Persistent Targeting DNA Nanocarrier Made of 3D Structural Unit Assembled from Only One Basic Multi‐Palindromic Oligonucleotide for Precise Gene Cancer Therapy

Abstract Construction of a simple, reconfigurable, and stimuli‐responsive DNA nanocarrier remains a technical challenge. In this contribution, by designing three palindromic fragments, a simplest four‐sticky end‐contained 3D structural unit (PS‐unit) made of two same DNA components is proposed. Via regulating the rotation angle of central longitudinal axis of PS‐unit, the oriented assembly of one‐component spherical architecture is accomplished with high efficiency. Introduction of an aptamer and sticky tail warehouse into one component creates a size‐change‐reversible targeted siRNA delivery nanovehicle. Volume swelling of 20 nm allows one carrier to load 1987 siPLK1s. Once entering cancer cells and responding to glutathione (GSH) stimuli, siPLK1s are almost 100% released and original size of nanovehicle is restored, inhibiting the expression of PLK1 protein and substantially suppressing tumor growth (superior to commercial transfection agents) in tumor‐bearing mice without systemic toxicity.