A Scale‐up DNA Network‐Driven Autophagy Trap Gated by Cascade Logic Circuits to Program Cancer Cell Death

The autophagy-lysosome system is an intrinsic pathway to degrade intracellular targets, but is limited by the payload size. Those large-scale targets can overload this system, thereby resulting in autophagic cell death. Taking advantage of this feature, here we smartly engineer a scale-up DNA network-driven autophagic overload trap gated by a computing circuit that controls a well-designed DNA nanorobot (GA-AP) to recognize cascade extra/intracellular microenvironments and then execute the downstream tasks in a spatiotemporal sequence. This design allows the in situ construction of scale-up DNA networks inside the targeted cancer cells, overwhelming the autophagy-lysosome system with LC3-II accumulation comparable to that induced by RAPA, but at a ∼30-fold lower effective molar concentration, and thereby selectively killing cancer cells via autophagic overload. This autophagic overload trap thus establishes a conceptually new paradigm for programming cancer cell death with cascade microenvironment-gated DNA nanorobots, providing an in vitro proof-of-concept.