PEDF-Enriched Extracellular Vesicle for Vessel Normalization to Potentiate Immune Checkpoint Blockade Therapy

The abnormal tumor vasculature acts as the physical and functional barrier to the infiltration and activity of effector T cells, leading to the low response rate of immune checkpoint inhibitors (ICIs). Herein, antiangiogenic extracellular vesicles that enable normalization of the tumor-associated vasculature were prepared to potentiate the efficacy of ICIs. Small extracellular vesicles were exploited as the delivery platform to protect the antiangiogenic protein, pigment epithelium-derived factor (PEDF), from proteolytic degradation. Along with the physicochemical characteristics of the PEDF-enriched extracellular vesicles (P-EVs), their inhibitory effects on migration, proliferation, and tube formation of endothelial cells were investigated in vitro. In tumor-bearing mice, it was confirmed that, compared to bare PEDFs, P-EVs efficiently reduced vessel leakiness, improved blood perfusion, and attenuated hypoxia. Consequently, when combined with anti-PD-1 antibodies, P-EVs remarkably augmented the antitumor immunity, as evidenced by increased infiltration of CD8⁺ T cells and reduced regulatory T cells. These results suggest that P-EVs are promising therapeutics for tumors refractory to ICIs.