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백신 제조사의 입장에서는 기업의 비밀을 유지할 수 있다는 점도 mRNA 백신을 개발하는 이유이다. mRNA는 리보솜의 단백질 형성이 끝나면 분해된다. 따라서 백신 제조사가 공개하지 않는 한 다른 경쟁사가 백신 투여자에게서 mRNA 정보를 얻을 수 없다. 제작 원리를 알고 있다고 하더라도 경쟁사는 처음 단계부터 개발비를 투자하여 스스로 제작할 수 밖에 없기 때문에 백신 복제의 잇점을 얻을 수 없다.<ref>{{cite newspaper | newspaper=[[The Independent]] | date=18 November 2020 | access-date=3 December 2020 | url=https://www.independent.co.uk/news/world/americas/covid-vaccine-ingredients-pfizer-moderna-fda-b1729324.html | title='What is Covid vaccine made of?' trends on Google as Pfizer and Moderna seek FDA approval | vauthors = Vallejo J }}</ref>
== Delivery약물 전달 ==
mRNA 백신의 [[약물 전달]]은 생체 외부 방식과 내부 방식로 나뉠 수 있다.<ref name="Verbeke_2019"/>
The methods of [[drug delivery]] can be broadly classified by whether the RNA transfer to cells happens within (''[[in vivo]]'') or outside (''[[ex vivo]]'') the organism.<ref name="Verbeke_2019"/>
=== ''Ex생체 vivo''외부 방식 ===
[[Dendritic면역 cell]]s세포 are가운데 a type of immune cells that display antigens on their하나인 [[Cell수지상 surface|surfaces세포]], leading to interactions with는 [[T cellT세포]]s가 읽을 to수 initiate있도록 an표면에 immune항원을 response늘어놓는다. Dendritic특정한 cells항원을 can지닌 be수지상 collected세포를 from환자에게서 patients채취하여 and항원을 be형성시킬 programmedmRNA를 with설계할 mRNA수 있다. Then,생체 they외부에서 can인공적으로 be만들어진 re-administeredmRNA는 back다시 into환자에 patients투여하여 to목적한 create항체가 an형성되는 immune지를 response관찰한다.<ref>{{cite journal | vauthors = Benteyn D, Heirman C, Bonehill A, Thielemans K, Breckpot K | title = mRNA-based dendritic cell vaccines | journal = Expert Review of Vaccines | volume = 14 | issue = 2 | pages = 161–76 | date = February 2015 | pmid = 25196947 | doi = 10.1586/14760584.2014.957684 | s2cid = 38292712 }}</ref> 이 방식의 가장 큰 장점은 별다른 전달 분자 없이 직접 사용할 수 있다는 것이다. 백신 개발 이전에도 [[암]] 치료의 목적으로 사용되어 왔다.<ref name="김원근" />
=== ''In생체 vivo''내부 방식 ===
SincemRNA의 the발현을 discovery시험관에서 of확인할 ''[[in수 vitro]]''있게 transcribed되면서 mRNA생체 expression내부에서 ''in vivo'' following direct administration, ''in vivo''직접 approachesRNA를 have조절하는 become생체 more내부 and방식이 more선호되고 attractive있다.<ref>{{cite journal | vauthors = Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A, Felgner PL | title = Direct gene transfer into mouse muscle in vivo | journal = Science | volume = 247 | issue = 4949 Pt 1 | pages = 1465–8 | date = March 1990 | pmid = 1690918 | doi = 10.1126/science.1690918 | bibcode = 1990Sci...247.1465W }}</ref> They환자에게서 offer수지상 some세포를 advantages계속하여 over"수확"해야 ''ex하는 vivo''외부 methods,방식보다 particularly비용이 by적게 avoiding들기 the cost of harvesting and adapting dendritic cells from patients and by imitating a regular infection때문이다. There그러나 are생체 still내 obstacles전달의 for효율은 these아직 methods생체 to외부 be방식에 overcome비해 for효율성이 RNA vaccination to be a potent procedure떨어진다.<ref name="김원근">[[Evolution|Evolutionary mechanisms]] that prevent the infiltration of unknown [[Nucleic acid|nucleic material]] and promote degradation by [[RNase]]s need to be circumvented in order to initiate translationhttps://www.ibric.org/myboard/read.php?Board=report&id=3228 InmRNA addition,백신 the– mobility백신학의 of새로운 RNA on its own is dependent on regular cell processes because it is too heavy to [[Diffusion|diffuse]시대], whichBRIC is likely to be eliminated, halting translation.View</ref>
==== Naked벌거벗은 mRNA injection주입 ====
This벌거벗은 modemRNA는 of다른 mRNA전달 uptake물질 has없이 been[[피부]]나 known[[림프절]]에 for직접 overmRNA를 two주입하는 decades and the worldwide first clinical studies (Tuebingen, Germany) using direct injections of방식이다. mRNA for백신 vaccination연구 consisted초기부터 in사용된 injections of naked mRNA in the dermis,방식으로<ref>{{cite journal | vauthors = Probst J, Weide B, Scheel B, Pichler BJ, Hoerr I, Rammensee HG, Pascolo S | title = Spontaneous cellular uptake of exogenous messenger RNA in vivo is nucleic acid-specific, saturable and ion dependent | journal = Gene Therapy | volume = 14 | issue = 15 | pages = 1175–80 | date = August 2007 | pmid = 17476302 | doi = 10.1038/sj.gt.3302964 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lorenz C, Fotin-Mleczek M, Roth G, Becker C, Dam TC, Verdurmen WP, Brock R, Probst J, Schlake T | display-authors = 6 | title = Protein expression from exogenous mRNA: uptake by receptor-mediated endocytosis and trafficking via the lysosomal pathway | journal = RNA Biology | volume = 8 | issue = 4 | pages = 627–36 | date = July 2011 | pmid = 21654214 | doi = 10.4161/rna.8.4.15394 | doi-access = free }}</ref> and1990년대에 the자기 use증폭 of방식 RNAmRNA를 as a vaccine tool was discovered in the 1990s in the form of self-amplifying mRNA백신화하였다.