Extracellularly Activated Logic‐Gated DNA Nanodevice for Molecular Transport via Reprogrammed Transferrin Receptor Trafficking

Abstract Overexpressed transferrin receptor (TfR) on cancer cell membranes mediates the endocytosis of iron‐loaded transferrin, which is subsequently recycled to the plasma membrane through endosomal pathways to meet the elevated iron demand. Here, an extracellularly activated “AND” logic‐gated DNA nanodevice is presented, that hijacks and reprograms TfR trafficking to disrupt iron metabolism of cancer cells and enable molecular transport. This nanoplatform undergoes dynamic assembly in response to mildly acidic pH and specific extracellular molecular cues in the cancer microenvironment. Guided by aptamer recognition, it captures TfRs and redirects them toward lysosomal degradation via tetrahedral framework nucleic acid (tFNA)‐mediated targeting, rather than membrane recycling, thereby impairing iron homeostasis and suppressing cancer cell migration. Meanwhile, the incorporated photosensitizer chlorin e6 (Ce6) is efficiently transported into cells, where it induces cytoplasmic perturbations and triggers self‐destruction, achieving dual inhibition of cancer cell growth and motility. This nanodevice demonstrates intelligent cell‐level recognition and holds broad potential for extracellular molecular computation and precision nanomedicine.