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 treatments1,2,3,4. 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.
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Data availability
The code used to analyse the data in this study is available from the GitHub repository for this article (https://github.com/kevintang725/ultrasound-programmable-hydrogen-bonded-organic-frameworks-for-sono-chemogenetics). Crystallographic data for the structures in this article have been deposited at the Cambridge Crystallographic Data Centre under deposition no. CCDC 2338302 (HOF-TATB). Copies of the data can be obtained free of charge from https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available in the article and its Supplementary information and Supplementary Data. Source data are provided with this paper.
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Acknowledgements
TEM image acquisition was performed with the help of M. Mikesh at the Center for Biomedical Research Support Microscopy and Imaging Facility at UT Austin (RRID# SCR_021756). H.W. acknowledges funding support from the National Science Foundation (NSF) CAREER award (2340964), NIH Maximizing Investigators’ Research Award (National Institute of General Medical Sciences 1R35GM147408), the University of Texas at Austin Startup Fund, Robert A. Welch Foundation Grant (no. F-2084-20210327) and Craig H. Neilsen Foundation Pilot Research Grant. We acknowledge BioRender.com for the figures drawing.
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W.W. and H.W. designed the project. W.W. led the materials characterization, cell tests, animal tests and their analysis. Y.S., Y.X. and B.C. designed, synthesized and characterized the HOF materials. N.H., W.Z. and D.W.M. performed the electron diffraction tests and crystal analysis. W.H. helped with high-performance liquid chromatography tests. W.C. and G.H. conducted molecular simulation computing and discussed the data. K.W.K.T., I.P., X.L. and X.S. helped W.W. to build animal models and animal behaviour tests. J.J., J.-C.H., A.R.L. and B.A. helped with animal behaviour data analysis and immunohistology tests. B.S., N.B.S. and T.P. conducted the blood–brain barrier opening tests. All of the co-authors contributed to the writing of the manuscript. B.C. and H.W. supervised the project.
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H.W., W.W., Y.S. and B.C. declare that a patent application (PCT/US2024/042314) relating to this work has been filed. The other authors declare no competing interests.
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Extended data figures and tables
Extended Data Fig. 1 Morphology, size and crystal structure of all four different HOF nanocrystals that were characterized.
a–d, TEM images and hydrodynamic size distribution measured by DLS of HOF-TATB nanocrystals (a), HOF-BTB nanocrystals (b), HOF-101 nanocrystals (c) and HOF-102 nanocrystals (d). e–h, The X-ray diffraction tests of HOF nanocrystals: HOF-TATB (e), HOF-BTB (f), HOF-101 (g), HOF-102 (h). n = 3 independent experiments for each sample.
Extended Data Fig. 2 Topology analysis of HOF-TATB.
a, Structures of two different hydrogen-bonding motifs and their simplified forms. b, 3D structure of the interpenetrated network in HOF-TATB and its simplified 3,4-connected topology viewed from the c axis. c, Perspective view of a simplified single net. d,e, Calculated pore surface of 1D pore channel of HOF-TATB: view along a axis (d); view along b axis (e). (Connolly surface with pore radius of 1.2 Å). f–h, Crystal structure scheme of HOF-TATB: view along a axis (f); view along b axis (g); view along c axis (h).
Extended Data Fig. 3 Porosity characterization of the four different nanocrystals.
a, Single-component sorption isotherms of nitrogen at 77 K of HOF-TATB, indicating the framework flexibility. b, Single-component sorption isotherms of CO2 at 195 K of HOF-BTB (no nitrogen adsorption is observed at 77 K), indicating framework flexibility. c, Single-component sorption isotherms of nitrogen at 77 K of HOF-101. d, Single-component sorption isotherms of nitrogen at 77 K of HOF-102. n = 3 independent experiments for each sample.
Extended Data Fig. 4 Thermal dissociation tests of HOF nanocrystals.
a, HOF-TATB, b, HOF-BTB, c, HOF-101, d, HOF-102. The HOF nanocrystals were incubated at different temperatures for 5 min. After that, the HOFs solution was extracted and centrifuged and the supernatant was used to perform UV-Vis tests for HOFs dissociation determination. The thermal dissociation occurred around 60 °C. Only around a 2% increase was observed at HOF-TATB and HOF-BTB and no thermal dissociation was observed in HOF-101 and HOF-102, at temperature 100 °C. Mean ± s.e.m., n = 3 independent experiments for each sample.
Extended Data Fig. 5 Theoretical modelling of mechanochemical scission in HOFs.
a, A linear model fits the relationship between the ultrasound peak pressure and the ln(k) of HOFs when the peak pressure is less than 1.55 MPa; n = 3 independent experiments for each sample. b, A linear model fits the relationship between the ultrasound peak pressure and the ln(k) of HOFs when the peak pressure is up to 1.55 MPa. n = 3 independent experiments for each sample. c, A linear model qualitatively fits the relationship between the Ecohesive of HOFs and the ln(k) at fixed EUS. With 1.72, 3.94, 6.49 and 8.04 MPa peak pressure, ln(k) of HOF-TATB, HOF-BTB, HOF-101 and HOF-102 correlate to their cohesion energy linearly, respectively. n = 3 independent experiments for each sample. d, When ln(k) is held constant, a linear correlation is observed between the ultrasound peak pressure and the cohesive energy of HOFs. To achieve a targeted 10%, 20%, 30%, 40%, 50% and 60% dissociation of HOFs at a fixed ultrasound peak pressure, it is possible to calculate the corresponding Ecohesive of HOFs using the established linear relationship.
