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To use a DNA origami structure in vivo, the instability of the DNA structure and the activation of the immune system are obstacles to further application. Therefore, it is necessary to suppress both degradation of the DNA structure against the nuclease and the suppression of immune activation in vivo. Natural biological particles such as viruses have a mechanism to avoid immune recognition during infection by covering the structure with lipids.

Shih and coworker prepared an octahedral frame‐type DNA origami (c. 50 nm in diameter) covered with a lipid bilayer to prevent degradation and circulate in the blood stream of mice (Figure 1.15c) [110]. By coating with a PEG (polyethylene glycol)‐modified lipid bilayer, the DNA origami device showed resistance to degradation by nucleases. Immune activation was significantly reduced compared to uncoated structures. When these structures were injected into mice, the noncoated DNA origami was rapidly excreted (half‐life = 38 minutes), whereas the lipid‐coated DNA origami was retained for much longer (half‐life = 370 minutes). Furthermore, the researchers confirmed that the DNA origami structures were stable in low salt concentrations and in the medium by covering a barrel‐shaped DNA origami structure with cationic polymers (Figure 1.15d) [111]. In particular, it was found that by covering with a PEG‐conjugated cationic polymer, the DNA origami structure can stably exist in the body of a mouse up to 24 hours. In this way, by establishing a method suitable for biological applications, a medically applicable DNA nanodevices have also been developed.