Cordycepin‐Loaded Macrophage Vesicles for Targeted Nonalcoholic Steatohepatitis Attenuation

Cordycepin (3′‐deoxyadenosine) has a demonstrated value in ameliorating nonalcoholic steatohepatitis (NASH); however, its short in vivo metabolism time and high dose‐induced cytotoxicity are challenges limiting its clinical application. Herein, a cordycepin‐loaded macrophage vesicle (C‐MV) is developed for targeted cordycepin delivery to achieve stable and durable mitigation of NASH. The C‐MV is obtained using cytochalasin B‐stimulated RAW 264.7 cells to produce MV, followed by repeated freeze‐thawing and extrusion of MV and cordycepin. C‐MV selectively delivers cordycepin to macrophages at the site of liver injury, slowly releases cordycepin, reduces the toxicity associated with high cordycepin doses, and increases the mice's survival rate from 40% to 90%. Moreover, C‐MV reduces liver apoptosis and attenuated NASH liver injury by activating AMP‐activated protein kinase and inhibiting caspase 6 activity. Overall, C‐MV exhibits better anti‐inflammatory, lipid‐lowering, and anti‐apoptosis properties than free cordycepin, making it a promising delivery system for the potential clinical application of cordycepin. MV combined with cordycepin provides an inspiring bionic strategy for NASH treatment that can achieve effective therapeutic effects in vivo. Through intravenous injection, the cordycepin‐loaded macrophage vesicles can be selectively enriched to the liver inflammation site. Additionally, the vehicle releases cordycepin slowly, enabling a long‐lasting and stable effect of cordycepin in lowering lipid and anti‐inflammation, and controlling hepatocyte apoptosis through the molecular mechanism of AMP‐activated protein kinase (AMPK)‐caspase 6, thereby reducing nonalcoholic steatohepatitis.