The precise control of mechanochemical activation within deep tissues via non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments. However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored. Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound programmably triggered drug activation to control specific cellular events in the deep brain, through on-demand scission of the supramolecular interactions. A theoretical model is developed to visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials at the molecular level to achieve programmable and spatiotemporal activation control. To demonstrate the practicality of this approach, we encapsulate designer drug clozapine N-oxide (CNO) into the optimal HOF nanoparticles for FUS gated release to activate engineered G-protein-coupled receptors in the mice and rat ventral tegmental area (VTA), and hence achieved targeted neural circuits modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interaction and develops ultrasound programmable HOFs to minimally invasive and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities. We anticipate that this research could serve as a source of inspiration for precise and non-invasive molecular manipulation techniques, potentially applicable in programming molecular robots to achieve sophisticated control over cellular events in deep tissues.