<ref>{{cite journal | vauthors = Zhou X, Berglund P, Rhodes G, Parker SE, Jondal M, Liljeström P | title = Self-replicating Semliki Forest virus RNA as recombinant vaccine | journal = Vaccine | volume = 12 | issue = 16 | pages = 1510–4 | date = December 1994 | pmid = 7879415 | doi = 10.1016/0264-410x(94)90074-4 }}</ref><ref name = "Berglund_1998">{{cite journal | vauthors = Berglund P, Smerdou C, Fleeton MN, Tubulekas I, Liljeström P | title = Enhancing immune responses using suicidal DNA vaccines | journal = Nature Biotechnology | volume = 16 | issue = 6 | pages = 562–5 | date = June 1998 | pmid = 9624688 | doi = 10.1038/nbt0698-562 | s2cid = 38532700 }}</ref> It피부나 has혈액 also또는 emerged근육과 that같이 the다양한 different투여 routes방식이 of있지만 [[Injection림프절 (medicine)|injection]],투여가 suchT세포 as활성화에 into가장 the큰 [[skin]], [[blood]] or to [[muscle]]s, resulted in varying levels of mRNA uptake, making the choice of administration route a critical aspect of delivery. Kreiter et al. demonstrated, in comparing different routes, that [[lymph node]] injection leads to the largest T효과가 cell있다고 response보고되었다.<ref>{{cite journal | vauthors = Kreiter S, Selmi A, Diken M, Koslowski M, Britten CM, Huber C, Türeci O, Sahin U | display-authors = 6 | title = Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity | journal = Cancer Research | volume = 70 | issue = 22 | pages = 9031–40 | date = November 2010 | pmid = 21045153 | doi = 10.1158/0008-5472.can-10-0699 | doi-access = free }}</ref> The그러나 mechanismsRNA and분자는 consequently매우 the크기 evaluation때문에 of자가 self-amplifying증폭 mRNA방식 couldmRNA를 be직접 different,투여하는 as방식의 they효능은 are사례별로 fundamentally different by being a much bigger molecule in차이가 size크다.<ref name="Verbeke_2019" />
==== Polyplexes폴리플렉스 ====
[[Cationic양이온 polymerization|Cationic polymer중합화]]s를 can이용하여 be mixed with mRNA to generatemRNA와 [[Vectors in gene therapy#Polyplexes|polyplexes폴리플렉스]]를 that결합시킬 protect수 the있다. recombinant이 mRNA방법은 from세포에 [[ribonuclease]]s침투할 and때 assist까지 its penetration in cells.mRNA가 [[Protamine리보뉴클레이스]]와 is재결합 a하는 natural것을 cationic방지하기 peptide위해 and has been used to complex mRNA for vaccination고안되었다.{{primary-source inline|date=December 2020}}<ref>{{primary-source inline|date=December 2020}}{{cite journal |vauthors=Weide B, Pascolo S, Scheel B, Derhovanessian E, Pflugfelder A, Eigentler TK, Pawelec G, Hoerr I, Rammensee HG, Garbe C |title=Direct injection of protamine-protected mRNA: results of a phase 1/2 vaccination trial in metastatic melanoma patients |journal=J Immunother |volume=32 |issue=5 |pages=498–507 |date=June 2009 |pmid=19609242 |doi=10.1097/CJI.0b013e3181a00068 |url=}}</ref>
==== Lipid지질 nanoparticles나노입자 ====
The[[미국 first식품의약국]]은 time2018년 the[[hATTR FDA아밀로이드증]]의 approved치료를 the use of위한 [[solid짧은 lipid간섭 nanoparticles|lipidRNA]]인 nanoparticles[[온파트로]]의 as약물 a전달 drug delivery system was in 2018, when the agency approved the first방식으로 [[Small고형 interfering지질 RNA|siRNA나노입자]] drug,방식을 [[Onpattro]]처음 승인하였다.<ref name=Stat4>{{cite website | website=[[Stat (website)|Stat]] | date=1 December 2020 | access-date=3 December 2020 | url=https://www.statnews.com/2020/12/01/how-nanotechnology-helps-mrna-covid19-vaccines-work/ | title=How nanotechnology helps mRNA Covid-19 vaccines work | vauthors = Cooney E }}</ref> Encapsulating고형 the지질 mRNA나노입자는 molecule인지질을 in비롯한 lipid다양한 nanoparticles음이온성 was물질로 a작은 critical캡슐을 breakthrough만들고 for그 producing안에 viable약품을 mRNA넣어 vaccines목적하는 곳까지 전달하는 방식이다.