Cells release extracellular vesicles (EVs) for intercellular communication, homeostasis, and microenvironment remodeling, yet how physiological matrix stiffness controls EV cargo sorting remains unclear. Here we show that stiffness programs a cargo-selective sorting pathway in migrasomes, where matrix stiffness couples Integrin β1–FAK–AKT to AKT-dependent phosphorylation of WDR44. Critically, phosphorylated WDR44 acts as a molecular gate that enables Rab11b-dependent trafficking of intraluminal nanovesicles via Myosin Va into migrasomes. Consistently, physiologically stiffness-programmed migrasomes enriched in CSF1 enhance macrophage-recruiting transport and accelerate wound closure in vitro. Together, these findings reveal a mechanistic framework for stiffness-regulated migrasome cargo sorting, and the tunable GA hydrogel platform (300–2,300 Pa) provides a scalable way to guide EV production under defined mechanical conditions.