Abstract

Sepsis-induced acute lung injury (ALI) is a life-threatening condition with limited therapeutic options, driven by a dysregulated inflammatory response within the pulmonary microenvironment. Although hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1) is recognized as a key contributor to inflammation and cellular injury, its cell type–specific roles in sepsis and strategies for targeted inhibition remain insufficiently explored. In this study, we first identified pulmonary epithelial cells and macrophages as major pro-inflammatory hubs in the septic lung using single-cell RNA sequencing. Based on these findings, we engineered a lung-targeted nanotherapeutic by encapsulating the PARP-1 inhibitor olaparib (OLA) into surfactant protein A (SPA)-functionalized microparticles (OLA@SPA MPs). The OLA@SPA MPs exhibited enhanced pulmonary accumulation and efficient internalization by target cells, resulting in robust suppression of PARP-1 activation. In murine models of sepsis, treatment with OLA@SPA MPs markedly reduced vascular leakage, modulated the cytokine storm, attenuated lung histopathological damage, and significantly improved survival. Mechanistically, transcriptomic analyses revealed that OLA@SPA MPs reversed sepsis-associated gene expression signatures, particularly by downregulating key pro-inflammatory pathways such as NOD-like receptor and tumor necrosis factor (TNF) signaling. Collectively, this work establishes a targeted therapeutic paradigm that translates mechanistic insights into an effective intervention for sepsis-induced lung injury.