Programming Extracellular Vesicle-Biomaterial Interfaces for Diabetic Wounds: Barrier-Matched Design and Translational Criteria.

Diabetic wounds are sustained by a coupled network of unresolved inflammation, vascular insufficiency, oxidative injury, infection and biofilms, and matrix dysfunction. Although extracellular vesicles (EVs) can convey regenerative signals and engineered cargo, therapeutic performance is ultimately determined by how a wound-contact material preserves, presents, and releases them. This review reframes EV-based treatment as the programming of an EV-biomaterial interface. It relates wound barriers to cargo function; compares donor-cell engineering, post-isolation loading, surface modification, EV mimetics, and hybrid systems; and examines how composition, crosslinking, architecture, adhesion, mechanics, degradation, and stimulus responsiveness govern local exposure. Preclinical and emerging clinical evidence is evaluated alongside product-defining measurements, including EV identity and purity, cargo content and encapsulation efficiency, removal of free cargo, recovery, release, potency, safety, sterility, and batch consistency. The analysis shows that added functional complexity is not inherently advantageous unless each component is mechanistically necessary and quantitatively controlled. A barrier-matched, fully characterized interface therefore offers a rigorous basis for developing reproducible and clinically testable EV-enabled wound therapeutics.