In vivo polymer mechanochemistry with polynucleotides

Polymer mechanochemistry utilizes mechanical force to activate latent functionalities in macromolecules and widely relies on ultrasonication techniques. Although ultrasound is a clinically established modality, fundamental constraints of frequency and power intensity have prohibited the application of the polymer mechanochemistry principles in a biomedical context up to now. Here, a universal polynucleotide framework is presented that allows the binding and release of therapeutic oligonucleotides, both DNA- and RNA-based, as cargo by biocompatible imaging ultrasound. It is shown that the high molar mass, colloidal assembly, and a distinct mechanochemical mechanism enable the force-induced release of cargo and subsequent activation of biological function in vitro and in vivo. Thereby, an avenue for the exploration of biological questions and therapeutics development steered by mechanical force is uncovered.