Combination Therapy with Resveratrol and Celastrol Using Folic Acid‐Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis

Abstract Overactivated macrophages are a prominent feature of many inflammatory and autoimmune diseases, including sepsis. Attention and regulation of macrophages activity is of great significance for sepsis treatment. Herein, this study shows that folic acid‐functionalized exosomes accumulate in the lung of septic mice and specifically target inflammatory macrophages. Therefore, FA‐functionalized exosomes co‐loaded with resveratrol (an anti‐inflammatory polyphenol) and celastrol (an immunosuppressive pentacyclic triterpenoid; FA‐Exo/R+C), which exhibit powerful anti‐inflammatory and immunosuppressive activities against LPS‐stimulated macrophages in vitro by regulating NF‐κB and ERK1/2 signaling pathways, are designed. Encouraged by these positive data, the efficacy of FA‐Exo/R+C is systematically investigated in an LPS‐induced mouse sepsis model. FA‐Exo/R+C shows striking therapeutic benefits in terms of attenuated cytokine storm, reduced acute lung injury, and increased survival of septic mice by inhibiting the inflammation and proliferation of proinflammatory M1 macrophages. Importantly, multiple administrations of FA‐Exo/R+C significantly enhance and prolong the protective effect, and resist rechallenge to LPS. Collectively, the strategy of co‐delivering drugs combination through functionalized exosomes offers a new avenue for sepsis treatment.