Engineered Milk‐Derived Extracellular Vesicles Integrate PCSK9 Silencing and Inflammation Modulation for Hyperlipidemia Therapy

Hyperlipidemia is a systemic metabolic disorder closely associated with chronic inflammation. Effective management requires integrated strategies that simultaneously lower lipid level and attenuate inflammation. Nucleic acid therapeutics, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) siRNA, represent a breakthrough in lipid-lowering therapy. However, they either lack direct anti-inflammatory effects (GalNAc-siRNA) or are prone to triggering unintended inflammatory responses themselves such as lipid nanoparticles (LNPs). Milk-derived extracellular vesicles (MDEs) emerge as naturally anti-inflammatory nanocarriers that suppress key pro-inflammatory cytokines by 30.0%-96.5% in vitro. However, MDEs predominantly undergo endocytic trafficking with substantial endosomal/lysosomal sequestration, which can limit productive cytosolic siRNA delivery. To address this, we developed engineered MDEs by incorporating 30.0% (w/w) probiotic-derived glycolipids into their membranes to facilitate early endosomal escape. When loaded with PCSK9 siRNA, the engineered MDEs achieved a remarkable silencing efficiency of 90.2 ± 0.2%, significantly outperforming both unmodified MDEs and conventional LNPs. In hyperlipidemic mice, systemic administration of engineered MDEs improved serum lipid profiles, reduced lipid accumulation and systemic inflammation, and showed a favorable safety profile under the conditions examined. Collectively, this work provides a promising nucleic acid delivery platform based on engineered MDEs for enhanced hyperlipidemia therapy through simultaneous lipid-lowering and anti-inflammatory effects.