Injectable hydrogel with miR-222-engineered extracellular vesicles ameliorates myocardial ischemic reperfusion injury via mechanotransduction.

Cardiac ischemic reperfusion injury (IRI) significantly exacerbates cardiac dysfunction and heart failure, causing high mortality. Despite the severity of IRI, effective therapeutic strategies remain elusive. Acellular cardiac patches have shown considerable efficacy in delivering therapeutics directly to cardiac tissues. Herein, we develop injectable GelMA (GEL) hydrogels with controlled mechanical properties. Targeting miR-222-engineered extracellular vesicles (TeEVs), tailored with cardiac-ischemia-targeting peptides (CTPs), are developed as ischemic TeEV therapeutics. These TeEVs are encapsulated within mechanical hydrogels to create injectable TeEV-loaded cardiac patches, enabling minimal invasiveness to attenuate IRI. The injectable patches facilitate the precise targeting of TeEVs for the efficient rescue of damaged cells. Persistent delivery of TeEVs into the infarcted region alleviates acute IRI and mitigated remodeling post IRI. This is linked to focal adhesion activation, cytoskeleton force enhancement, and nuclear force-sensing preservation. These findings may pave the way for force-sensing approaches to cardiac therapy using bioengineered therapeutic patches.