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.