<ref>이정은 외, solving〈[https://www.koreascience.or.kr/article/JAKO200802727132911.pdf a음이온성 number지질을 of포함한 key지질나노입자의 technical제조 barriers및 in물리적 delivering특성]〉, the《한국화학학회지》, 2008년, 제52권 3호 </ref> mRNA molecule백신의 경우 RNA를 지질막으로 둘러쌓아 into인체 the세포까지 human전달하게 cell된다.<ref name=Stat4/><ref>{{cite journal | vauthors = Reichmuth AM, Oberli MA, Jaklenec A, Langer R, Blankschtein D | title = mRNA vaccine delivery using lipid nanoparticles | journal = Therapeutic Delivery | volume = 7 | issue = 5 | pages = 319–34 | date = May 2016 | pmid = 27075952 | pmc = 5439223 | doi = 10.4155/tde-2016-0006 }}</ref> Principally, the [[Lipid bilayer|lipid]] provides a layer of protection against degradation, allowing more robust translational output. In addition, the customization of the lipid outer layer allows the targeting of desired cell types through [[ligand]] interactions. However, many studies have also highlighted the difficulty of studying this type of delivery, demonstrating that there is an inconsistency between ''in vivo'' and ''in vitro'' applications of nanoparticles in terms of cellular intake.<ref>{{cite journal | vauthors = Paunovska K, Sago CD, Monaco CM, Hudson WH, Castro MG, Rudoltz TG, Kalathoor S, Vanover DA, Santangelo PJ, Ahmed R, Bryksin AV, Dahlman JE | display-authors = 6 | title = A Direct Comparison of in Vitro and in Vivo Nucleic Acid Delivery Mediated by Hundreds of Nanoparticles Reveals a Weak Correlation | journal = Nano Letters | volume = 18 | issue = 3 | pages = 2148–2157 | date = March 2018 | pmid = 29489381 | pmc = 6054134 | doi = 10.1021/acs.nanolett.8b00432 | bibcode = 2018NanoL..18.2148P }}</ref> The nanoparticles can be administered to the body and transported via multiple routes, such as [[Intravenous therapy|intravenously]] or through the [[lymphatic system]].<ref name=Stat4/>
=== Viral바이럴 vectors벡터 ===
{{further|Viral vector}}
In addition to non-viral delivery methods, [[RNA virus]]es have been [[Biological engineering|engineered]] to achieve similar immunological responses. Typical RNA viruses used as vectors include [[retrovirus]]es, [[lentivirus]]es, [[alphavirus]]es and [[Rhabdoviridae|rhabdoviruses]], each of which can differ in structure and function.<ref>{{cite journal | vauthors = Lundstrom K | title = RNA Viruses as Tools in Gene Therapy and Vaccine Development | journal = Genes | volume = 10 | issue = 3 | pages = 189 | date = March 2019 | pmid = 30832256 | pmc = 6471356 | doi = 10.3390/genes10030189 }}</ref> Clinical studies have utilized such viruses on a range of diseases in [[Model organism|model animals]] such as [[Mouse|mice]], [[chicken]] and [[primate]]s.<ref>{{cite journal | vauthors = Huang TT, Parab S, Burnett R, Diago O, Ostertag D, Hofman FM, Espinoza FL, Martin B, Ibañez CE, Kasahara N, Gruber HE, Pertschuk D, Jolly DJ, Robbins JM | display-authors = 6 | title = Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model | journal = Human Gene Therapy | volume = 26 | issue = 2 | pages = 82–93 | date = February 2015 | pmid = 25419577 | pmc = 4326030 | doi = 10.1089/hum.2014.100 }}</ref><ref>{{cite journal | vauthors = Schultz-Cherry S, Dybing JK, Davis NL, Williamson C, Suarez DL, Johnston R, Perdue ML | title = Influenza virus (A/HK/156/97) hemagglutinin expressed by an alphavirus replicon system protects chickens against lethal infection with Hong Kong-origin H5N1 viruses | journal = Virology | volume = 278 | issue = 1 | pages = 55–9 | date = December 2000 | pmid = 11112481 | doi = 10.1006/viro.2000.0635 }}</ref><ref>{{cite journal | vauthors = Geisbert TW, Feldmann H | title = Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections | journal = The Journal of Infectious Diseases | volume = 204 Suppl 3 | issue = suppl_3 | pages = S1075-81 | date = November 2011 | pmid = 21987744 | pmc = 3218670 | doi = 10.1093/infdis/jir349 }}</ref>
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