J. Coller,et al.  Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression , 2021, Nature Reviews Molecular Cell Biology.

[11]  Byung-Kwan Cho,et al.  Modifications of mRNA vaccine structural elements for improving mRNA stability and translation efficiency , 2021, Molecular & cellular toxicology.

[12]  Jing Yang,et al.  Self-assembled polymeric micelle as a novel mRNA delivery carrier , 2021, Journal of Controlled Release.

[13]  E. Koonin,et al.  Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery , 2021, Science.

[14]  Guofang Zhang,et al.  Intrinsic bioactivity of black phosphorus nanomaterials on mitotic centrosome destabilization through suppression of PLK1 kinase , 2021, Nature Nanotechnology.

[15]  X. Xia.  Detailed Dissection and Critical Evaluation of the Pfizer/BioNTech and Moderna mRNA Vaccines , 2021, Vaccines.

[16]  Ruosen Xie,et al.  In vivo targeted delivery of nucleic acids and CRISPR genome editors enabled by GSH-responsive silica nanoparticles. , 2021, Journal of controlled release : official journal of the Controlled Release Society.

[17]  Qun Wang,et al.  Effects of polyethylene glycol on the surface of nanoparticles for targeted drug delivery. , 2021, Nanoscale.

[18]  Moganavelli Singh,et al.  Dendrimer-Coated Gold Nanoparticles for Efficient Folate-Targeted mRNA Delivery In Vitro , 2021, Pharmaceutics.

[19]  Johan Liu,et al.  A Novel Graphene Quantum Dot‐Based mRNA Delivery Platform , 2021, ChemistryOpen.

[20]  Xianhui Kang,et al.  The role of mRNA in the development, diagnosis, treatment and prognosis of neural tumors , 2021, Molecular cancer.

[21]  M. Nussenzweig,et al.  mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants , 2021, Nature.

[22]  C. Zurla,et al.  Treatment of influenza and SARS-CoV-2 infections via mRNA-encoded Cas13a in rodents , 2021, Nature Biotechnology.

[23]  E. Gabellieri,et al.  Exploiting gold nanoparticles for diagnosis and cancer treatments , 2021, Nanotechnology.

[24]  Xiaodong Sun,et al.  Lentiviral delivery of co-packaged Cas9 mRNA and a Vegfa-targeting guide RNA prevents wet age-related macular degeneration in mice , 2021, Nature Biomedical Engineering.

[25]  P. Nelson,et al.  In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo , 2020, Nature Communications.

[26]  anonymous.  Nanomedicine and the COVID-19 vaccines , 2020, Nature Nanotechnology.

[27]  Y. Miyahara,et al.  Guanidine-phosphate interactions stabilize polyion complex micelles based on flexible catiomers to improve mRNA delivery , 2020 .

[28]  K. Tsumoto,et al.  mRNA Delivery: Polymeric Nanocarriers with Controlled Chain Flexibility Boost mRNA Delivery In Vivo through Enhanced Structural Fastening (Adv. Healthcare Mater. 16/2020) , 2020 .

[29]  J. Karlsson,et al.  Poly(beta-amino ester)s as gene delivery vehicles: challenges and opportunities , 2020, Expert opinion on drug delivery.

[30]  G. Ippolito,et al.  Structure-based design of prefusion-stabilized SARS-CoV-2 spikes , 2020, Science.

[31]  Haifa Shen,et al.  Nanoplatforms for mRNA Therapeutics , 2020 .

[32]  C. Puglia,et al.  Curcumin Containing PEGylated Solid Lipid Nanoparticles for Systemic Administration: A Preliminary Study , 2020, Molecules.

[33]  J. Rehwinkel,et al.  RIG-I-like receptors: their regulation and roles in RNA sensing , 2020, Nature Reviews Immunology.

[34]  Qiang Cheng,et al.  Selective ORgan Targeting (SORT) nanoparticles for tissue specific mRNA delivery and CRISPR/Cas gene editing , 2020, Nature Nanotechnology.

