Project Summary / Abstract Research in the Robb group is focused on expanding the frontiers of the emergent field of polymer mechanochemistry, where mechanical force is harnessed to selectively activate productive chemical transformations in stress-sensitive molecules known as mechanophores. Our expertise is in the molecular design and development of new mechanophores and reaction strategies, enabling access to stimuli-responsive polymers that address challenges in a variety of areas including stress sensing and mechanically triggered molecular release. Our research advances the fundamental understanding of mechanochemical reactivity through the development of structure–activity relationships and novel molecular design principles, providing a foundation for creating innovative materials. Nevertheless, critical gaps remain that have limited the translation of polymer mechanochemistry to applications in biology and medicine. In this proposal, we outline a multifaceted approach for the development of systems that enable acoustically controlled molecular delivery from mechanochemically active polymers using biocompatible focused ultrasound, specifically targeting biological applications that have thus far remained out of reach. In the five-year period of this MIRA grant, we will build on a powerful mechanophore platform developed in our group for the mechanically triggered release of diverse small molecule payloads that leverages the mechanochemical activation of masked 2-furylcarbinol derivatives. While ultrasonication is routinely used in the laboratory for the mechanochemical activation of polymers, the strong acoustic cavitation of dissolved gases at these acoustic pressures is highly destructive to tissues, making it incompatible for most biological applications. Complementing our development of novel chemistries, we propose to develop unprecedented systems for achieving remote control of mechanochemical reactions using focused ultrasound under physiological conditions with spatial and temporal precision. The unique synergy provided by novel materials design and biocompatible acoustic activation strategies will realize the translational potential of polymer mechanochemistry and establish mechanophores for triggered release as an untapped biomedical tool. Our research will target the delivery of a wide range of payloads useful for theranostics to bioimaging that demonstrate the power of this approach and pave the way toward diverse applications in biology, medicine, and human health.