In summary, we have developed a hydrogel system that can degrade in response to external compressive stress. This generalizable approach, embedding mechanosensitive vesicles, may enable creation of different functional hydrogels that can dynamically change their network by responding to external stress, depending on the type of hydrogel and the compound loaded in vesicles. Moreover, this system offers many adjustable parameters, including vesicle size, density, and membrane composition, which allow tuning the responsiveness for specific stress intensity.