• Ionic liquids (ILs) and deep eutectic solvents (DESs) enhance nucleic acid stability. • ILs and DESs protect nucleic acids by reducing hydrolysis and enzymatic degradation. • Cholinium- and lipid-based ILs and DESs enhance transdermal delivery of nucleic acid therapeutics. • Designed ILs and DESs preserve nucleic acid conformation and prolong storage stability. • ILs and DESs bridge nanotechnology, green chemistry, and gene-based therapeutics. Nucleic acid-based biopharmaceuticals, including small interfering RNA (siRNA), messenger RNA (mRNA) vaccines, and antisense oligonucleotides (ASOs), represent one of the fastest-growing classes of therapeutics due to their ability to modulate gene expression and treat previously incurable diseases. However, their clinical translation remains constrained by intrinsic instability, susceptibility to enzymatic degradation, and complex storage and delivery requirements. Preserving molecular integrity while ensuring efficient and safe delivery, therefore, remains a central challenge in expanding their therapeutic applications. Ionic liquids (ILs) and deep eutectic solvents (DESs) have recently emerged as versatile media for the stabilization and functionalization of nucleic acid biopharmaceuticals. Their tunable ionic environments, extensive hydrogen-bond networks, and physicochemical versatility enable the preservation of DNA and RNA structures while mitigating hydrolysis, oxidation, and nuclease activity. Over the past decade, biocompatible cholinium- and other ammonium-based ILs, as well as cholinium-derived DESs, have been successfully applied to siRNA, ASO, and mRNA formulations, improving long-term stability and enhancing transdermal or intracellular delivery. Innovative strategies such as IL-robed RNA and surface-active ionic liquids (SAILs) were also proposed, integrating molecular protection with intrinsic delivery capacities, while supporting greener and more scalable formulation approaches. Despite these advances, challenges remain, particularly with respect to cytotoxicity and viscosity issues of ILs and DESs, and the absence of clear regulatory frameworks for pharmaceutical use. Overall, IL- and DES-based media are multifunctional platforms capable of overcoming key limitations of nucleic acid therapeutics and advancing the development of disruptive, safer, and more sustainable next-generation biopharmaceutical formulations. This critical perspective reviews recent progress in the application of ILs and DESs to nucleic acid stabilization and delivery, supported by a SWOT analysis and a personal insight into the future of the field.
Veríssimo et al. (Wed,) studied this question.