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.