Inflammation-Instructed Hierarchical Delivery Of Il-4/Mir-21 Orchestrates Osteoimmune Microenvironment Toward The Treatment Of Rheumatoid Arthritis

Dysregulated inflammation and failure in resolution account for the incidence and deterioration of rheumatoid arthritis (RA). IL-4 and miR-21 possess complementary functions in inhibiting inflammation and fostering resolution. Thus, inflammation-instructed nanocomplexes (NCs) are herein developed to mediate hierarchical co-delivery of miR-21 and IL-4 to orchestrate the osteoimmune microenvironment against RA. The NCs comprise a cationic inner core assembled from the membrane-penetrating, helical polypeptide (PG) and miR-21, an outer layer based on the acid-responsive, charge reversal polymer (PLL-CA), and surface-adsorbed IL-4. The negatively charged NCs enable prolonged blood circulation after systemic administration, and thus passively accumulate in the inflamed joint. In the slightly acidic microenvironment of inflamed synovium, PLL-CA transforms from negative to positive, which sheds off to liberate IL-4 extracellularly and facilitate the intracellular delivery of the PG/miR-21 core into macrophages. Thus, the anti-inflammatory miR-21 cooperates with the proresolving IL-4 to attenuate inflammation via NF-kappa B inhibition, promote macrophage polarization to M2a/M2c phenotypes, propel resolution, and promote tissue repair against Zymosan A-induced arthritis. This study provides an effective strategy toward the programmed delivery of drug/gene cargoes at different extracellular/intracellular locations, and the combined mechanism of anti-inflammation and proresolution renders insights into the treatment of inflammatory diseases.