Nucleic acids are considered as one of the most potent therapeutic modalities, as their roles go beyond storing genetic information and chemical energy or as signal transducers. Attenuation or expression of desired genes through nucleic acids have profound implications in gene therapy, gene editing, and even in vaccine development. Although nucleic acid therapeutics bring in overwhelming possibilities toward the development of molecular medicines, there are significant loopholes in their effective clinical translation. One of the major pitfalls lies in the traditional design concepts of nucleic acid drug carriers, namely, cationic charge induced cytotoxicity. Targeting this bottleneck, several innovative carrier designs have been proposed accommodating charge‐conversion approaches, whereby built‐in functionalities convert from cationic to neutral or anionic, or even from anionic to cationic enabling the carrier to overcome several critical barriers for therapeutics delivery, such as serum deactivation, instability in circulation, low transfection, and poor endosomal escape. This review will critically analyze various molecular designs of charge‐converting nanocarriers in a classified approach for the successful delivery of nucleic acids. Accompanied by the narrative on recent clinical nucleic acid candidates, the review concludes with a discussion on the pitfalls and scope of these emerging approaches.

Self-assembled nanostructures that are sensitive to environmental stimuli are promising nanomaterials for drug delivery. In this class, disulfide-containing redox-sensitive strategies have gained enormous attention because of their wide applicability and simplicity of nanoparticle design. In the context of nucleic acid delivery, numerous disulfide-based materials have been designed by relying on covalent or noncovalent interactions. In this review, we highlight major advances in the design of disulfide-containing materials for nucleic acid encapsulation, including covalent nucleic acid conjugates, viral vectors or virus-like particles, dendrimers, peptides, polymers, lipids, hydrogels, inorganic nanoparticles, and nucleic acid nanostructures. Our discussion will focus on the context of the design of materials and their impact on addressing the current shortcomings in the intracellular delivery of nucleic acids.

Recent success of mRNA-based COVID-19 vaccines have bolstered the strength of nucleic acids as a therapeutic platform. The number of new clinical trial candidates is skyrocketing with the potential to address many unmet clinical needs. Despite advancements in other aspects, the systemic delivery of nucleic acids to target sites remains a major challenge. Thus, nucleic acid based therapy has yet to reach its full potential. In this review, we shed light on a select few prospective technologies that exhibit substantial potential over traditional nanocarrier designs for nucleic acid delivery. We critically analyze these systems with specific attention to the possibilities for clinical translation.