Extended Data Fig. 6 Ultrasound-triggered drug release from different HOF nanocrystals.
a, HOF-TATB. b, HOF-BTB. c, HOF-101. d, HOF-102. The fluorescence dye RB was first loaded into the HOF nanocrystals. After that, the ultrasound irradiated the RB-loaded nanocrystals with different power densities. At fixed time points, the solution was taken out and centrifuged. The released RB concentration was determined through UV-Vis from the supernatant. Mean ± s.e.m., n = 3 independent experiments for each sample. e–h, Ultrasound-triggered drug release from HOF-TATB. The fluorescence dye RB was first loaded into the HOF-TATB nanocrystals (TATB@RB). After that, the TATB@RB nanocrystals were irradiated by the ultrasound with different power densities, including 0.51 MPa (e), 0.89 MPa (f) and 1.08 MPa (g), and the quantification of drug release percentage without ultrasound and with ultrasound for 90 s (h). Mean ± s.e.m., n ≥ 3 independent samples. One-way ANOVA and Dunnett’s multiple comparison tests (P ≥ 0.05 (ns), *0.01 ≤ P < 0.05, **0.001 ≤ P < 0.01, ****P < 0.0001). Mean ± s.e.m., n = 3 independent experiments for each sample.
Extended Data Fig. 7 Ultrasound-triggered release of various drugs.
a, Deschloroclozapine. b, Dopamine. c, Procaine. d, CNO from HOF-TATB at 1.5 MHz, 1.55 MPa (mean ± s.e.m., n = 3 independent samples).
Extended Data Fig. 8 Biosafety and biocompatibility evaluation of UltraHOF.
a, The cell viability tests of HOF-TATB nanocrystals in human embryonic kidney 293 (HEK-293T) cells. Mean ± s.e.m.; at least three independent tests (n = 5). The hemolysis tests of HOF-TATB nanocrystals: photograph (b) and hemolysis statistical analysis (c); mean ± s.e.m.; at least three independent tests (n ≥ 3). d, In vivo biosafety evaluation by haematoxylin and eosin staining after sono-chemogenetics. Scale bar, 100 μm. n = 3 independent experiments for each sample. e, In vivo biocompatibility evaluation of the sono-chemogenetics by means of determining microglia (Iba1) activation. Statistical analysis of the Iba1 intensity. Mean ± s.e.m., n ≥ 3 mice in each group. Two-way ANOVA and Tukey’s multiple comparison tests. f, In vivo biocompatibility evaluation of the sono-chemogenetics by means of determining neuron apoptosis (caspase-3). Statistical analysis of the caspase-3 intensity. Mean ± s.e.m., n ≥ 3 mice in each group. Two-way ANOVA and Tukey’s multiple comparison tests. g, In vivo biocompatibility evaluation of the sono-chemogenetics by determining astrocytes (GFAP) activation. Mean ± s.e.m., n ≥ 3 mice in each group. Two-way ANOVA and Tukey’s multiple comparison tests. Statistical significance: P ≥ 0.05 (ns).
Extended Data Fig. 9 Ultrasound power delivery in the tissue and biosafety evaluation.
a, To measure ultrasound power transfer efficiency through tissue, pork skin of varying depths was placed on a 1.5-MHz, 2.40-MPa FUS transducer. The results showed that 1.5-MHz ultrasound could penetrate up to 20 mm, with a power transfer efficiency of 37% at 10 mm depth; mean ± s.e.m.; n = 3. b, The in vivo ultrasound power transfer in the mouse head with FUS focus length of 5 mm. The ultrasound peak pressure heat map in the mouse head shows that around 0.90 MPa was delivered to the mouse VTA when 1.40 MPa primary ultrasound peak pressure was used. c, Ultrasound-induced blood-brain barrier opening evaluation through Evans blue staining. (i) Brains from mice injected with microbubbles and given 20 s ultrasound at 1.0 MPa (left) and 0.75 MPa (right). (ii) Brains from mice without microbubbles given 20 s ultrasound at 1.0 MPa. (iii) Brains from mice without microbubbles given 20 s ultrasound at 1.5 MPa. Red circles show ultrasound-treated areas. d, The evaluation of ultrasound-induced thermal effects at the focus. Real-time temperature detection was conducted at the mice VTA during FUS stimulation (1.5 MHz, 1.55 MPa, duration 20 s). No substantial temperature changes were observed during the initial 10 s of ultrasound exposure, with only a slight increase of approximately 1.25 °C detected after the 20 s stimulus. Mean ± s.e.m., n = 3 independent experiments for each sample. e, The in vivo ultrasound power transfer in rat heads with FUS focus length of 10 mm. The ultrasound peak pressure heat map in the rat head shows that around 1.19–1.39 MPa was delivered to the rat VTA when 2.45 MPa primary ultrasound peak pressure was used.
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Wang, W., Shi, Y., Chai, W. et al. H-bonded organic frameworks as ultrasound-programmable delivery platform. Nature 638, 401–410 (2025). https://doi.org/10.1038/s41586-024-08401-0
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DOI: https://doi.org/10.1038/s41586-024-08401-0
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