Throughput-scalable manufacturing of SARS-CoV-2 mRNA lipid nanoparticle vaccines.
Throughput-scalable manufacturing of SARS-CoV-2 mRNA lipid nanoparticle vaccines.
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严重急性呼吸综合征冠状病毒2（SARS-CoV-2）信使核糖核酸（mRNA）脂质纳米颗粒疫苗的通量可扩展制造。
DOI：
10.1073/pnas.2303567120
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发表时间：
2023-08-15
影响因子：
11.1
通讯作者：
Mitchell, Michael J.
中科院分区：
文献类型：
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作者：
Shepherd, Sarah J.;Han, Xuexiang;Mukalel, Alvin J.;El-Mayta, Rakan;Thatte, Ajay S.;Wu, Jingyu;Padilla, Marshall S.;Alameh, Mohamad-Gabriel;Srikumar, Neha;Lee, Daeyeon;Weissman, Drew;Issadore, David;Mitchell, Michael J.
用于RNA治疗剂和疫苗的脂质纳米颗粒（LNP）的发展中的一个主要未满足的需求是开发可以在从小规模发现实验到大规模临床试验的各种规模的药物开发中产生LNP的制剂技术。微流体技术，制定具有精确定义的属性的LNP，已被限制的可扩展性的挑战。为了克服这一点，我们制造了一个硅和玻璃微流体平台，用于mRNA-LNP疫苗的生产量可扩展的制造。该技术可广泛应用于纳米颗粒制剂，并可加速基于LNP的RNA疗法和疫苗的开发，以应对新出现的病原体和突发疫情。脂质纳米粒（LNPs）是一种有效的递送技术，使得最近在mRNA治疗和疫苗方面的临床突破成为可能。mRNA疗法和疫苗的更广泛实施的一个关键挑战是开发生产精确定义的LNP制剂的技术，其生产量可以从发现到商业生产并满足制药行业严格的生产标准。为了应对这些挑战，我们开发了一种微流控芯片，该芯片集成了1×、10×或256× LNP生成单元，可实现高达17 L/h的精确定义的LNP的可扩展生产率。使用这些芯片，我们证明了LNP的物理性质和效力在体内是不变的，因为吞吐量的规模。我们的芯片由硅和玻璃基板制成，具有出色的溶剂兼容性，与制药兼容性，并且可以完全重置和重复使用。由我们的芯片配制的SARS-CoV-2 mRNA-LNP疫苗在临床前研究中引发了有效的抗体应答。这些结果证明了将微流体产生的LNP直接转化为商业生产所需规模的可行性。
A major unmet need in the advancement of lipid nanoparticles (LNPs) for RNA therapeutics and vaccines is the development of formulation technologies that can generate LNPs across the various scales of drug development, from small-scale discovery experiments to large-scale clinical trials. Microfluidic technologies, which formulate LNPs with precisely defined properties, have been limited by scalability challenges. To overcome this, we fabricated a silicon and glass microfluidic platform for throughput-scalable manufacturing of mRNA-LNP vaccines. This technology can be widely applied to nanoparticle formulations and can accelerate the development of LNP-based RNA therapeutics and vaccines to address emerging pathogens and sudden outbreaks. Lipid nanoparticles (LNPs) are a potent delivery technology that have made it possible for the recent clinical breakthroughs in mRNA therapeutics and vaccines. A key challenge to the broader implementation of mRNA therapeutics and vaccines is the development of technology to produce precisely defined LNP formulations, with throughput that can scale from discovery to commercial manufacturing and meet the stringent manufacturing standards of the pharmaceutical industry. To address these challenges, we have developed a microfluidic chip that incorporates 1×, 10×, or 256× LNP-generating units that achieve scalable production rates of up to 17 L/h of precisely defined LNPs. Using these chips, we demonstrate that LNP physical properties and potency in vivo are unchanged as throughput is scaled. Our chips are fabricated out of silicon and glass substrates, which have excellent solvent compatibility, compatibility with pharmaceutical manufacturing, and can be fully reset and reused. SARS-CoV-2 mRNA-LNP vaccines formulated by our chips triggered potent antibody responses in a preclinical study. These results demonstrate the feasibility of directly translating microfluidic-generated LNPs to the scale necessary for commercial production.
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影响因子：
32.4
作者：
Alameh MG;Tombácz I;Bettini E;Lederer K;Sittplangkoon C;Wilmore JR;Gaudette BT;Soliman OY;Pine M;Hicks P;Manzoni TB;Knox JJ;Johnson JL;Laczkó D;Muramatsu H;Davis B;Meng W;Rosenfeld AM;Strohmeier S;Lin PJC;Mui BL;Tam YK;Karikó K;Jacquet A;Krammer F;Bates P;Cancro MP;Weissman D;Luning Prak ET;Allman D;Locci M;Pardi N
通讯作者：
Pardi N
DOI：
10.1038/s41578-021-00358-0
发表时间：
2021
期刊：
Nature reviews. Materials
影响因子：
--
作者：
Hou X;Zaks T;Langer R;Dong Y
通讯作者：
Dong Y
影响因子：
16.6
作者：
Han X;Zhang H;Butowska K;Swingle KL;Alameh MG;Weissman D;Mitchell MJ
通讯作者：
Mitchell MJ
影响因子：
15
作者：
Chen, Delai;Love, Kevin T.;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
DOI：
10.1038/mtna.2012.28
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
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