# Modulating a Massive Set of Biomolecular Structures by Sono‐Mechanical Force

## TL;DR

Low-power ultrasound can generate tiny forces to reversibly unfold DNA structures both inside and outside cells, potentially enabling new drug delivery methods.

## Contribution

This study demonstrates the first quantification of sono-mechanical forces capable of unfolding DNA structures reversibly in cells.

## Key findings

- Low-power ultrasound generates at least 29 pN of force to unfold DNA structures like G-quadruplexes and hairpins.
- Doxorubicin ligands are released from DNA hairpins in cells after sono-mechanical unfolding, inducing targeted cancer cell death.
- Sono-mechanical forces can manipulate biomolecules without requiring fixed orientations or causing irreversible damage.

## Abstract

Mechanical modulation of biomolecular structures by single‐molecule techniques, such as optical tweezers, has revealed subtle conformational dynamics and enabled precise modulation of functional properties. However, such tools are limited to manipulating one or a few molecules at a time in extracellular settings, posing significant challenges for scaling force‐based methods to achieve high sensitivity and efficacy both outside and within cells. Here, low‐power (<5.3 mW cm−2) ultrasound is employed to generate sono‐mechanical forces without formation of sonodynamic radicals, which are known to irreversibly alter molecular structures. By calibrating against optical‐tweezers‐based single‐molecule force spectroscopy, this study quantifies for the first time that at least 29 pN sono‐mechanical force can be generated at 5.3 mW cm−2 sonication power, capable of simultaneously and reversibly unfold an ensemble set of DNA structures, including G‐quadruplexes and hairpins. Notably, the same sono‐mechanical unfolding is observed in cells, where intercalated doxorubicin ligands are released from unfolded DNA hairpin carriers, resulting in targeted cancer cell death. These findings show ultrasound can simultaneously manipulate a large population of biomolecules without requiring fixed orientations, offering a flexible and nonintrusive force generation to reversibly unfold molecular structures. This platform holds profound potential for applications in molecular biophysics, smart materials, and precision medicines.

Using low‐power ultrasound exposure, picoNewton forces are generated to release loaded drugs after unfolding secondary structures in DNA nanoassemblies. This opens a door to reversibly manipulate a large set of biomolecular structures both inside and outside cells without the damages incurred by high‐power sonications currently used in the field.