Microfluidic Co-Encapsulation of Exosomal miRNAs and Antioxidant Enzymes Ameliorates Hepatic Steatosis by Driving M2 Polarization and Reparative Neutrophil Recruitment

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder lacking universally effective pharmacotherapies due to its complex pathogenesis involving lipotoxicity, oxidative stress, and inflammation. While natural mesenchymal stem cell-derived exosomes present promising therapeutic potential, their clinical translation is hindered by low manufacturing yields, batch-to-batch heterogeneity, and rapid systemic clearance. To overcome these limitations, we report LSCR, an innovative exosome-mimetic nanotherapeutic fabricated via a single-step microfluidic assembly. By systematically decoding natural exosomes, we identified and co-encapsulated a core therapeutic payload—comprising three pivotal miRNAs (hsa-miR-29a-3p, hsa-miR-27a-3p, and hsa-miR-20a-5p) and two potent antioxidant enzymes (superoxide dismutase and catalase)—into liver-targeting lipid nanoparticles. The engineered LSCR exhibits exceptional colloidal stability, robust resistance to physical stress, and prolonged preservation of enzyme catalytic activity for over 30 days. In vivo evaluations in a high-fat diet-induced murine model demonstrate that LSCR selectively accumulates in the liver, effectively ameliorating hepatic steatosis, normalizing lipid profiles, and restoring liver function with an excellent biosafety profile. Mechanistically, LSCR synergistically reverses the pathological transcriptomic network by suppressing inflammatory and fibrotic signaling cascades, such as the AGE-RAGE, MAPK, and PI3K-Akt pathways. Furthermore, LSCR actively remodels the hepatic immune microenvironment by driving pro-resolving M2 macrophage polarization and recruiting indispensable tissue-reparative (N2-like) neutrophils. Ultimately, this highly translational nanomedicine platform offers a scalable and effective strategy for MASLD treatment and prevention.