[35]  Huijun Lu,et al.  mRNA Vaccines Encoding the HA Protein of Influenza A H1N1 Virus Delivered by Cationic Lipid Nanoparticles Induce Protective Immune Responses in Mice , 2020, Vaccines.

[36]  Moganavelli Singh,et al.  Folate-Targeted mRNA Delivery Using Chitosan-Functionalized Selenium Nanoparticles: Potential in Cancer Immunotherapy , 2019, Pharmaceuticals.

[37]  M. Carmo-Fonseca,et al.  Targeting mRNA processing as an anticancer strategy , 2019, Nature Reviews Drug Discovery.

[38]  Kimberly J. Hassett,et al.  Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines , 2019, Molecular therapy. Nucleic acids.

[39]  S. Pfeffer,et al.  NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes , 2019, The Journal of Biological Chemistry.

[40]  Hao Zhu,et al.  Dendrimer‐Based Lipid Nanoparticles Deliver Therapeutic FAH mRNA to Normalize Liver Function and Extend Survival in a Mouse Model of Hepatorenal Tyrosinemia Type I , 2018, Advanced materials.

[41]  Xiaoyuan Chen,et al.  Aptamer‐based targeted therapy , 2018, Advanced drug delivery reviews.

[42]  A. Niedzwiecka,et al.  Modified ARCA analogs providing enhanced translational properties of capped mRNAs , 2018, Cell cycle.

[43]  Xi Luo,et al.  Biodegradable Black Phosphorus Nanosheets Mediate Specific Delivery of hTERT siRNA for Synergistic Cancer Therapy. , 2018, ACS applied materials & interfaces.

[44]  Huang-Hao Yang,et al.  A black phosphorus nanosheet-based siRNA delivery system for synergistic photothermal and gene therapy. , 2018, Chemical communications.

[45]  A. Rentmeister,et al.  Synthetic mRNA capping , 2017, Beilstein journal of organic chemistry.

[46]  Man Li,et al.  Engineering intranasal mRNA vaccines to enhance lymph node trafficking and immune responses. , 2017, Acta biomaterialia.

[47]  Gene W. Yeo,et al.  Short Poly(A) Tails are a Conserved Feature of Highly Expressed Genes , 2017, Nature Structural & Molecular Biology.

[48]  Jun Lin,et al.  Assembly of Au Plasmonic Photothermal Agent and Iron Oxide Nanoparticles on Ultrathin Black Phosphorus for Targeted Photothermal and Photodynamic Cancer Therapy , 2017 .

[49]  Matthias T Stephan,et al.  In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. , 2017, Nature nanotechnology.

[50]  E. Grayhack,et al.  Synonymous Codons: Choose Wisely for Expression. , 2017, Trends in genetics : TIG.

[51]  David H Burkhardt,et al.  Operon mRNAs are organized into ORF-centric structures that predict translation efficiency , 2017, eLife.

[52]  J. Lv,et al.  Gold nanotriangles: Green synthesis and PDT & PTT effect , 2017 .

[53]  Antonio J Giraldez,et al.  Codon identity regulates mRNA stability and translation efficiency during the maternal‐to‐zygotic transition , 2016, The EMBO journal.

[54]  R. Sprangers,et al.  A general method for rapid and cost-efficient large-scale production of 5′ capped RNA , 2016, RNA.

[55]  Tae-Jin Lee,et al.  Efficient mRNA delivery with graphene oxide-polyethylenimine for generation of footprint-free human induced pluripotent stem cells. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[56]  Nicholas T. Ingolia,et al.  Differences in codon bias and GC content contribute to the balanced expression of TLR7 and TLR9 , 2016, Proceedings of the National Academy of Sciences.

[57]  Mark W. Tibbitt,et al.  Bioinspired Alkenyl Amino Alcohol Ionizable Lipid Materials for Highly Potent In Vivo mRNA Delivery , 2016, Advanced materials.

[58]  R. Weiss,et al.  N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. , 2015, Journal of controlled release : official journal of the Controlled Release Society.

