Polymer mechanochemistry in drug delivery: From controlled release to precise activation.

Controlled drug delivery systems that can respond to mechanical force offer a unique solution for on-demand activation and release under physiological conditions. Compression, tension, and shear forces encompass the most commonly utilized mechanical stimuli for controlled drug activation and release. While compression and tension forces have been extensively explored for designing mechanoresponsive drug release systems through object deformation, ultrasound (US) holds advantages in achieving spatiotemporally controlled drug release from micro-/nanocarriers such as microbubbles, liposomes, and micelles. Unlike light-based methods, the US bypasses drawbacks such as phototoxicity and limited tissue penetration. Conventional US-triggered drug release primarily relies on heat-induced phase transitions or chemical transformations in the nano-/micro-scale range. In contrast, the cutting-edge approach of "Sonopharmacology" leverages polymer mechanochemistry, where US-induced shear force activates latent sites containing active pharmaceutical ingredients incorporated into polymer chains more readily than other bonds within the polymeric structure. This article provides a brief overview of controlled drug release systems based on compression and tension, followed by recent significant studies on drug activation using the synergistic effects of US and polymer mechanochemistry. The remaining challenges and potential future directions in this subfield are also discussed. PROGRESS AND POTENTIAL: The precise spatiotemporal control of drug activity using exogenous signals holds great promise for achieving precise disease treatment with minimal side effects. Ultrasound, known for its safety, has found widespread application in clinical settings and offers adjustable tissue penetration depth and drug release control. However, challenges persist in achieving precise control over drug activity using ultrasound. In recent years, ultrasound-induced drug release utilizing the principle of polymer mechanochemistry (Sonopharmacology) has made significant progress and demonstrated its potential in achieving precise drug activation and release. These systems enable drug release at the sub-molecular level, allowing for selective control over drug activation. Sonopharmacology offers a unique advantage by integrating both chemical and biomedical perspectives, positioning it as a promising field with broad implications in polymer chemistry, nanoscience and technology, and pharmaceutics. This review article aims to examine recent advancements in ultrasound-triggered drug activation systems based on polymeric materials and with an focus on polymer mechanochemistry, identify remaining challenges, and propose potential perspectives in this rapidly evolving field. By providing a comprehensive understanding of the progress and potential of sonopharmacology, this article aims to guide future research and inspire the development of innovative drug delivery systems that offer enhanced selectivity and improved therapeutic outcomes.