Because　of　the　extraordinary　rarity,　CTC　detection　remains　a　technological　challenge.　In　this　contribution,　a　stimuli-responsive　intelligent　DNA　nanomachine　system　is　demonstrated　for　ultrasensitive　and　specific　CTC　detection　via　a　shell　penetration/free　energy-driven　autonomous　circuit.　The　responsive　toeholds　designed　in　linear　probes　are　shielded　by　protective　DNA　self-assembled　outer　shell　and　hidden　inwards　from　the　attack　of　fuel　strands,　proposing　an　innovative　concept　different　from　conventional　DNA　hairpin-based　catalytic　reactions.　DNA　machines　are　very　stable　in　the　‘OFF’　state,　almost　completely　suppressing　the　background　fluorescence.　A　linear　trigger　can　permeate　through　outer　shell　and　ignite　the　inner　responsive　toeholds,　achieving　an　amplification　fluorescent　signal.　CTC　is　specifically　screened　in　a　linear　response　range　of　three　orders　of　magnitude　with　a　detection　limit　of　2　cells/200　μL　with　almost　100%　accuracy,　indicating　3.450-fold　improvement　in　assay　ability.　©　2023