ConspectusTherapeutic nucleic acids have shown enormous potential to treat a vast number of diseases, ranging from cancers to inflammatory diseases. siRNA formulated within lipid nanoparticles (LNPs) achieved FDA approval for a rare liver disorder in 2018, followed shortly after by successful application of mRNA formulated in LNPs in 2020 to stave off a worldwide pandemic. Thus, in only a few short years, interest in nucleic acid drugs has skyrocketed, both within the academic world and the pharmaceutical industry. Despite the excitement surrounding these genetically encodable medicines, there remains much work to do to enable them to be as far reaching of a drug class as they have the potential to be. The major roadblock limiting their clinical potential is the inability of formulations to efficiently deliver nucleic acid cargo to the cytosol of cells, largely due to endosomal entrapment. Additionally, there are challenges associated with the ability of formulations to target nucleic acids to specific cells and subcellular locations. Here, we describe how our lab has been working to address many of these challenges using a new chemical formulation that is distinctly different from traditional liposomes and LNPs, built from the bottom up to specifically enable endosomal escape of its nucleic acid cargo. We took direct inspiration from viruses with the goal of imitating their dynamic design that changes in response to binding and internalization into cells, enabling them to release their genetic cargo into the cytosol by locally disrupting membranes all while maintaining the cells overall integrity.Herein, we will detail the design considerations and applications of our formulation, which we refer to as a ucleic cid anocapsule (), a versatile, programmable DNA nanomaterial that can be broken down by enzymes to release NA urfactant onjugates () with lipid membrane disrupting capabilities. We will describe how viral structure, cellular entry, and genome release mechanisms are being used in our lab as roadmaps for designing next generation nanocarriers and how such bioinspired synthetic approaches have led to our advancements in the areas of therapeutic efficacy and cytosolic delivery of nucleic acids. We will explain how our nanoscale NANs can be functionalized with therapeutically active RNA, catalytically functional DNA, and cell targeting aptamers by straightforward enzymatic ligation procedures. We will then discuss how structural tuning of the nanocapsule's chemical building blocks results in changes to its uptake mechanism and endosomal escape efficiency and how this modularity has enabled us to enhance oligonucleotide delivery. We will also describe details regarding how oligonucleotide cargo can be stabilized by our nanocarrier and the importance of the particle design as it relates to membrane disruption capabilities necessary for cytosolic delivery. Lastly, we will discuss the vast therapeutic potential of NANs based on the bioactivity of delivered nucleic acids in terms of gene silencing, protein expression, and subcellular targeting, highlighting both and studies. We will end with a vision for what still remains in order to achieve the ideal nonviral nucleic acid carrier formulation that could accelerate nucleic acids to clinical application.