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Engineered extracellular vesicles derived from sweet potato loaded with siPOLD1 for targeted therapy of glioma
Zhiyong Jin1, Shan Jiang1, Liujie Yuan1
1Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou 221002, China.
Introduction:
Glioma is the most common malignant tumor of the central nervous system, with high malignancy and poor prognosis, necessitating the development of novel targeted therapies. DNA polymerase delta catalytic subunit 1 (POLD1) is implicated in multiple cancers, but its role in glioma remains unclear. Plant-derived extracellular vesicles (PDEVs) have emerged as biocompatible, targetable nanocarriers with promising applications in cancer therapy.
Objective:
This study aims to elucidate the oncogenic function of POLD1 in glioma and develop a PDEVs -based delivery system for targeted therapy, with the goal of improving the current therapeutic landscape for glioma.
Methods:
POLD1 expression and prognostic significance were analyzed using clinical samples and databases. In vitro, CCK-8, Transwell, and flow cytometry assays evaluated the impact of POLD1 knockdown on glioma cell proliferation, invasion, migration, cell cycle, and apoptosis. In vivo tumorigenesis and survival were assessed in mouse models. Sweet potato-derived nano-vesicles (SPDELNVs) were isolated and characterized. An engineered A2-SPDELNVs-siPOLD1 system was developed via surface modification and siRNA loading, and its targeting efficiency and therapeutic efficacy were evaluated both in vitro and in vivo.
Results:
POLD1 was upregulated in glioma tissues and correlated with poor prognosis. Its knockdown suppressed proliferation, invasion, and migration, induced cell cycle arrest, and promoted apoptosis in vitro. In vivo, POLD1 targeting inhibited tumor growth and prolonged survival. SPDELNVs showed intrinsic anti-glioma activity and efficient cellular uptake. The engineered A2-SPDELNVs-siPOLD1 effectively delivered siRNA, silenced POLD1, and significantly inhibited tumor progression both in vitro and in vivo, with enhanced survival.
Conclusion:
Our findings uncover the oncogenic role of POLD1 in glioma and validate it as a promising therapeutic target. Furthermore, we establish a novel, plant-based A2-SPDELNVs-siPOLD1 delivery platform with effective BBB penetration and tumor targeting, offering a promising strategy for the treatment of glioma.
Insights
This study identifies DNA polymerase delta catalytic subunit 1 (POLD1) as an oncogene in glioma. A novel plant-derived nanoparticle system effectively targets POLD1, inhibiting glioma growth and improving survival.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Glioma, a prevalent central nervous system malignancy, demands novel targeted therapies due to its poor prognosis.
- The role of DNA polymerase delta catalytic subunit 1 (POLD1) in glioma pathogenesis is not well-defined.
- Plant-derived extracellular vesicles (PDEVs) offer biocompatible nanocarriers for targeted cancer therapy.
Purpose of the Study:
- To investigate the oncogenic function of POLD1 in glioma.
- To develop a PDEVs-based delivery system for targeted POLD1 inhibition in glioma.
- To enhance the therapeutic strategies for glioma treatment.
Main Methods:
- Analysis of POLD1 expression and prognostic value in clinical glioma samples and databases.
- In vitro assays (CCK-8, Transwell, flow cytometry) to assess POLD1 knockdown effects on glioma cell behavior.
- In vivo studies in mouse models to evaluate tumorigenesis and survival following POLD1 targeting.
- Isolation and characterization of sweet potato-derived nano-vesicles (SPDELNVs).
- Development and evaluation of an engineered A2-SPDELNVs-siPOLD1 system for targeted POLD1 silencing.
Main Results:
- POLD1 upregulation in glioma tissues correlates with poorer prognosis.
- POLD1 knockdown inhibits glioma cell proliferation, invasion, migration, and induces apoptosis and cell cycle arrest.
- Targeting POLD1 in vivo suppresses tumor growth and prolongs survival.
- SPDELNVs exhibit intrinsic anti-glioma activity and effective cellular uptake.
- The A2-SPDELNVs-siPOLD1 system efficiently delivers siRNA, silences POLD1, and significantly inhibits glioma progression in vitro and in vivo, improving survival.
Conclusions:
- POLD1 is confirmed as an oncogenic driver in glioma and a viable therapeutic target.
- A novel plant-based A2-SPDELNVs-siPOLD1 delivery platform demonstrates effective blood-brain barrier penetration and tumor targeting.
- This PDEVs-based strategy presents a promising new approach for glioma treatment.