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Nanoparticle-mediated siRNA Gene-silencing in Adult Zebrafish Heart
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PARPi Combining Nanoparticle LIN28B siRNA for the Management of Malignant Ascites
Yan Fang1,2,3, Qian Shen4, Yao Lin5
1Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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.
Insights
Dual targeting of LIN28B and PARP offers a novel therapeutic strategy for malignant ascites (MA), a severe complication in advanced cancers. This approach reduces vascular leakage and improves survival in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Nanotechnology
Background:
- Malignant serous effusion (MSE), encompassing malignant pleural effusion (MPE) and malignant ascites (MA), is a frequent and serious complication of advanced cancers.
- Current management strategies for MSE lack standardization, presenting significant clinical challenges and associated with poor prognosis and high recurrence rates.
Purpose of the Study:
- To investigate the therapeutic potential of targeting elevated LIN28B expression and dysregulated DNA repair pathways in MSE.
- To develop and evaluate a novel combination therapy for malignant ascites management.
Main Methods:
- Development of a targeted siRNA nanoparticle delivery system (siLin28B/DSSP@lip-PEG-FA) for LIN28B suppression.
- Combination therapy using siLin28B nanoparticles and the PARP inhibitor BMN673.
- Preclinical evaluation in an ovarian cancer (OC) model, including assessment of MA accumulation, survival, and systemic cytotoxicity.
- Mechanistic studies using single-cell RNA sequencing (scRNA-seq) to analyze immune microenvironment alterations.
- In vitro and in vivo experiments to investigate effects on vascular leakage and tight junction integrity.
Main Results:
- The combination therapy significantly alleviated malignant ascites accumulation and prolonged survival in a preclinical ovarian cancer model.
- The treatment demonstrated no systemic cytotoxicity.
- scRNA-seq revealed remodeling of the immune microenvironment, including decreased M2 macrophages and specific neutrophil populations (Arg1-positive neutrophils).
- Suppression of PARP and LIN28B effectively inhibited vascular leakage and reinforced tight junction integrity.
Conclusions:
- Dual targeting of PARP and LIN28B presents a promising synergistic therapeutic strategy for malignant ascites management.
- This approach has the potential to improve quality of life for patients with advanced cancers by reducing vascular leakage.
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