Fundamental Research · 3 authors, 3 centres
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This review summarizes the current state and future directions of mRNA therapeutics, covering prophylactic vaccines, cancer vaccines, and protein-replacement therapies. It highlights key challenges such as stability, immunogenicity, and targeted delivery, and discusses emerging solutions including circular RNA and self-amplifying RNA. The clinical significance lies in the potential of mRNA technology to provide rapid, versatile, and cost-effective treatments beyond COVID-19 vaccines.
**Background:** The concept of mRNA therapy has been conceived for decades but only realized during the COVID-19 pandemic with the emergency use authorizations of BNT162b2 and mRNA-1273. mRNA therapeutics offer advantages over protein and DNA therapies, including rapid development, low-cost production, and no risk of insertional mutagenesis. However, challenges remain in stability, immune modulation, and targeted delivery. This review provides an overview of mRNA-based therapeutics, focusing on innovative designs and future solutions, including circular mRNA and self-amplifying RNAs.
**Methods:** This is a narrative review that synthesizes published literature, clinical trial data, and technological developments in mRNA therapeutics. The authors categorize mRNA applications into prophylactic vaccines, therapeutic cancer vaccines, and protein-replacement therapies. They discuss common challenges such as stability, immunogenicity, and delivery, and review solutions including sequence optimization, nucleotide modification, LNP delivery systems, and the development of circular RNA (circRNA) and self-amplifying RNA (saRNA).
**Key Results:** The review reports that two 25-µg doses of mRNA-1273 vaccine elicited immune responses comparable to natural SARS-CoV-2 infection over 7 months. For Zika virus, mRNA-1893 was chosen over mRNA-1325 due to 20-fold higher potency in primate studies. In protein-replacement therapy, Cas9 mRNA/sgRNA formulated with BAMEA-O16B decreased proprotein convertase subtilisin/kexin type 9 levels in mouse serum to 20% of nontreatment. Circular RNA demonstrates higher cellular stability and lower immunogenicity than linear mRNA when purified to eliminate dsRNA and uncapped precursor RNA. The review notes that stringent liquid chromatography purification can improve translation of linear nucleoside-modified mRNA by almost 1000-fold. LNP-formulated mRNAs tend to accumulate in the liver due to ApoE binding, but organ targeting can be modified by adjusting lipid compositions, such as adding SORT lipids. The CureVac rabies vaccine candidate CV7201 induced functional antibodies only when administered by needle-free devices, not by needle-syringe.
**Clinical Implications:** mRNA technology has proven effective for prophylactic vaccines against infectious diseases, with potential for rapid response to emerging pathogens. Therapeutic cancer vaccines face challenges in antigen selection and overcoming the suppressive tumor microenvironment, often requiring combination with immune checkpoint inhibitors. Protein-replacement therapies require high and long-term expression, which may be addressed by saRNA or circRNA platforms. The development of targeted delivery systems, such as modified LNPs and cell-penetrating peptides, is crucial for tissue-specific applications. Bioinformatics and AI are increasingly used to optimize UTRs, ORFs, and epitope prediction. The review concludes that continued innovation in RNA platform technology and delivery methods will expand mRNA therapy into new frontiers, including in vivo cell programming and long non-coding RNA therapy.