H-bonded organic frameworks as ultrasound-programmable delivery platform

Wenliang Wang, Yanshu Shi, Wenrui Chai, Kai Wing Kevin Tang, Ilya Pyatnitskiy, Yi Xie, Xiangping Liu, Weilong He, Jinmo Jeong, Ju-Chun Hsieh, Anakaren Romero Lozano, Brinkley Artman, Xi Shi, Nicole Hoefer, Binita Shrestha, Noah B. Stern, Wei Zhou, David W. McComb, Tyrone Porter, Graeme Henkelman, Banglin Chen () and Huiliang Wang ()
Additional contact information
Wenliang Wang: The University of Texas at Austin
Yanshu Shi: The University of Texas at San Antonio
Wenrui Chai: The University of Texas at Austin
Kai Wing Kevin Tang: The University of Texas at Austin
Ilya Pyatnitskiy: The University of Texas at Austin
Yi Xie: The University of Texas at San Antonio
Xiangping Liu: The University of Texas at Austin
Weilong He: The University of Texas at Austin
Jinmo Jeong: The University of Texas at Austin
Ju-Chun Hsieh: The University of Texas at Austin
Anakaren Romero Lozano: The University of Texas at Austin
Brinkley Artman: The University of Texas at Austin
Xi Shi: The University of Texas at Austin
Nicole Hoefer: The Ohio State University
Binita Shrestha: The University of Texas at Austin
Noah B. Stern: The University of Texas at Austin
Wei Zhou: National Institute of Standards and Technology
David W. McComb: The Ohio State University
Tyrone Porter: The University of Texas at Austin
Graeme Henkelman: The University of Texas at Austin
Banglin Chen: The University of Texas at San Antonio
Huiliang Wang: The University of Texas at Austin

Nature, 2025, vol. 638, issue 8050, 401-410

Abstract: Abstract The precise control of mechanochemical activation within deep tissues using non-invasive ultrasound holds profound implications for advancing our understanding of fundamental biomedical sciences and revolutionizing disease treatments1–4. However, a theory-guided mechanoresponsive materials system with well-defined ultrasound activation has yet to be explored5,6. Here we present the concept of using porous hydrogen-bonded organic frameworks (HOFs) as toolkits for focused ultrasound (FUS) 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 potentially visualize the mechanochemical scission and ultrasound mechanics, providing valuable guidelines for the rational design of mechanoresponsive materials to achieve programmable control. To demonstrate the practicality of this approach, we encapsulate the designer drug clozapine N-oxide (CNO) into the optimal HOF nanocrystals for FUS-gated release to activate engineered G-protein-coupled receptors in the ventral tegmental area (VTA) of mice and rats and hence achieve targeted neural circuit modulation even at depth 9 mm with a latency of seconds. This work demonstrates the capability of ultrasound to precisely control molecular interactions and develops ultrasound-programmable HOFs to non-invasively and spatiotemporally control cellular events, thereby facilitating the establishment of precise molecular therapeutic possibilities.

Date: 2025
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DOI: 10.1038/s41586-024-08401-0

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