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

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.