[59]  Y. Furuichi,et al.  Discovery of m7G-cap in eukaryotic mRNAs , 2015, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[60]  V. Kim,et al.  TAIL-seq: genome-wide determination of poly(A) tail length and 3' end modifications. , 2014, Molecular cell.

[61]  J. Finer,et al.  Identification and validation of promoters and cis-acting regulatory elements. , 2014, Plant science : an international journal of experimental plant biology.

[62]  Giulio Caracciolo,et al.  Effect of polyethyleneglycol (PEG) chain length on the bio-nano-interactions between PEGylated lipid nanoparticles and biological fluids: from nanostructure to uptake in cancer cells. , 2014, Nanoscale.

[63]  Nikolai G Khlebtsov,et al.  Uptake of engineered gold nanoparticles into mammalian cells. , 2014, Chemical reviews.

[64]  K. G. Rajeev,et al.  Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[65]  T. Schlake,et al.  Developing mRNA-vaccine technologies , 2012, RNA biology.

[66]  Daniel G. Anderson,et al.  Five years of siRNA delivery: spotlight on gold nanoparticles. , 2011, Small.

[67]  A. Wanekaya,et al.  Functionalized gold nanoparticles for the binding, stabilization, and delivery of therapeutic DNA, RNA, and other biological macromolecules. , 2010, Nanotechnology, science and applications.

[68]  K. G. Rajeev,et al.  Targeted Delivery of RNAi Therapeutics With Endogenous and Exogenous Ligand-Based Mechanisms. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[69]  Hiroki Kato,et al.  Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[70]  J. Goldstein,et al.  NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes , 2008, Proceedings of the National Academy of Sciences.

[71]  Robert Langer,et al.  A combinatorial polymer library approach yields insight into nonviral gene delivery. , 2008, Accounts of chemical research.

[72]  D. Hoekstra,et al.  Cationic lipids, lipoplexes and intracellular delivery of genes. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[73]  Shubiao Zhang,et al.  Toxicity of cationic lipids and cationic polymers in gene delivery. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[74]  R. Rhoads,et al.  Differential Inhibition of mRNA Degradation Pathways by Novel Cap Analogs* , 2006, Journal of Biological Chemistry.

[75]  J. Heyes,et al.  Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[76]  Houping Ni,et al.  Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. , 2005, Immunity.

[77]  D. Bentley,et al.  Rules of engagement: co-transcriptional recruitment of pre-mRNA processing factors. , 2005, Current opinion in cell biology.

[78]  N. Elango,et al.  Optimized transfection of mRNA transcribed from a d(A/T)100 tail-containing vector. , 2005, Biochemical and biophysical research communications.

[79]  S. Peltz,et al.  The cap-to-tail guide to mRNA turnover , 2001, Nature Reviews Molecular Cell Biology.

[80]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[81]  M. Graf,et al.  Rev-independent expression of synthetic gag-pol genes of human immunodeficiency virus type 1 and simian immunodeficiency virus: implications for the safety of lentiviral vectors. , 2000, Human gene therapy.

[82]  T Salditt,et al.  An inverted hexagonal phase of cationic liposome-DNA complexes related to DNA release and delivery. , 1998, Science.

[83]  W. Hauswirth,et al.  A "humanized" green fluorescent protein cDNA adapted for high-level expression in mammalian cells , 1996, Journal of virology.

[84]  D. Gallie.  The cap and poly(A) tail function synergistically to regulate mRNA translational efficiency. , 1991, Genes & development.

[85]  C. Kurland.  Codon bias and gene expression , 1991, FEBS letters.

[86]  P. Bernstein,et al.  Poly(A), poly(A) binding protein and the regulation of mRNA stability. , 1989, Trends in biochemical sciences.

[87]  A. J. Carpousis,et al.  mRNA degradation. A tale of poly(A) and multiprotein machines. , 1999, Trends in genetics : TIG.

[88]  R. Epand,et al.  Promotion of hexagonal phase formation and lipid mixing by fatty acids with varying degrees of unsaturation. , 1991, Chemistry and physics of lipids.