Towards mRNA therapeutics 2.0

Key Points:

• mRNA vaccines and therapeutics have rapidly advanced, offering transformative potential beyond COVID-19, including treatments for infectious diseases, cancer, and genetic disorders, supported by innovations in RNA design, delivery, and immunogenicity control (Baden et al. 2021; Hogan & Pardi 2022; Parhiz et al. 2024).
• Lipid nanoparticles (LNPs) remain the leading delivery platform for mRNA therapeutics, with ongoing improvements in targeting specificity, safety, and immune response modulation, including organ-specific delivery and reduced immunogenicity through chemical and structural optimization of lipids and mRNA components (Cullis & Hope 2017; Hou et al. 2021, 2024; Chaudhary et al. 2024).
• Advances in mRNA sequence engineering, such as optimized 5′ and 3′ untranslated regions (UTRs), codon usage, nucleoside modifications (e.g., N1-methylpseudouridine), and poly(A) tail design, significantly enhance mRNA stability, translational efficiency, and reduce innate immune activation, enabling more effective and durable protein expression (Karikó et al. 2008, 2021; Zhang et al. 2023; Ma et al. 2025).
• Self-amplifying RNA (saRNA) vaccines and therapeutics represent a promising next-generation technology, achieving potent immune responses or protein expression at lower doses by encoding replicase machinery, with ongoing clinical evaluation for infectious diseases and protein replacement therapies (McKay et al. 2020; Casmil et al. 2025).
• mRNA-based gene editing and cell therapies, including in vivo delivery of CRISPR components and mRNA-encoded chimeric antigen receptor (CAR) T cells, are emerging as transformative approaches for treating genetic diseases, cancer, and autoimmune disorders, supported by targeted LNP systems and advances in precision editing technologies (Gillmore et al. 2021; Breda et al. 2023; Hunter et al. 2025).