Extracellular vesicles as dynamic crosslinkers for bioactive injectable hydrogels

Hydrogels are multifunctional biomaterials but are often composed of synthetic building blocks that do not inherently present biological signals to cells. Extracellular vesicles (EVs) offer unique bioactivity, but stably incorporating them into hydrogels remains a challenge. Here, we define the design principles for supramolecular hydrogels crosslinked by EVs. Bovine-derived yogurt EVs are used as a scalable source of bioactive EVs for systematic hydrogel development. Mixing EVs with optimally modified cellulose-based polymers yields injectable hydrogels with tunable mechanical properties. Following optimization with yogurt EVs, this platform’s versatility is demonstrated by formulating hydrogels with artificial microbial and mammalian nanovesicles. In vivo studies show EV hydrogel biocompatibility, intrinsic angiogenic activity, and emergence of an immune niche with broad immune-cell engagement, highlighting their potential in regenerative medicine. These findings establish a framework for designing EV-crosslinked supramolecular hydrogels that integrate the natural bioactivity of EVs with the biomedical potential of injectable hydrogel technology.