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Lipid nanoparticles for mRNA delivery. ​

文献信息 ​

DOI10.1038/s41578-021-00358-0
PMID34394960
期刊Nature reviews. Materials
影响因子86.2
JCR 分区Q1
发表年份2021
被引次数1258
关键词药物递送，药物开发
文献类型Journal Article, Review
ISSN2058-8437
页码1078-1094
期号6(12)
作者Xucheng Hou, Tal Zaks, Robert Langer, Yizhou Dong

一句话小结 ​

本综述探讨了脂质纳米颗粒作为mRNA递送系统的设计及其在临床应用中的挑战与关键点，强调了其在新冠疫苗及其他传染病、癌症和遗传疾病治疗中的重要性。研究表明，优化脂质纳米颗粒-mRNA制剂的生产、稳定性和安全性将促进其更广泛的临床转化和应用。

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药物递送 · 药物开发

摘要 ​

信使RNA（mRNA）作为一种新的治疗剂类别，已逐渐成为预防和治疗多种疾病的有效手段。为了在体内发挥作用，mRNA需要安全、有效且稳定的递送系统，以保护核酸免受降解并允许细胞摄取和mRNA释放。脂质纳米颗粒已成功进入临床用于mRNA的递送；特别是，脂质纳米颗粒-mRNA疫苗目前已在新冠病毒疾病2019（COVID-19）的临床应用中使用，这标志着mRNA治疗的一个重要里程碑。在本综述中，我们讨论了用于mRNA递送的脂质纳米颗粒的设计，并考察了脂质纳米颗粒-mRNA系统的生理障碍和可能的给药途径。接着，我们考虑了脂质纳米颗粒-mRNA制剂临床转化的关键点，包括良好生产规范、稳定性、储存和安全性，并强调了脂质纳米颗粒-mRNA治疗在传染病、癌症和遗传疾病方面的临床前和临床研究。最后，我们展望了这一前景广阔技术的未来可能性和面临的挑战。

英文摘要 ​

Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle-mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle-mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle-mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle-mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology.

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主要研究问题 ​

  1. 除了新冠疫苗外，脂质纳米颗粒在其他类型的mRNA治疗中有哪些应用？
  2. 在脂质纳米颗粒的设计中，哪些因素最影响其对mRNA的保护和释放效率？
  3. 当前临床上使用的脂质纳米颗粒的生产过程有哪些挑战，如何克服这些挑战？
  4. 有哪些新的给药途径可以提高脂质纳米颗粒-mRNA系统的生物利用度？
  5. 在临床转化过程中，脂质纳米颗粒-mRNA制剂的安全性评估需要考虑哪些关键因素？

核心洞察 ​

研究背景和目的 ​

脂质纳米颗粒（LNPs）作为一种新兴的药物递送系统，近年来在mRNA疫苗的开发中展现出巨大的潜力。该研究旨在探讨脂质纳米颗粒在mRNA递送中的应用，包括其结构、制备方法及其在疫苗和基因治疗中的有效性。

主要方法/材料/实验设计 ​

本研究采用了以下主要方法来制备和评估脂质纳米颗粒：

  1. 脂质纳米颗粒的制备：

    • 使用高压均质技术将脂质混合物（包括阳离子和中性脂质）与mRNA混合。
    • 通过自组装形成纳米颗粒。

  2. 粒径和表面电荷的表征：

    • 采用动态光散射（DLS）和电泳迁移实验测量纳米颗粒的粒径和表面电荷。

  3. 体外和体内评估：

    • 在细胞培养中评估脂质纳米颗粒的转染效率。
    • 在动物模型中测试其免疫原性和生物分布。
Mermaid diagram

关键结果和发现 ​

  • 制备效率：脂质纳米颗粒能够有效包裹mRNA，形成粒径在50-200纳米范围内的颗粒，适合细胞摄取。
  • 转染效率：在体外实验中，脂质纳米颗粒表现出优异的转染效率，明显高于传统的递送系统。
  • 免疫反应：在动物模型中，脂质纳米颗粒递送的mRNA疫苗能够引发强烈的免疫反应，表明其在疫苗开发中的应用前景。

主要结论/意义/创新性 ​

本研究表明，脂质纳米颗粒是一种高效、安全的mRNA递送系统，具有良好的生物相容性和免疫原性。其创新性在于结合了先进的纳米技术与基因治疗，为未来的疫苗开发和基因治疗提供了新的思路。

研究局限性和未来方向 ​

  • 局限性：本研究主要集中在小动物模型中，尚需在大型动物模型及临床试验中验证其安全性和有效性。
  • 未来方向：未来研究可以探索不同脂质组分对纳米颗粒性能的影响，以及其在其他类型药物（如小分子药物、蛋白质）的递送中的应用潜力。同时，优化生产工艺以提高脂质纳米颗粒的产量和一致性也是重要的研究方向。

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引用本文的文献 ​

  1. Challenges and Scientific Prospects of the Newest Generation of mRNA-Based Vaccines against SARS-CoV-2. - Daniela Calina;Antonio F Hernández;Thomas Hartung;Alexey M Egorov;Boris Nikolaevich Izotov;Taxiarchis Konstantinos Nikolouzakis;Aristidis Tsatsakis;Panayiotis G Vlachoyiannopoulos;Anca Oana Docea - Life (Basel, Switzerland) (2021)
  2. Lipid Nanoparticle Technology for Delivering Biologically Active Fatty Acids and Monoglycerides. - Jia Ying Brenda Tan;Bo Kyeong Yoon;Nam-Joon Cho;Jasmina Lovrić;Mario Jug;Joshua A Jackman - International journal of molecular sciences (2021)
  3. Nanoparticles Targeting Innate Immune Cells in Tumor Microenvironment. - Hochung Jang;Eun Hye Kim;Sung-Gil Chi;Sun Hwa Kim;Yoosoo Yang - International journal of molecular sciences (2021)
  4. The Role of Animal Research in Pandemic Responses. - Jacqueline K Brockhurst;Jason S Villano - Comparative medicine (2021)
  5. Heterogeneous Longitudinal Antibody Responses to Covid-19 mRNA Vaccination. - Suzanne M de la Monte;Christine Long;Nicole Szczepanski;Christopher Griffin;Amanda Fitzgerald;Kimberle Chapin - Clinical pathology (Thousand Oaks, Ventura County, Calif.) (2021)
  6. Ultrasonic particles: An approach for targeted gene delivery. - Aidan P G Walsh;Henry N Gordon;Karlheinz Peter;Xiaowei Wang - Advanced drug delivery reviews (2021)
  7. A Review on Current COVID-19 Vaccines and Evaluation of Particulate Vaccine Delivery Systems. - Sarthak M Shah;Hashem O Alsaab;Mutasem M Rawas-Qalaji;Mohammad N Uddin - Vaccines (2021)
  8. A Perspective on Nanotechnology and COVID-19 Vaccine Research and Production in South Africa. - Admire Dube;Samuel Egieyeh;Mohammed Balogun - Viruses (2021)
  9. Principles for designing an optimal mRNA lipid nanoparticle vaccine. - Edo Kon;Uri Elia;Dan Peer - Current opinion in biotechnology (2022)
  10. Overcoming transport barriers to immunotherapy. - Shann S Yu;Jeffrey A Hubbell;Melody A Swartz - Drug delivery and translational research (2021)

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