Mol Pharm. 2023 Sep 4;20(9):4387-4403. doi: 10.1021/acs.molpharmaceut.3c00439. Epub 2023 Aug 10.
Messenger RNA (mRNA)-based therapies have gained significant attention, following the successful deployment of mRNA-based COVID-19 vaccines. Compared with traditional methods of genetic modification, mRNA-based therapies offer several advantages, including a lower risk of genetic mutations, temporary and controlled therapeutic gene expression, and a shorter production time, which facilitates rapid responses to emerging health challenges. Moreover, mRNA-based therapies have shown immense potential in treating a wide range of diseases including cancers, immune diseases, and neurological disorders. However, the current limitations of non-viral vectors for efficient and safe delivery of mRNA therapies, such as low encapsulation efficiency, potential toxicity, and limited stability, necessitate the exploration of novel strategies to overcome these challenges and fully realize the potential of mRNA-based therapeutics. Coacervate-based delivery systems have recently emerged as promising strategies for enhancing mRNA delivery. Coacervates, which are formed by the aggregation of two or more macromolecules, have shown great potential in delivering a wide range of therapeutics due to their ability to form a separated macromolecular-rich fluid phase in an aqueous environment. This phase separation enables the entrapment and protection of therapeutic agents from degradation as well as efficient cellular uptake and controlled release. Additionally, the natural affinity of coacervates for mRNA molecules presents an excellent opportunity for enhancing mRNA delivery to targeted cells and tissues, making coacervate-based delivery systems an attractive option for mRNA-based therapies. This review highlights the limitations of current strategies for mRNA delivery and the advantages of coacervate-based delivery systems to enable mRNA therapeutics. Coacervates protect mRNA from enzymatic degradation and enhance cellular uptake, leading to sustained and controlled gene expression. Despite their promising properties, the specific use of coacervates as mRNA delivery vehicles remains underexplored. This review aims to provide a comprehensive overview of coacervate-mediated delivery of mRNA, exploring the properties and applications of different coacervating agents as well as the challenges and optimization strategies involved in mRNA encapsulation, release, stability, and translation via coacervate-mediated delivery. Through a comprehensive analysis of recent advancements and recommended future directions, our review sheds light on the promising role of coacervate-mediated delivery for RNA therapeutics, highlighting its potential to enable groundbreaking applications in drug delivery and gene therapy.
信使 RNA（mRNA）为基础的疗法引起了极大的关注，继 mRNA 为基础的 COVID-19 疫苗成功部署之后。与传统的基因修饰方法相比，mRNA 为基础的疗法具有几个优势，包括遗传突变风险较低、治疗基因表达的暂时性和可控性，以及较短的生产时间，这有利于对新出现的健康挑战迅速作出反应。此外，mRNA 为基础的疗法在治疗多种疾病方面显示出巨大的潜力，包括癌症、免疫疾病和神经疾病。然而，目前非病毒载体在高效和安全传递 mRNA 疗法方面的局限性，如封装效率低、潜在毒性和有限的稳定性，需要探索新的策略来克服这些挑战，充分发挥 mRNA 为基础的治疗方法的潜力。凝聚物为基础的递药系统最近作为增强 mRNA 递药的有前途的策略出现。凝聚物是由两种或更多的大分子聚集而成的，由于其在水相环境中形成一个分离的大分子丰富的流体相的能力，在递药方面显示出巨大的潜力。这种相分离使治疗剂免受降解、有效细胞摄取和控制释放的保护。此外，凝聚物与 mRNA 分子的天然亲和力为增强靶向细胞和组织的 mRNA 递药提供了极好的机会，使凝聚物为基础的递药系统成为 mRNA 为基础的治疗的一个有吸引力的选择。这篇综述强调了目前的 mRNA 递药策略的局限性和凝聚物为基础的递药系统的优势，以实现 mRNA 治疗。凝聚物保护 mRNA 免受酶降解并增强细胞摄取，从而实现持续和可控的基因表达。尽管它们具有有前途的特性，但凝聚物作为 mRNA 递药载体的具体用途仍未得到充分探索。本综述旨在全面概述凝聚物介导的 mRNA 递药，探讨不同凝聚形成剂的性质和应用，以及在凝聚物介导的递药中涉及的 mRNA 包封、释放、稳定性和翻译的挑战和优化策略。通过对最近进展的全面分析和建议的未来方向，我们的综述揭示了凝聚物介导的递药在 RNA 治疗中的有前途的作用，强调了它在药物递药和基因治疗方面具有开创性应用的潜力。
