Recent Advances in Lipid Nanoparticles for Delivery of mRNA
Abstract
:1. Introduction
2. The Vectors for mRNA Delivery
2.1. The Delivery of mRNA Requires Vectors
2.2. Selection of mRNA Delivery Vectors
2.2.1. Viral Vectors
2.2.2. Non-Viral Vectors
Advantages | Disadvantages | |
---|---|---|
Retrovirus | Stable integration into the genome, high transfection rate, long gene expression time, weak immunogenicity. | Only integrate into dividing cells, risk of insertional mutations, low delivery efficiency in vivo, small package capacity [9]. |
Adenovirus | Capable of carrying relatively large gene fragments. | Immunogenic, complex operation, short gene expression time. |
AAV | Weak immune response, high transfection rate, no integration of host DNA. | Small package capacity |
Lentiviral | Stable integration into genome or dividing cells, long duration of gene expression, weak immunogenicity. | Risk of insertional mutations, low delivery efficiency in vivo [9]. |
LNP | Protect mRNA from degradation by ribonucleases, high mRNA delivery efficiency, high yield, and easy scale-up of production. | Potential side effects, weak targeting and stability. |
Protamine | Protect mRNA from degradation by ribonucleases and adjuvant activity of the protamine–mRNA complex. | Low delivery efficiency and low efficiency of mRNA translation. |
Cationic polymer | Promote internalization through adsorption-mediated cellular endocytosis, effectively compress nucleic acids and protect them from enzymatic degradation through surface amine groups [48], and provide pH-buffering capacity through the large number of tertiary amine groups in the core [49]. | Mostly non-degradable and highly cytotoxic [50]. |
Peptide | Highly functional. | Low delivery efficiency |
Cationic nanoemulsion | Protects mRNA from degradation by ribonucleases, has the ability to protect and efficiently deliver nucleic acids, and can trigger a strong immune response as a vaccine adjuvant [51]. | High cytotoxicity |
Cell-penetrating peptide | Low charge density and excellent ability to cross cell membranes. | Only a few peptides are effective and there is an urgent need to develop new effective compounds to expand the material pool for peptide delivery systems. |
Exosome | Biocompatible and not easily cleared by immunity [52]. | Difficult to produce, isolate, and purify [53]. |
Inorganic nanoparticle | Easily modified for surface modification and unique versatility. | Poor biocompatibility and difficult to biodegrade. |
3. Lipid Nanoparticles (LNPs)
3.1. The Development of LNPs
3.2. Components and Structural Features of LNPs
3.3. Preparation of LNPs
3.3.1. Ethanol Dilution Method and Manual Mixing Method
3.3.2. T-Mix Method
3.3.3. Microfluidics
4. The Factors Affecting the Efficiency of LNP@mRNA Delivery
4.1. Modification of mRNA
4.1.1. Nucleoside Modification
4.1.2. Adjusting the Cap Structure
4.1.3. Optimization of Regulation Elements for 5′ UTR and 3′ UTR
4.1.4. Design of the Open Reading Frame (ORF)
4.1.5. Adding A-Tail
4.2. Ionizable Lipids
4.2.1. The Effects of Ionizable Lipid Structure on the Efficiency of LNP Transfection
Head
Connecting Fragment
Tail
4.2.2. Key Points in the Design of Chemical Structures for Ionizable Lipids
pKa
Endosome Escape
4.2.3. Progress in the Study of Ionizable Lipids
4.3. PEGylated Lipids
4.4. Auxiliary Phospholipids
4.5. Cholesterol
4.6. Particle Size of LNPs
5. The Factors Affecting the Distribution of LNP@mRNA In Vivo
5.1. Route of Administration
5.2. Targeted Molecular Modification
5.3. High-Throughput Screening and Design of Predictable LNP
5.4. Discovery of Novel Ionizable Lipids
6. Problems in Clinical Application of LNP@mRNA
6.1. Immune-Related Adverse Effects
6.2. Side Effects of PEG
6.3. Instability Issues of LNP@mRNA
7. Optimization of LNP@mRNA Recipes for Clinical Therapeutic Requirements
7.1. Optimization of LNP@mRNA Recipes
7.2. Designing Novel PEGylated Lipids
8. The Brief Landscape of LNP@mRNA in Clinical Gene Therapy
8.1. LNP@mRNA for Infectious Disease Treatment
8.2. LNP@mRNA for Cardiovascular Disease Treatment
8.3. LNP@mRNA for Liver Disease Treatment
8.4. LNP@mRNA Research for the Cancer Treatment
8.5. LNP@mRNA for Rare Disease Treatment
9. Conclusions and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Technology Path | Vaccine Name | Companies | First Posted | Clinical Trial Number | Phase |
---|---|---|---|---|---|
mRNA vaccines | Comirnaty BNT162B2 | Pfizer (New York, NY, USA)/BioNTech SE (Mainz, Germany) | Approved. Emergency use authorization in several countries around the world | ||
Spikevax mRNA-1273 | ModernaTX, Inc. (Cambridge, MA, USA) | ||||
mRNA-1273.351 | ModernaTX, Inc. (Cambridge, MA, USA) | 28 May 2020 | NCT04405076 | Phase II | |
