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 USinduced 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.