DNA–drug conjugates enable logic-gated drug delivery amplified by hybridization chain reactions

Abstract Antibody–drug conjugates enable highly specific delivery of potent cytotoxics to biomarker-expressing cells. In parallel, advances in DNA circuitry and DNA–protein conjugates have allowed programmable integration of molecular inputs and signal amplification via hybridization chain reactions (HCRs). Here we present a system using affibody–DNA and aptamer–DNA conjugates to execute a Boolean logic operation on cell-surface biomarkers, resulting in amplified payload delivery using an HCR of DNA–drug conjugates. Proximity-induced assembly of the biomarker binders generates the initiator that triggers an HCR. The resulting assembly undergoes endocytosis, enabling controlled payload release of drugs conjugated to the DNA with cathepsin-cleavable linkers. We show that DNA–drug conjugates achieve targeted delivery with >100-fold amplification relative to the input biomarkers using fluorescence quantifications. We also identify payloads that strongly influence delivery efficiency and demonstrate delivery of different drug combinations. Finally, we show that biomarker-triggered HCRs can recruit generic antibodies. This modular technology enables tailored combinations of biomarker inputs and drug outputs toward more precise and personalized treatment.