DNA-templated synthesis takes advantage of the programmability of DNA-DNA interactions to accelerate chemical reactions under diluted conditions upon sequence-specific hybridization. While this strategy has proven advantageous for a variety of applications, including sensing and drug discovery, it has been so far limited to the use of nucleic acids as templating elements. Here, we report the rational design of DNA templated synthesis controlled by specific IgG antibodies. Our approach is based on the co-localization of reactants induced by the bivalent binding of a specific IgG antibody to two antigen-conjugated DNA templating strands that triggers a chemical reaction that would be otherwise too slow under diluted conditions. This strategy is versatile, orthogonal and adaptable to different IgG antibodies and can be employed to achieve the targeted synthesis of clinically-relevant molecules in the presence of specific IgG biomarker antibodies.

DNA-templated chemical reactions have found wide applications in drug discovery, programmed multistep synthesis, nucleic acid detection and targeted drug delivery. The control of these reactions has, however, been limited to nucleic acid hybridization as a means to direct the proximity between reactants.In this work we introduce a system capable of translating protein-protein binding events into a DNAtemplated reaction which leads to the covalent formation of a product. We achieve protein-templated reactions by employing two DNA-antibody conjugates that are both able to recognize the same target protein and to colocalize a pair of reactant DNA strands able to undergo a click reaction. We engineered two individual systems each responsive to human serum albumin (HSA) and human IgG and we demonstrated that, while no reaction occurs in the absence of proteins, both protein-templated reactions can occur simultaneously in the same solution without any inter-system crosstalk.

Nucleic acid-based biosensors for the detection of specific proteins combine the typical programmability of synthetic DNA systems with artificially controlled DNA-protein communication. The high-affinity interaction between a target protein and a specific ligand, such as an aptamer sequence, or a double stranded DNA domain, or a small peptide, is paired with a nature-mimicking molecular mechanism allowing for probing, processing, and translating protein binding activity into a measurable signal. In this Review, two main strategies developed in the context of protein-responsive nucleic acid-based biosensors are discussed. One is the design of proximity-based assays harnessing the spatial colocalization of functional probes within the volume of a multivalent protein. The other is the engineering of dynamic DNA structures that undergo a controlled conformational or structural change upon protein binding. Examples of applications from optical and electrochemical detection of antibodies in biofluids to fluorescence imaging of transcription factors in living cells are reported, and suggestions along with possible future directions in the field are discussed.