Transmembrane　signal　transduction　is　of　profound　significance　in　many　biological　processes.　The　dimerization　of　cell-surface　receptors　is　one　prominent　mechanism　by　which　signals　are　transmitted　across　the　membrane　and　trigger　intracellular　cascade　amplification　reactions.　Recreating　such　processes　in　artificial　systems　has　potential　applications　in　sensing,　drug　delivery,　bioengineering,　and　providing　a　new　route　for　a　deep　understanding　of　fundamental　biological　processes.　However,　it　remains　a　challenge　to　design　artificial　signal　transduction　systems　working　by　the　receptor　dimerization　mechanism　in　a　predictable　and　smart　manner.　Here,　benefitting　from　DNA　with　features　of　programmability,　controllability,　and　flexible　design,　we　use　DNA　as　a　building　material　to　construct　an　artificial　system　mimicking　dimerization　of　receptors　for　signal　transduction　and　cascade　amplification.　DNA-based　membrane-spanning　receptor　analogues　are　designed　to　recognize　external　signals,　which　drives　two　receptors　into　close　spatial　proximity　to　activate　DNAzymes　inside　the　cell-mimicking　system.　The　activation　of　the　DNAzyme　initiates　the　catalyzed　cleavage　of　encapsulated　substrates　and　leads　to　the　release　of　fluorescent　second　messengers　for　signal　amplification.　Such　an　artificial　signal　transduction　system　extends　the　range　of　biomimetic　DNA-based　signaling　systems,　providing　a　new　avenue　to　study　natural　cell　signaling　processes　and　artificially　regulate　biological　processes.　©　2021　American　Chemical　Society.