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Chemically modified DNA has been widely developed to fabricate various nucleic acid nanostructures for biomedical applications. Herein, we report a facile strategy for construction of branched antisense DNA and small interfering RNA (siRNA) co‐assembled nanoplatform for combined gene silencing in vitro and in vivo. In our design, the branched antisense can efficiently capture siRNA with 3′ overhangs through DNA–RNA hybridization. After being equipped with an active targeting group and an endosomal escape peptide by host–guest interaction, the tailored nucleic acid nanostructure functions efficiently as both delivery carrier and therapeutic cargo, which is released by endogenous RNase H digestion. The multifunctional nucleic acid nanosystem elicits an efficient inhibition of tumor growth based on the combined gene silencing of the tumor‐associated gene polo‐like kinase 1 (PLK1). This biocompatible nucleic acid nanoplatform presents a new strategy for the development of gene therapy. [ABSTRACT FROM AUTHOR]

DNA nanostructures have played an important role in the development of novel drug delivery systems. Herein, we report a DNA origami‐based CRISPR/Cas9 gene editing system for efficient gene therapy in vivo. In our design, a PAM‐rich region precisely organized on the surface of DNA origami can easily recruit and load sgRNA/Cas9 complex by PAM‐guided assembly and pre‐designed DNA/RNA hybridization. After loading the sgRNA/Cas9 complex, the DNA origami can be further rolled up by the locking strands with a disulfide bond. With the incorporation of DNA aptamer and influenza hemagglutinin (HA) peptide, the cargo‐loaded DNA origami can realize the targeted delivery and effective endosomal escape. After reduction by GSH, the opened DNA origami can release the sgRNA/Cas9 complex by RNase H cleavage to achieve a pronounced gene editing of a tumor‐associated gene for gene therapy in vivo. This rationally developed DNA origami‐based gene editing system presents a new avenue for the development of gene therapy. [ABSTRACT FROM AUTHOR]