Delivery of mRNA Therapeutics Beyond Infectious Diseases: Design Innovations and Applications in Oncology, Cardiovascular, and Rare Genetic Diseases.

Empowered by nanotechnology, messenger RNA (mRNA) therapeutics have shown a rapid evolution post COVID-19 from a conceptual platform to a clinically validated modality, and they diversified into oncology, cardiovascular diseases, and rare disorders. As a template for in situ protein production, it offers several advantages over traditional proteins and DNA drugs. The intrinsic stability of mRNA and its sensitivity to innate immune sensing hinder its capacity for immediate cellular entry, necessitating its need for a delivery system to obtain optimal therapeutic potential. This review explores the innovations in nanocarrier engineering, design principles for lipid nanoparticles-mRNA (LNPs) platforms, and their clinical translation across the prominent indications. It also addresses their safety, immunogenicity, and scalability while addressing the key limitations and manufacturing scalability through comparative platform analysis. Although LNPs usually dominate their delivery through encapsulation and manufacturability, their limitations, like repeat dose reactogenicity and liver tropism, require next-generation designs like SORT lipids, stimuli-responsive hybrids for extrahepatic targeting. In oncology, LNP-mRNA drives the neoantigen vaccines, and rare diseases leverage the transient enzyme replacement. While the safety profiles highlight the innate immune tuning through nucleoside mods and lipid biodegradability, chronic administration risks are still persistent. While there are novel scalability options like microfluidic mixing to support the production gaps in organ selectivity and durability, their adoption is hindered. We outline the future directions to perceive mRNA's full potential as a broader therapeutic class.