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H-bonded organic frameworks as ultrasound-programmable delivery platform
Summary:
The authors from The University of Texas at Austin and The University of Texas at San Antonio developed porous hydrogen-bonded organic frameworks (HOFs) with ultrasound-programmable mechanoresponsive characteristics, achieving non-invasive spatiotemporal control of neural circuit activation in the deep brain (ventral tegmental area) of mice and rats at depths up to 9 mm with sub-second to second-scale latency.
Background:
1. To address the challenge of achieving precise mechanochemical activation within deep tissues, previous researchers developed ultrasound-triggered microbubbles, nanoemulsions, and liposomal systems, achieving success in local drug delivery; however, these systems often require high ultrasound power densities with extended response times (hours), and lack theoretical frameworks to correlate molecular scission efficiency with framework structure and acoustic parameters.
2. The authors in this study proposed an innovative method utilizing hydrogen-bonded organic frameworks (HOFs) as mechanoresponsive delivery platforms, establishing a theoretical model linking cohesive energy to ultrasound scission thresholds, and obtained programmable drug release with high temporal resolution for targeted cellular control in deep tissues.
Research Content:
1. Synthesis:
The authors synthesized four types of HOF nanocrystals (HOF-TATB, HOF-BTB, HOF-101, and HOF-102) using a precipitation method from organic molecular building units (OMBUs: H3TATB, H3BTB, H4TBAPy, and H4PTTNA) via self-assembly through hydrogen bonding and π–π stacking interactions.
2. Characterizations:
1) BET and gas adsorption isotherms (77-K N2 or 195-K CO2) confirmed the porous structures, with HOF-TATB exhibiting a 50.3% solvent-accessible void volume and 1D pore channels (12.2×23.9 Å);
2) SEM/TEM tests show the particle size of the material ranged from 250 to 600 nm with a polydispersity index of approximately 0.2–0.3;
3) Powder X-ray diffraction and microcrystal electron diffraction (MicroED) confirmed phase purity and crystal structures; UV-Vis spectroscopy quantified ultrasound-induced dissociation percentages.
3. Application:
The material was tested for sono-chemogenetics applications by encapsulating clozapine N-oxide (CNO) into HOF-TATB nanocrystals. In vivo experiments demonstrated focused ultrasound (1.5 MHz, 1.4–2.45 MPa) triggered rapid CNO release to activate engineered hM3D(Gq) receptors in the VTA, achieving neural activation latencies of 3.5 s (mice) and 8.8 s (rats), and successfully modulating reward-learning behaviors (conditioned place preference) and reducing immobility in forced swim tests.
4. Mechanism:
the analysis of the experiment result showed that ultrasound stress, rather than thermal effects, drives the mechanochemical scission of supramolecular interactions. The calculation using density functional theory (DFT) reasoned for the performance: cohesive energy (Ecohesive) comprising hydrogen-bonding and π–π stacking interactions determines the ultrasound scission threshold. A linear relationship was established between ln(k) (dissociation equilibrium constant), Ecohesive, and ultrasound peak pressure (EUS), enabling quantitative prediction of dissociation percentages based on framework cohesive energies (ranging from -1.62 eV for HOF-TATB to -8.95 eV for HOF-102).
Outlook:
This research establishes ultrasound-programmable HOFs as a versatile platform for non-invasive, deep-tissue molecular manipulation with high spatiotemporal precision. The development of a predictive theoretical model for mechanochemical scission provides valuable guidelines for the rational design of mechanoresponsive materials, opening new avenues for precision medicine, neural circuit modulation, and sophisticated cellular control in biomedical applications.
H-bonded organic frameworks as ultrasound-programmable delivery platform
Authors: 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, Huiliang Wang
DOI: 10.1038/s41586-024-08401-0
Link: https://doi.org/10.1038/s41586-024-08401-0
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