Targeted inhibition of PARP-1 in pulmonary epithelial cells and macrophages via SPA-functionalized microparticles attenuates sepsis-induced lung injury

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.