Logic‐Gated DNA Intelligent Nanorobots for Cellular Lysosome Interference and Enhanced Therapeutics

Abstract Environment‐recognizing DNA nanodevices have proven promising for cellular manipulation and disease treatment, whereas how to sequentially respond to different cellular microenvironments remains a challenge. To this end, here we elaborate a logic‐gated intelligent DNA nanorobot (Gi‐DR) for the cascade response to inter‐ and intra‐cellular microenvironments, thereby achieving lysosome‐targeted cargo delivery for subcellular interference and tumor treatment with enhanced efficacy. Utilizing G‐quadruplexes to respond to high‐level K + in cancer cell surrounding, this Gi‐DR nanorobot can activate an aptamer‐based transmembrane DNA machine that delivers molecular payloads to cellular lysosome. Accordingly, the nanoassembly of Gi‐DR is promoted by the folding of heterodimeric i‐motifs in the acidic microenvironment. Such a design allows the extra‐/intra‐cellular behaviors of the Gi‐DR nanorobot to be programmed by an YES‐AND logic circuit, with environmental K + and H + as two inputs. As a consequence, DNA nanostrips are controllably formed in living cells, interfering with lysosomal function and thereby preventing cellular proliferation. Further, a therapeutic agent (i.e. ligand‐drug conjugate) is delivered into target cancer cells for synergistic tumor treatment in vivo, exhibiting the super‐enhanced cancer cell lethality and anti‐tumor efficacy. It well illustrates that our designed logic‐gated DNA nanorobot has broad application prospects in modulating cellular function and precision disease treatment.