Engineered iNK cell-derived exosomes with sequential chitosan-galactose coating for ASGR1-targeted therapy of nonalcoholic steatohepatitis

초록

Nonalcoholic steatohepatitis (NASH) remains a formidable global health challenge, yet precision-targeted therapeutic interventions remain scarce. Although natural killer (NK) cell–derived exosomes (Exo) exhibit innate immunomodulatory and anti-fibrotic properties, their therapeutic potential remains hindered by suboptimal physiological stability and inadequate hepatocyte specificity. In this study, we engineered a high-performance therapeutic nanoplatform by implementing a sequential surface coating of chitosan and galactose onto iPSC-derived NK cell exosomes (iNK-Exo), enabling improved physiological stability and enhanced hepatocyte-specific targeting. The resulting galactosylated exosomes (G-Exo) featured a uniform hydrodynamic diameter of approximately 240 nm and a positive zeta potential of 21.6 mV, which significantly augmented colloidal stability in complex physiological environments. Mechanistic investigations revealed that the galactose moiety enhances hepatocyte-associated uptake consistent with ASGR1 (asialoglycoprotein receptor 1)-associated recognition in the liver. In a methionine-choline deficient (MCD) diet-induced NASH mouse model, G-Exo treatment demonstrated a multifaceted therapeutic impact including effectively attenuating hepatic lipid sequestration, downregulating fibrotic gene expression, and suppressing macrophage-associated profibrotic cytokine production. These findings demonstrate that G-Exo functions not only as a stabilized exosome-based delivery system but also as an active therapeutic modality that enables selective hepatocyte targeting, leading to suppression of key pathological features of NASH.

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