Integrin β4‐Enriched Small Extracellular Vesicle as Drug Delivery Vehicle for Targeting Pulmonary Metastasis of Hepatocellular Carcinoma

Small extracellular vesicles (sEVs) hold significant promise for targeted drug delivery, owing to their unique ability to target and accumulate in specific tissues. The organotropism of sEVs is primarily determined by the presence of integrins on their surface. In this study, sEVs with enriched integrin β4, designated as XP-ITGβ4-sEV, are engineered to enhance lung-targeting capabilities. The therapeutic efficacy of doxorubicin-loaded XP-ITGβ4-sEV (XP-ITGβ4-sEV/Dox) is evaluated in targeting pulmonary metastasis of advanced hepatocellular carcinoma (HCC) using a murine lung metastasis model. Remarkably, treatment with XP-ITGβ4-sEV/Dox effectively suppresses tumor cell colonization in the lungs compared to an equivalent dose of free doxorubicin. Histological analyses reveal a reduction in lung metastatic foci, inhibition of proliferation, and an increase in apoptosis of HCC cells. Notably, XP-ITGβ4-sEV/Dox exhibits a superior therapeutic efficacy with an improved safety profile compared to a higher dose of free doxorubicin that demonstrates similar efficacy. These findings collectively underscore the potential of integrin β4-enriched sEVs as a targeted drug delivery system for addressing pulmonary metastasis of HCC.