Immunosuppressive termination of pro-inflammatory miRNA degradation via circular RNA nanosponge for sepsis-induced cardiomyopathy treatment.

Managing inflammatory cytokine storms is prevalent in treatment of sepsis-induced cardiomyopathy (SICM), yet it remains a challenge to immunosuppression weaning. We herein propose an immunosuppressive termination of pro-inflammatory microRNA-33 (miR-33) degradation strategy for on-demand anti-inflammatory management. Inspired by circular RNA (cRNA) sponging capacity, we designed a miR-33-targeted sequence of cRNA (cRNA-33), including 11 of miR-33 binding sites and a single microRNA-223 (miR-223)-specific immunosuppression binding site. To improve drugability, cRNA-33 is compressed into reactive oxygen species (ROS)-responsive polymeric assembly, and covered by tannic acid-modified hyaluronic acid to enhance cardiac inflammatory macrophage accumulation. Triggered by intracellular ROS, cRNA-33 rapidly dissociates from assembly and binds sufficient miR-33 to alleviate inflammatory actions of NLRP3 and IL-1β induction. Macrophages are subsequently shifted from pro-inflammatory to anti-inflammatory phenotype, resulting in high expression of miR-223 that destabilizes cRNA-33 through the miR-223-responsive site to discontinue immune responses. The cRNA-33 treatment yields 80% decrease of inflammation efficacy, 90% cardiac function recovery and 87.5% survival rate in study mice. Collectively, this study has provided an advanced anti-inflammatory therapy for SICM, at a safe level.