Virus-inspired membrane encapsulation of DNA nanostructures to achieve in vivo stability.
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 nm(2). 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.
Wyss Institute for Biologically Inspired Engineering and ‡Biological Chemistry and Molecular Pharmacology, Harvard Medical School , Boston, Massachusetts 02115, United States .
Steven D
SD
Perrault
William M
WM
Shih
D000818:Animals; D002213:Capsid / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D004797:Enzyme-Linked Immunosorbent Assay; D016679:Genome, Viral; D007107:Immune System; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods*; D049329:Nanostructures / Q000737:chemistry*; D055095:Optics and Photonics; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012235:Rhodamines / Q000737:chemistry; D013154:Spleen / Q000166:cytology; D013501:Surface-Active Agents / Q000737:chemistry; D014780:Viruses / Q000737:chemistry*
D008024:Ligands; D008051:Lipid Bilayers; D008055:Lipids; D008081:Liposomes; D008823:Micelles; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D012235:Rhodamines; D013501:Surface-Active Agents; C067972:dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine; D011092:Polyethylene Glycols; D004247:DNA; D002784:Cholesterol; C017251:1,2-oleoylphosphatidylcholine