A Cyclodextrin‐Based pH‐Responsive MicroRNA Delivery Platform Targeting Polarization of M1 to M2 Macrophages for Sepsis Therapy

Abstract The mortality rate of sepsis remains high despite improvements in the diagnosis and treatment of sepsis using symptomatic and supportive therapies, such as anti‐infection therapy and fluid resuscitation. Nucleic acid‐based drugs have therapeutic potential, although their poor stability and low delivery efficiency have hindered their widespread use. Herein, it is confirmed that miR‐223 can polarize proinflammation M1 macrophages to anti‐inflammation M2 macrophages. A pH‐sensitive nano‐drug delivery system comprising β‐cyclodextrin‐poly(2‐(diisopropylamino)ethyl methacrylate)/distearoyl phosphoethanolamine‐polyethylene glycol (β‐CD‐PDPA/DSPE‐PEG) is synthesized and developed to target M1 macrophages and miR‐223 is encapsulated into nanoparticles (NPs) for sepsis treatment. NPs/miR‐223 demonstrated in vitro pH responsiveness with favorable biosafety, stability, and high delivery efficiency. In vivo studies demonstrate that NPs/miR‐223 are preferentially accumulated and retained in the inflammation site, thereby reducing inflammation and improving the survival rate of mice with sepsis while exhibiting ideal biosafety. Mechanically, NPs/miR‐223 regulates macrophage polarization by targeting Pknox1 and inhibiting the activation of the NF‐κB signaling pathway, thereby achieving an anti‐inflammatory effect. Collectively, it is demonstrated that the miRNA delivery vector described here provides a new approach for sepsis treatment and accelerates the advancement of nucleic acid drug therapy.