Programmable DNA Dendrimer from a Single Symmetric Y‐Shaped Structural Unit for Targeted Tumor Therapy with One Hundred Inhibition Efficiency

Abstract Due to fascinating properties, such as structural stability, excellent biocompatibility, and desirable drug delivery efficiency, DNA dendrimer nanostructures are attracting growing scientific interest in biomedical diagnosis and therapy. However, they are lagging behind in clinical development because of complicated design, complicated assembly process, inconvenience of modification with targeting ligands, and limited drug loading capability. In this study, via introducing three identical palindromic fragments, a rotationally‐symmetric Y‐shaped structural unit (SYSU) is designed for constructing the simplest programmable DNA dendrimer (PDD) and nondeformable DNA hydrogel by one‐pot self‐assembly. The assembly efficiency is almost up to 100%. After the surface is functionalized with aptamers with the help of two leg‐shaped retaining screws, PDD is developed into a highly‐precise drug delivery carrier. The two‐point‐fixed aptamers display a rigidified structure so that they can resist the attack of endogenous nucleases and possess a persistent cell‐targeting ability in living organisms. PDD‐aptamer is almost not degraded upon 24 h incubation in a complex biological environment and holds up to 1500 times higher cargo holding capability (76 700 Dox per particle). After intravenous administration into tumor‐bearing mice, Dox‐PDD‐sgc8 can cause largely negative growth in tumor volume without any notable systemic toxicity, manifesting the enormous potential for precision cancer therapy.