# PARPi Combining Nanoparticle LIN28B siRNA for the Management of Malignant Ascites

## TL;DR

This study explores a new treatment combining a nanoparticle and a drug to manage malignant ascites in advanced cancer patients, improving survival and reducing harmful immune cell infiltration.

## Contribution

A novel nanoparticle-based siRNA delivery system combined with a PARP inhibitor is developed to target malignant ascites.

## Key findings

- The combination therapy significantly reduced malignant ascites and prolonged survival in a preclinical ovarian cancer model.
- The treatment decreased immunosuppressive M2 macrophages and Arg1-positive neutrophils, improving the immune microenvironment.
- Inhibition of PARP and LIN28B reduced vascular leakage and strengthened tight junction integrity.

## Abstract

Malignant serous effusion (MSE), including malignant pleural effusion (MPE) and malignant ascites (MA), is a common and severe complication in advanced malignancies, associated with poor prognosis and high recurrence rates. Currently, no standardized treatments are available for MSE management, posing significant clinical challenges. Here, we identify elevated LIN28B expression and dysregulation of DNA repair pathways as two major features associated with MSE from patient and preclinical samples. We develop a targeted siRNA nanoparticle delivery system (siLin28B/DSSP@lip‐PEG‐FA) in combination with the PARP inhibitor BMN673, providing a synergistic therapeutic strategy against MSE. This combination significantly alleviated MA accumulation and prolonged survival in a preclinical ovarian cancer (OC) model without causing systemic cytotoxicity. Mechanistically, single‐cell RNA sequencing (scRNA‐seq) revealed that this combination therapy markedly remodeled the immune microenvironment by decreasing M2 macrophages and neutrophil populations with altered subtypes. Notably, Arg1‐positive neutrophils, producing pro‐inflammatory cytokines to increase vascular permeability, were diminished after the combination treatment. Furthermore, in vitro and in vivo experiments demonstrated that suppression of PARP and LIN28B inhibited vascular leakage and reinforced tight junction integrity. Collectively, our findings highlight dual targeting of PARP and LIN28B as a promising MA management approach in patients with advanced cancers, with the potential to improve patient quality of life.

This study demonstrates that co‐inhibition of LIN28B and PARP using siLin28b/DSSP@lip‐PEG‐FA nanoparticles in combination with the PARP inhibitor BMN673 effectively suppresses the accumulation of malignant ascites associated with advanced cancers. This therapeutic strategy improves vascular integrity, reduces infiltration of immunosuppressive macrophages, and attenuates the secretion of pro‐tumorigenic cytokines.