Complex Coacervates as a Promising Vehicle for mRNA Delivery: A Comprehensive Review of Recent Advances and Challenges

Messenger RNA (mRNA)-based therapies have gained significantattention,following the successful deployment of mRNA-based COVID-19 vaccines.Compared with traditional methods of genetic modification, mRNA-basedtherapies offer several advantages, including a lower risk of geneticmutations, temporary and controlled therapeutic gene expression, anda shorter production time, which facilitates rapid responses to emerginghealth challenges. Moreover, mRNA-based therapies have shown immensepotential in treating a wide range of diseases including cancers,immune diseases, and neurological disorders. However, the currentlimitations of non-viral vectors for efficient and safe delivery ofmRNA therapies, such as low encapsulation efficiency, potential toxicity,and limited stability, necessitate the exploration of novel strategiesto overcome these challenges and fully realize the potential of mRNA-basedtherapeutics. Coacervate-based delivery systems have recently emergedas 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 therapeuticsdue to their ability to form a separated macromolecular-rich fluidphase in an aqueous environment. This phase separation enables theentrapment and protection of therapeutic agents from degradation aswell as efficient cellular uptake and controlled release. Additionally,the natural affinity of coacervates for mRNA molecules presents anexcellent opportunity for enhancing mRNA delivery to targeted cellsand tissues, making coacervate-based delivery systems an attractiveoption for mRNA-based therapies. This review highlights the limitationsof current strategies for mRNA delivery and the advantages of coacervate-baseddelivery systems to enable mRNA therapeutics. Coacervates protectmRNA from enzymatic degradation and enhance cellular uptake, leadingto sustained and controlled gene expression. Despite their promisingproperties, the specific use of coacervates as mRNA delivery vehiclesremains underexplored. This review aims to provide a comprehensiveoverview of coacervate-mediated delivery of mRNA, exploring the propertiesand applications of different coacervating agents as well as the challengesand optimization strategies involved in mRNA encapsulation, release,stability, and translation via coacervate-mediated delivery. Througha comprehensive analysis of recent advancements and recommended futuredirections, our review sheds light on the promising role of coacervate-mediateddelivery for RNA therapeutics, highlighting its potential to enablegroundbreaking applications in drug delivery and gene therapy.

Automated summary

Messenger RNA (mRNA)-based therapies have gained significant attention due to their advantages over traditional genetic modification methods. Coacervate-based delivery systems have emerged as promising strategies for enhancing mRNA delivery, as they protect mRNA from degradation and improve cellular uptake. However, the specific use of coacervates as mRNA delivery vehicles remains underexplored, and further research is needed to optimize their encapsulation, release, stability, and translation.