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

## TL;DR

A new targeted therapy using PARP-1 inhibitors delivered via specialized microparticles reduces lung damage and improves survival in sepsis.

## Contribution

A cell-specific, lung-targeted nanotherapeutic using PARP-1 inhibition is developed and shown to effectively treat sepsis-induced lung injury.

## Key findings

- Pulmonary epithelial cells and macrophages are identified as key pro-inflammatory hubs in septic lungs.
- OLA@SPA MPs significantly reduce lung injury, cytokine storm, and improve survival in sepsis models.
- The therapy reverses sepsis-associated gene signatures, particularly in NOD-like receptor and TNF signaling pathways.

## 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.

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•Single-Cell Guided Target Identification: Single-cell RNA sequencing of the septic lung microenvironment identified pulmonary epithelial cells and macrophages as central pro-inflammatory hubs, revealing their specific upregulation of PARP-1 and providing a foundational rationale for cell-specific targeting.•Innovative Biomimetic Nanotherapeutic: A novel lung-targeted delivery system was engineered by encapsulating the PARP-1 inhibitor Olaparib into surfactant protein A (SPA)-functionalized microparticles (OLA@SPA-MPs), which demonstrated enhanced pulmonary accumulation and efficient internalization by the target epithelial cells and macrophages.•Potent Therapeutic Efficacy and Survival Benefit: In murine sepsis models, OLA@SPA-MPs treatment robustly attenuated lung injury, modulated the systemic and local cytokine storm, and most importantly, conferred a significant survival advantage, outperforming non-targeted formulations and free drug.•Comprehensive Mechanistic Elucidation: The therapeutic action was mechanistically linked to the potent inhibition of PARP-1 hyperactivation and the downstream parthanatos pathway in target cells, coupled with a transcriptomic reprogramming that reversed sepsis-associated gene signatures, particularly in key pro-inflammatory pathways like NOD-like receptor and TNF signaling.

Single-Cell Guided Target Identification: Single-cell RNA sequencing of the septic lung microenvironment identified pulmonary epithelial cells and macrophages as central pro-inflammatory hubs, revealing their specific upregulation of PARP-1 and providing a foundational rationale for cell-specific targeting.

Innovative Biomimetic Nanotherapeutic: A novel lung-targeted delivery system was engineered by encapsulating the PARP-1 inhibitor Olaparib into surfactant protein A (SPA)-functionalized microparticles (OLA@SPA-MPs), which demonstrated enhanced pulmonary accumulation and efficient internalization by the target epithelial cells and macrophages.

Potent Therapeutic Efficacy and Survival Benefit: In murine sepsis models, OLA@SPA-MPs treatment robustly attenuated lung injury, modulated the systemic and local cytokine storm, and most importantly, conferred a significant survival advantage, outperforming non-targeted formulations and free drug.

Comprehensive Mechanistic Elucidation: The therapeutic action was mechanistically linked to the potent inhibition of PARP-1 hyperactivation and the downstream parthanatos pathway in target cells, coupled with a transcriptomic reprogramming that reversed sepsis-associated gene signatures, particularly in key pro-inflammatory pathways like NOD-like receptor and TNF signaling.