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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\u2010PEG\u2010FA) 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\u2010cell RNA sequencing (scRNA\u2010seq) revealed that this combination therapy markedly remodeled the immune microenvironment by decreasing M2 macrophages and neutrophil populations with altered subtypes. Notably, Arg1\u2010positive neutrophils, producing pro\u2010inflammatory 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.<\/jats:p>","DOI":"10.1002\/advs.202510547","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T04:47:27Z","timestamp":1769143647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PARPi Combining Nanoparticle LIN28B siRNA for the Management of Malignant Ascites"],"prefix":"10.1002","volume":"13","author":[{"given":"Yan","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology  Shanghai China"},{"name":"Institute of Translational Medicine National Facility for Translational Medicine Shanghai 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