Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Growing evidence has indicated that uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress. There are currently no effective ways to counter this crosstalk in a targeted manner. Here we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, an endogenous lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, a natural antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the vascular endothelial barrier dysfunction at sites of acute inflammation, these multidrug nanoparticles could deliver the therapeutic agents in a targeted manner and conferred a significant survival advantage to treated animals in lethal models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel approach for the treatment of acute inflammation with reduced-side effects and high therapeutic potential.

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