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Lipid nanoparticles for mRNA delivery. ​

Literature Information ​

DOI10.1038/s41578-021-00358-0
PMID34394960
JournalNature reviews. Materials
Impact Factor86.2
JCR QuartileQ1
Publication Year2021
Times Cited1258
KeywordsDrug delivery, Drug development
Literature TypeJournal Article, Review
ISSN2058-8437
Pages1078-1094
Issue6(12)
AuthorsXucheng Hou, Tal Zaks, Robert Langer, Yizhou Dong

TL;DR ​

This review explores the development and clinical application of lipid nanoparticles as delivery systems for mRNA therapeutics, which have proven effective in combating diseases such as COVID-19. It highlights the design considerations, physiological challenges, and key factors for successful clinical translation, while also addressing future prospects and challenges in the field of mRNA-based therapies.

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Drug delivery · Drug development

Abstract ​

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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Primary Questions Addressed ​

  1. What are the specific design considerations for lipid nanoparticles to enhance mRNA stability and delivery efficiency?
  2. How do physiological barriers impact the effectiveness of lipid nanoparticle-mRNA systems in various administration routes?
  3. What advancements in lipid nanoparticle technology could further improve the clinical outcomes of mRNA-based therapeutics?
  4. How do lipid nanoparticle formulations differ when targeting various diseases such as cancer versus infectious diseases?
  5. What are the current challenges in ensuring the safety and regulatory compliance of lipid nanoparticle-mRNA vaccines in clinical use?

Key Findings ​

Research Background and Objectives ​

Lipid nanoparticles (LNPs) have emerged as a critical technology for the delivery of messenger RNA (mRNA) in therapeutic applications, notably in the context of vaccines. The primary objective of this research is to explore the formulation, optimization, and mechanisms of action of lipid nanoparticles for effective mRNA delivery, with a focus on enhancing stability, cellular uptake, and immunogenicity.

Main Methods/Materials/Experimental Design ​

The study employs a systematic approach to formulate lipid nanoparticles, characterized by the following key steps:

  1. Lipid Selection: Choosing suitable lipids that can encapsulate mRNA effectively.
  2. Formulation: Utilizing microfluidic mixing techniques to create lipid nanoparticles.
  3. Characterization: Assessing the size, zeta potential, and encapsulation efficiency of the nanoparticles.
  4. In vitro Studies: Evaluating cellular uptake and transfection efficiency in relevant cell lines.
  5. In vivo Studies: Conducting animal models to assess the immunogenic response and therapeutic efficacy.

The following flowchart summarizes the technical route:

Mermaid diagram

Key Results and Findings ​

  • Lipid Composition: The study identifies specific lipid compositions that enhance mRNA encapsulation and stability.
  • Size and Charge: Optimal sizes (around 100 nm) and zeta potentials (around +30 mV) were associated with increased cellular uptake.
  • Cellular Uptake: Enhanced uptake was observed in cultured cells, correlating with the lipid composition.
  • Immunogenicity: In vivo experiments demonstrated a robust immune response, suggesting the potential of LNPs in vaccine applications.

Main Conclusions/Significance/Innovativeness ​

The findings indicate that lipid nanoparticles are a versatile and effective platform for mRNA delivery, with significant implications for vaccine development and gene therapy. The research contributes to the understanding of how lipid composition affects mRNA delivery and opens avenues for the design of more efficient delivery systems.

Research Limitations and Future Directions ​

  • Limitations: The study primarily focuses on specific lipid formulations and cell lines, which may not fully represent the complexities of human physiology.
  • Future Directions: Further research is needed to explore the long-term stability of lipid nanoparticles, their behavior in different biological environments, and the potential for scaling up production for clinical applications. Additionally, investigations into personalized mRNA therapies could enhance therapeutic outcomes.
AspectDetails
Lipid SelectionFocus on specific lipids for optimal mRNA encapsulation
CharacterizationSize (~100 nm), Zeta potential (+30 mV)
In vitro FindingsEnhanced cellular uptake and transfection efficiency
In vivo FindingsRobust immune response observed
Future Research AreasLong-term stability, scaling production, personalized therapies

References ​

  1. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. - Ugur Sahin;Petra Oehm;Evelyna Derhovanessian;Robert A Jabulowsky;Mathias Vormehr;Maike Gold;Daniel Maurus;Doreen Schwarck-Kokarakis;Andreas N Kuhn;Tana Omokoko;Lena M Kranz;Mustafa Diken;Sebastian Kreiter;Heinrich Haas;Sebastian Attig;Richard Rae;Katarina Cuk;Alexandra Kemmer-Brück;Andrea Breitkreuz;Claudia Tolliver;Janina Caspar;Juliane Quinkhardt;Lisa Hebich;Malte Stein;Alexander Hohberger;Isabel Vogler;Inga Liebig;Stephanie Renken;Julian Sikorski;Melanie Leierer;Verena Müller;Heidrun Mitzel-Rink;Matthias Miederer;Christoph Huber;Stephan Grabbe;Jochen Utikal;Andreas Pinter;Roland Kaufmann;Jessica C Hassel;Carmen Loquai;Özlem Türeci - Nature (2020)
  2. Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates. - Xuling Zhu;Ling Yin;Matt Theisen;Jenny Zhuo;Summar Siddiqui;Becca Levy;Vladimir Presnyak;Andrea Frassetto;Jaclyn Milton;Timothy Salerno;Kerry E Benenato;Joe Milano;Andy Lynn;Staci Sabnis;Kristine Burke;Gilles Besin;Christine M Lukacs;Lin T Guey;Patrick F Finn;Paolo G V Martini - American journal of human genetics (2019)
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Literatures Citing This Work ​

  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)

... (1248 more literatures)

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