SYS6006 | CSPC ZhongQi Pharmaceutical Technology Co., Ltd. (Shijiazhuang, China) | 30 June 2022 | NCT05439824 | Phase II | |
CanSino Biologics Inc. (Tianjin, China) | 13 May 2022 | NCT05373472 | Phase II | ||
ABO1009-DP | Suzhou Abogen Biosciences Co., Ltd. (Suzhou, China) | 28 June 2022 | NCT05434585 | Phase I | |
ABO-CoV.617.2 | |||||
LVRNA009 | AIM Vaccine Co., Ltd. (Beijing, China) | 6 May 2022 | NCT05364047 | Phase I | |
RQ3013 | Walvax Biotechnology Co., Ltd. (Kunming, China) | 31 May 2022 | NCT05396573 | Phase I | |
PTX-COVID19-B | Providence Therapeutics Holdings Inc. (Toronto, ON, Canada) | 21 February 2021 | NCT04765436 | Phase I | |
CV0501 | GlaxoSmithKline (Brentford, England) | 28 July 2022 | NCT05477186 | Phase I | |
Lyophilized mRNA vaccine | RH109 | Wuhan Recogen Biotechnology Co., Ltd. (Wuhan, China) | 9 May 2022 | NCT05366296 | Phase I |
Viral Vectors | Non-Viral Vectors | |
---|---|---|
Advantages | High transfection efficiency | Low toxicity, low immune response, low chance of exogenous gene integration, no size limitation of gene insert, easy to use, easy to prepare, easy to store and test, high safety, high potential, low cost, simple preparation and modifiability |
Disadvantages | Potentially carcinogenic, autoimmunogenicity, cytopathic changes, small genetic capacity, toxic side effects, high preparation costs | Low transfection efficiency |
Name | Cost | Scalability | Encapsulation Efficiency | Reproducibility | Polydispersity Index |
---|---|---|---|---|---|
Ethanol dilution method | Low | Moderate | Moderate | Moderate | High |
Manual mixing method | Low | Low | Low | Low | High |
T-mix method | Low | High | High | High | Moderate |
Microfluidics | High | High | High | High | Low |
Institution | Name | Indication | mRNA Encoding | Route of Administration | Delivery Vector | Clinical Trial Number (Phase) |
---|---|---|---|---|---|---|
ModernaTX, Inc. | mRNA-1647 | Cytomegalovirus (CMV) Infection | Human cytomegalovirus envelope glycoprotein H | i.m. | LNP V1GL | NCT03382405 (I) NCT04232280 (II) |
mRNA-1443 | LNP | NCT03382405 (I) | ||||
mRNA-1653 | Human metapneumovirus (hMPV) and human parainfluenza 3 virus (PIV3) | hMPV and PIV3 membrane fusion protein | i.m. | LNP | NCT03392389 (I) NCT04144348 (I) | |
VAL-506440; mRNA-1440 | Influenza A virus (H10N8) | Influenza hemagglutinin H10N8 | i.m. | LNP | NCT03076385 (I) | |
VAL-339851; mRNA-1851 | Influenza A virus (H7N9) | Influenza hemagglutinin H7N9 | i.m. | LNP | NCT03345043 (I) | |
mRNA-1345 | Respiratory syncytial virus (RSV) | RSV pre-infused F protein | i.m. | LNP | NCT04528719 (I) | |
VAL-181388; mRNA-1388; | Chikungunya virus (CHIKV) | Anti-CHKV monoclonal antibody | i.m. | LNP | NCT03325075 (I) | |
mRNA-1944 | Prevention of CHIKV infection | CHIKV-specific monoclonal neutralizing antibody (CHKV-24) | i.m. | LNP | NCT03829384 (I) | |
mRNA-1325; | Zika virus | PrM and E | i.m. | LNP | NCT03014089 (I) | |
mRNA-1893 | i.m. | LNP V1GL | NCT04064905 (I) | |||
mRNA-2752 | Solid tumor malignancies or lymphoma/ovarian cancer | Human OX40L, IL-23, and IL-36γ | Intratumoral injection | LNP | NCT03739931 (1) | |
mRNA-2416 | Human OX40L | Intratumoral injection | LNP | NCT03323398 (I/II) | ||
mRNA-4157 | Melanoma | Personalized | i.m. | LNP | NCT03897881 (II) | |
Solid tumors | Personalized | i.m. | LNP | NCT03313778 (I) | ||
BioNTech SE | Lipo-MERIT | Melanoma | Four selected malignant melanoma-associated antigens: New York-ESO 1 (NY-ESO-1), tyrosinase, melanoma-associated antigen A3 (MAGE-A3), and trans-membrane phosphatase with tensin homology (TPTE) | i.m. | Lipoplex | NCT02410733 (I) |
CureVac | CV7202 | Rabies | Rabies virus glycoprotein (RABV-G) | i.m. | LNP | NCT03713086 (I) |
GlaxoSmithKline | RG-SAM (CNE) vaccine (GSK3903133A) | Viral diseases | Rabies glycoprotein G (RG) | i.m. | CNE | NCT04062669 (I) |
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Yang, L.; Gong, L.; Wang, P.; Zhao, X.; Zhao, F.; Zhang, Z.; Li, Y.; Huang, W. Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics 2022, 14, 2682. https://doi.org/10.3390/pharmaceutics14122682
Yang L, Gong L, Wang P, Zhao X, Zhao F, Zhang Z, Li Y, Huang W. Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics. 2022; 14(12):2682. https://doi.org/10.3390/pharmaceutics14122682
Chicago/Turabian StyleYang, Lei, Liming Gong, Ping Wang, Xinghui Zhao, Feng Zhao, Zhijie Zhang, Yunfei Li, and Wei Huang. 2022. "Recent Advances in Lipid Nanoparticles for Delivery of mRNA" Pharmaceutics 14, no. 12: 2682. https://doi.org/10.3390/pharmaceutics14122682
APA StyleYang, L., Gong, L., Wang, P., Zhao, X., Zhao, F., Zhang, Z., Li, Y., & Huang, W. (2022). Recent Advances in Lipid Nanoparticles for Delivery of mRNA. Pharmaceutics, 14(12), 2682. https://doi.org/10.3390/pharmaceutics14122682