Outward Movement of Targeting Ligands from a Built‐In Reserve Pool in Nuclease‐Resistant 3D Hierarchical DNA Nanocluster for in Vivo High‐Precision Cancer Therapy

Nanostructures made entirely of DNAs display great potential as chemotherapeutic drug carriers but so far cannot achieve sufficient clinic therapy outcomes due to off‐target toxicity. In this contribution, an aptamer‐embedded hierarchical DNA nanocluster (Apt‐eNC) is constructed as an intelligent carrier for cancer‐targeted drug delivery. Specifically, Apt‐eNC is designed to have a built‐in reserve pool in the interior cavity from which aptamers may move outward to function as needed. When surface aptamers are degraded, ones in reserve pool can move outward to offer the compensation, thereby magically preserving tumor‐targeting performance in vivo. Even if withstanding extensive aptamer depletion, Apt‐eNC displays a 115‐fold enhanced cell targeting compared with traditional counterparts and at least 60‐fold improved tumor accumulation. Moreover, one Apt‐eNC accommodates 5670 chemotherapeutic agents. As such, when systemically administrated into HeLa tumor‐bearing BALB/c nude mouse model, drug‐loaded Apt‐eNC significantly inhibits tumor growth without systemic toxicity, holding great promise for high precision therapy.