Targeting alveolar epithelial cells with lipid micelle-encapsulated necroptosis inhibitors to alleviate acute lung injury.

Abstract

Acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS), represents a critical condition characterized by extensive inflammation within the airways. Necroptosis, a form of cell death, has been implicated in the pathogenesis of various inflammatory diseases. However, the precise characteristics and mechanisms of necroptosis in ARDS remain unclear. Thus, our study seeks to elucidate the specific alterations and regulatory factors associated with necroptosis in ARDS and to identify potential therapeutic targets for the disease. We discovered that necroptosis mediates the progression of ALI through the activation and formation of the RIPK1/RIPK3/MLKL complex. Moreover, we substantiated the involvement of both MYD88 and TRIF in the activation of the TLR4 signaling pathway in ALI. Furthermore, we have developed a lipid micelle-encapsulated drug targeting MLKL in alveolar type II epithelial cells and successfully applied it to treat ALI in mice. This targeted nanoparticle selectively inhibited necroptosis, thereby mitigating epithelial cell damage and reducing inflammatory injury. Our study delves into the specific mechanisms of necroptosis in ALI and proposes novel targeted therapeutic agents, presenting innovative strategies for the management of ARDS.