Virus-Inspired Membrane Encapsulation of DNA Nanostructures To Achieve <i>In Vivo</i> Stability

TLDR

DNA nanotechnology offers precise molecular‑scale design, yet instability and immune activation limit in vivo use, while viruses protect their genomes with lipid envelopes. The study introduces virus‑inspired enveloped DNA nanostructures as a design strategy for biomedical applications. The authors encapsulate DNA nanostructures in PEGylated lipid bilayers, precisely controlling lipid conjugate density to produce tightly wrapped unilamellar particles. The resulting PEGylated, unilamellar DNA nanostructures exhibit high yield, nuclease resistance, 100‑fold reduced immune activation, 17‑fold improved pharmacokinetics, and provide a platform for translation‑ready DNA nanodevices.

Abstract

DNA nanotechnology enables engineering of molecular-scale devices with exquisite control over geometry and site-specific functionalization. This capability promises compelling advantages in advancing nanomedicine; nevertheless, instability in biological environments and innate immune activation remain as obstacles for in vivo application. Natural particle systems (i.e., viruses) have evolved mechanisms to maintain structural integrity and avoid immune recognition during infection, including encapsulation of their genome and protein capsid shell in a lipid envelope. Here we introduce virus-inspired enveloped DNA nanostructures as a design strategy for biomedical applications. Achieving a high yield of tightly wrapped unilamellar nanostructures, mimicking the morphology of enveloped virus particles, required precise control over the density of attached lipid conjugates and was achieved at 1 per ∼180 nm2. Envelopment of DNA nanostructures in PEGylated lipid bilayers conferred protection against nuclease digestion. Immune activation was decreased 2 orders of magnitude below controls, and pharmacokinetic bioavailability improved by a factor of 17. By establishing a design strategy suitable for biomedical applications, we have provided a platform for the engineering of sophisticated, translation-ready DNA nanodevices.