EngineeredNanomicelles Delivering the Combinationof Steroids and Antioxidants Can Mitigate Local and Systemic Inflammation,Including Sepsis

Chronic inflammation is mainly characterized by the release of proinflammatory cytokines (cytokine storm) and reactive oxygen/nitrogen species. Sepsis is a life-threatening condition resulting from the successive chronic inflammatory responses toward infection, leading to multiple organ failure and, ultimately, death. As inflammation and oxidative stress are known to nourish each other and initiate an uncontrolled immune response, inhibiting the cross-talk between the inflammatory response using anti-inflammatory drugs and oxidative stress using antioxidants can be a promising strategy to target sepsis. Here, we present the engineering of chimeric nanomicelles (NMs) using an ester-linked polyethylene glycol-derived lithocholic acid–drug conjugate using dexamethasone (DEX), a potent glucocorticoid possessing anti-inflammatory properties, and vitamin E (VITE), an antioxidant to target oxidative stress. Interestingly, these chimeric DEX-VITE NMs show enhanced accumulation at the inflamed sites driven by enhanced permeation and retention effect and mitigate localized acute inflammation in paw, lung, and liver inflammation models. We further demonstrated the efficacy of these NMs in mitigating LPS-induced endotoxemia and CLP-induced microbial sepsis, conferring survival advantages. DEX-VITE NMs also modulate immune homeostasis by decreasing the infiltration of total immune cells, neutrophils, and overall macrophages. Finally, administration of DEX-VITE NMs also reduces the release of proinflammatory cytokines and prevents vascular damage, two critical factors of sepsis pathogenesis. Therefore, this therapeutic approach of chimeric NMs can effectively deliver steroids and antioxidants to mitigate uncontrolled localized and systemic inflammation.