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

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. Here we showed that folic acid-functionalized exosomes accumulated in the lung of septic mice and specifically targeted inflammatory macrophages. We therefore designed FA-functionalized exosomes co-loaded with resveratrol (an anti-inflammatory polyphenol) and celastrol (an immunosuppressive pentacyclic triterpenoid; FA-Exo/R+C), which exhibited powerful anti-inflammatory and immunosuppressive activities against LPS-stimulated macrophages in vitro by regulating NF-κB and ERK1/2 signaling pathways. Encouraged by these positive data, the efficacy of FA-Exo/R+C was systematically investigated in an LPS-induced mouse sepsis model. FA-Exo/R+C showed 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 enhanced and prolonged the protective effect, and resisted re-challenge to LPS. Collectively, the strategy of co-delivering drugs combination through functionalized exosomes offers a new avenue for sepsis treatment. This article is protected by copyright. All rights reserved.