Design and delivery of RNA vaccines

YANG Lu; ZHANG Jingming; XU Shan; TONG Yigang

doi:10.12211/2096-8280.2025-085

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Design and delivery of RNA vaccines

Invited Review | 更新时间：2026-03-07

- Design and delivery of RNA vaccines
- Synthetic Biology Journal Vol. 7, Issue 1, Pages: 129-151(2026)
- 作者机构：
  
  1.北京化工大学生命科学与技术学院，绿色生物制造国家重点实验室，中国北京 100029
  2.合肥市综合性国家中心大健康研究院，先进医药与再生医学研究所，安徽合肥 230601
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2025-085
  CLC： R392
- Received：15 August 2025，
  
  Revised：2025-09-28，
  
  Published：28 February 2026
- 稿件说明：
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杨璐，张镜明，徐杉，童贻刚. RNA疫苗的设计与递送［J］. 合成生物学， 2026， 7（1）： 129-151

YANG Lu， ZHANG Jingming， XU Shan， TONG Yigang. Design and delivery of RNA vaccines［J］. Synthetic Biology Journal， 2026， 7（1）： 129-151
杨璐，张镜明，徐杉，童贻刚. RNA疫苗的设计与递送［J］. 合成生物学， 2026， 7（1）： 129-151 DOI： 10.12211/2096-8280.2025-085.

YANG Lu， ZHANG Jingming， XU Shan， TONG Yigang. Design and delivery of RNA vaccines［J］. Synthetic Biology Journal， 2026， 7（1）： 129-151 DOI： 10.12211/2096-8280.2025-085.

摘要

RNA疫苗因其快速开发和高效免疫原性成为疫苗领域的革命性技术。本文综述了RNA疫苗的设计优化与递送策略，聚焦线性mRNA、环状RNA（circular RNA，circRNA）和自扩增RNA（self-amplifying RNA，saRNA）三大类型的分子特征与应用潜力。在设计优化方面，线性mRNA通过5′帽结构、UTR（untranslated region，UTR）优化、密码子选择和poly（A）尾延长提升稳定性和翻译效率；circRNA凭借共价闭合结构抵抗核酸酶降解，实现长效表达；saRNA利用病毒复制机制扩增抗原产量，降低剂量需求。在递送系统中，脂质纳米颗粒（lipid nanoparticle，LNP）仍占据主导地位，但其可电离脂质设计和靶向配体修饰正不断优化递送效率。此外，病毒样颗粒（virus-like particle，VLP）作为新型递送载体，凭借天然的空心结构和自组装特性，兼具高生物相容性与高效mRNA装载能力，同时可模拟天然病毒入侵途径，增强细胞摄取。最后展望了其在个性化肿瘤疫苗和通用型传染病预防中的应用前景，通过整合创新递送系统（如VLP）与智能化设计，mRNA疫苗技术将迈向更精准、安全的下一代平台。

Abstract

RNA vaccines have emerged as a revolutionary technology in vaccinology due to their rapid development and high immunogenicity. This article systematically reviews the latest research progress in molecular design and delivery systems of mRNA vaccines

with a focus on three major types: linear mRNA

circular RNA (circRNA)

and self-amplifying RNA (saRNA). It highlights that mRNA vaccines

with their rapid development

high immunogenicity

and favorable safety profiles

have become a significant breakthrough in vaccine technology

demonstrating immense potentials

especially during the COVID-19 pandemic. In terms of design optimization

linear mRNA improves its stability and translation efficiency through strategies such as 5′cap

untranslated region (UTR) optimization

codon selection

and poly(A) tail elongation. Circular RNA

with its covalently closed circular structure

exhibits excellent resistance to nucleases and long-lasting expression properties

providing a new avenue for sustained antigen presentation. Self-amplifying RNA leverages viral replication mechanism to achieve intracellular self-replication

significantly reducing vaccine dosage requirements and enhancing immune responses. The article also notes that while mRNA vaccines inherently possesses certain immune-stimulatory effects (acting as a built-in adjuvant)

excessive activation of innate immunity may compromise their efficacy. Thus

balancing immunogenicity and expression efficiency requires modifications of nucleotides (

e.g

pseudouridine

1-methyl-pseudouridine) and purification processes (

e.g

HPLC

FPLC). As for the delivery systems

lipid nanoparticles (LNPs) remain as the mainstream platform. Through the rational composition of ionizable lipids

phospholipids

cholesterol

and PEGylated lipids

LNPs achieve efficient mRNA encapsulation and prevent endosomal escape. Additionally

virus-like particles

as an emerging bioinspired carrier

show great promise with their

natural hollow structure

self-assembly properties

and high biocompatibility

enabling enhanced uptake efficiency by antigen-presenting cells and mimicking viral invasion pathways. Other delivery strategies

such as polymer nanoparticles

peptide/protein carriers

and

ex vivo

dendritic cells loading

are also being continuously optimized. This article further explores the tremendous potential of mRNA vaccines in personalized cancer therapy and the prevention of broad-spectrum infectious diseases. It also identifies current challenges

including formulation stability (reliance on cold chains)

limited targeting specificity

high production cost

and the regulation of prolonged immune response. Looking ahead

the integration of interdisciplinary innovations—such as artificial intelligence for sequence optimization

development of novel lyophilization techniques

and modular manufacturing—will gradually overcome existing limitations

advancing mRNA vaccine technology toward a more precise

safe

and efficient next-generation platform. This progress will not only play a vital role in human medicine

but also promote the implementation of the “One Health” strategy in veterinary medicine.

关键词

Keywords

references

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