Polyphosphate- and Antioxidant Peptide-Based Coacervate Delivers miRNA

RNA-based therapies are often hampered by low RNA stability and cytoplasmic delivery efficiency. Coacervate droplets formed by liquid–liquid phase separation (LLPS) exhibit great potential in drug loading and transfection efficiency for delivering biomacromolecules into the cytoplasm due to their condensed and fluid nature. Here, we developed a type of coacervate droplet as the delivery vector formed by the LLPS of sodium hexametaphosphate (SHMP) and antioxidant peptide SS-31, followed by loading with microRNA-223 (miRNA-223) as a coacervate artificial cell (Coac@miR). In addition, an erythrocyte membrane coating on the Coac@miR (EMCoac@miR) is employed to shield the miRNA-223 from ribonuclease degradation during blood transfer. The coacervate artificial cells demonstrate increased cytoplasmic delivery efficiency of miRNA-223 by 10-fold higher than the miRNA-223 alone. With acute lung injury (ALI) mouse model, we find that both intratracheal injection (i.t.) of Coac@miR and intravenous injection (i.v.) of EMCoac@miR could alleviate ALI by reprogramming macrophages to an anti-inflammatory (M2) phenotype, inhibiting inflammatory factors, and relieving ROS stress. This work provides a novel delivery system for miRNAs within polyP-peptide-based coacervate artificial cells, demonstrating therapeutic potential for immune-related and inflammatory diseases.