DNA-Drug Conjugates (DDCs) for computed delivery

Antibody-drug conjugates (ADCs) offer the potential to deliver potent cytotoxics with unprecedented specificity with respect to a given biomarker. In parallel, development in DNA circuitry and DNA-protein conjugates provide opportunities to design systems that integrate inputs and compute outputs with the potential of amplified responses through hybridization chain reactions (HCRs). Herein, we report a system based on affinity miniproteins (affibodies)-DNA conjugates and aptamer-DNA conjugates to target specific cells via biomarker recognition, yielding a logic-gated response. We demonstrate that this system can be used to trigger HCRs conditionally either on the presence of two biomarkers or based on the density of a single biomarker. Additionally, we show that receptor-mediated uptake of the HCR-generated assemblies can be used to release a combination of payloads. This mechanism successfully achieves the targeted delivery of payloads through a cleavable linker in DNA-Drug conjugates (DDCs), in analogy to ADCs with an added amplification reaching above 100-fold. Crucially, we find that the nature of the drug in DDC is critical for the efficiency of this delivery and that a combination of drugs can be administered simultaneously. Finally, we show that biomarker-triggered HCRs can also be used to recruit generic antibodies.