Therapeutic nucleic acids represent a powerful class of drug molecules to control gene expression and protein synthesis. A major challenge in this field is that soluble oligonucleotides have limited serum stability, and the majority of nucleic acids that enter the cells are trapped within endosomes. Delivery efficiency can be improved using lipid scaffolds. One such example is the nanodisc (ND), a self-assembled nanostructure composed of phospholipids and peptides and modeled after high density lipoproteins (HDLs). Herein, we describe the development of the nanodiscoidal nucleic acid (NNA) which is a ND covalently modified with nucleic acids on the top and bottom lipid faces as well as the lateral peptide belt. The 13 nm ND was doped with thiolated phospholipids and thiol-containing peptides and coupled in a one-pot reaction with oligonucleotides to achieve ∼30 DNA/NNA nucleic acid density. NNAs showed superior nuclease resistance and enhanced cellular uptake that was mediated through the scavenger receptor B1. Time-dependent Förster resonance energy transfer (FRET) analysis of internalized NNA confirmed that NNAs display increased stability. NNAs modified with clinically validated antisense oligonucleotides (ASOs) that target hypoxia inducible factor 1-α (HIF-1-α) mRNA showed enhanced activity compared with that of the soluble DNA across multiple cell lines as well as a 3D cancer spheroid model. Lastly, in vivo experiments show that ASO-modified NNAs are primarily localized into livers and kidneys, and NNAs were potent in downregulating HIF-1-α using 5-fold lower doses than previously reported. Collectively, our results highlight the therapeutic potential for NNAs.