The in vivo performance of drug delivery systems (DDS) is profoundly dictated by their interactions with the biomechanical environment. Consequently, actively tuning the mechanical properties of DDS, such as softness and deformability, has emerged as an important design principle for enhancing their therapeutic efficacy. By intelligently adapting to the body's complex biomechanical system, these engineered DDS can orchestrate specific biological responses, such as enhanced tissue penetration, prolonged systemic circulation, and even regulated cellular signaling pathways through mechanotransduction. This review systematically explores, from a biomechanical perspective, how to optimize the behavior of DDS in the complex biological environments by actively designing their mechanical properties. We discuss how this principle was applied across diverse platforms, including coacervates, hydrogels, Pickering emulsions, extracellular vesicles, and liposomes, to achieve enhanced therapeutic behavior for treating challenging diseases like cancer, chronic wounds, and neurological disorders. By focusing on these tunable mechanical properties, this review aims to provide a theoretical framework and insights for the future development of DDS with improved adaptability and therapeutic efficacy in clinical settings.

Drug delivery systems  /  Flexibility  /  Biomechanical design  /  Mechanotransduction  /  Therapeutic applications  /  Tunable stiffness  /  Biological barriers  /  Mechanoimmunity