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Attention and regulation of macrophages activity is of great significance for sepsis treatment. Herein, this study\u00a0shows\u00a0that folic acid\u2010functionalized exosomes accumulate\u00a0in the lung of septic mice and specifically target\u00a0inflammatory macrophages. Therefore,\u00a0FA\u2010functionalized exosomes co\u2010loaded with resveratrol (an anti\u2010inflammatory polyphenol) and celastrol (an immunosuppressive pentacyclic triterpenoid; FA\u2010Exo\/R+C), which exhibit powerful anti\u2010inflammatory and immunosuppressive activities against LPS\u2010stimulated macrophages in vitro by regulating NF\u2010\u03baB and ERK1\/2 signaling pathways, are designed. Encouraged by these positive data, the efficacy of FA\u2010Exo\/R+C is systematically investigated in an LPS\u2010induced mouse sepsis model. FA\u2010Exo\/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\u2010Exo\/R+C significantly enhance and prolong the protective effect, and resist rechallenge to LPS. Collectively, the strategy of co\u2010delivering drugs combination through functionalized exosomes offers a new avenue for sepsis treatment.<\/jats:p>","DOI":"10.1002\/adhm.202301325","type":"journal-article","created":{"date-parts":[[2023,8,2]],"date-time":"2023-08-02T07:55:00Z","timestamp":1690962900000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Combination Therapy with Resveratrol and Celastrol Using Folic Acid\u2010Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis"],"prefix":"10.1002","volume":"12","author":[{"given":"Xue","family":"Zheng","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology College of Pharmacy College of Life Sciences Key Laboratory of Molecular Drug Research and KLMDASR of Tianjin Nankai University  Tongyan Road Haihe Education Park Tianjin 300350 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