MFG-E8 glycoprotein in inflammatory tissue regeneration: molecular mechanisms, therapeutic potential and advanced polymeric biomaterial delivery strategies

Milk fat globule epidermal growth factor 8 (MFG-E8) is a multifunctional glycoprotein that coordinates efferocytosis, inflammatory resolution, angiogenesis, and matrix remodeling during tissue repair. In ischemic and inflammatory microenvironments, endogenous MFG-E8 is functionally deficient due to proteolytic cleavage and oxidative inactivation, while free recombinant protein suffers from rapid clearance and poor targeting. Polymeric biomaterials, including nanoparticles, hydrogels, and extracellular vesicle carriers, offer protection, sustained release, and targeted delivery. This review systematically compares silk fibroin, PLGA, collagen, and chitosan-based platforms for MFG-E8 delivery, critically discusses translational bottlenecks (protein-polymer compatibility, manufacturing reproducibility, and safety), and proposes AI-driven co-engineering, closed-loop responsive systems, and biomarker-stratified strategies to accelerate clinical translation.