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Restoration of TP53 strategy via specific nanoparticles for ovarian cancer therapy
Menglei Zhang1,2, Yuanyuan Gu1,2, Fang Shen1,2
1Department of Gynecology, The Obstetrics and Gynecology Hospital of Fudan University, 419 Fang-Xie Road, Shanghai, 200011, P.R. China.
Abstract:
The p53 tumor suppressor gene, a master regulator of diverse cellular pathways, is frequently altered in various cancers. Loss of function in tumor suppressor genes is commonly associated with the onset/progression of cancer and treatment resistance. Currently, approaches for restoration of TP53 expression, including small molecules and DNA therapies, have yielded progressive success, but each has formidable drawbacks. Here, we introduced an endogenous nanoplatform to effectively deliver the TP53 protein. Briefly speaking, the endogenous TP53 proteins were fused by the Lamp2b and loaded into extracellular vesicles-based nanoparticles, which could markedly restore the TP53 expression in natural TP53-deficient ovarian cancer (OCs) and subsequently inhibit cell proliferation as well as induce cell apoptosis. Moreover, a well-known biotin streptavidin binding strategy was used to confer the nanoplatform targeting ability. Since mesothelin (MSLN) expressed highly in ovarian cancer, the anti-MSLN nanoplatform were engineered to deliver TP53 proteins to MSLN ovarian cancer and exert the anti-tumor ability. Our findings indicated that restoration of tumor suppressors by the targeting nanoplatform could be promising nanotechnology approaches for potential ovarian cancer treatment.
Insights
This study developed a novel nanoplatform using extracellular vesicles to deliver the TP53 protein, restoring its expression in ovarian cancer. This approach effectively inhibited cancer cell growth and promoted apoptosis, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Nanotechnology
- Biochemistry
Background:
- The p53 tumor suppressor gene is crucial in regulating cellular pathways and is frequently altered in cancers.
- Loss of tumor suppressor function contributes to cancer development, progression, and treatment resistance.
- Current TP53 restoration methods have limitations.
Purpose of the Study:
- To develop an endogenous nanoplatform for effective TP53 protein delivery.
- To restore TP53 expression in TP53-deficient ovarian cancer.
- To investigate the anti-tumor efficacy of targeted TP53 delivery.
Main Methods:
- Engineered extracellular vesicles-based nanoparticles loaded with TP53 protein fused to Lamp2b.
- Utilized a biotin-streptavidin binding strategy for targeted delivery.
- Targeted anti-mesothelin (MSLN) nanoplatforms for ovarian cancer treatment.
Main Results:
- The nanoplatform successfully restored TP53 expression in TP53-deficient ovarian cancer cells.
- TP53 delivery inhibited cancer cell proliferation and induced apoptosis.
- Targeted delivery to MSLN-expressing ovarian cancer demonstrated anti-tumor effects.
Conclusions:
- Restoring tumor suppressor function via targeted nanodelivery is a viable strategy.
- This nanotechnology approach shows promise for ovarian cancer treatment.
- The developed nanoplatform offers a potential new therapeutic avenue for ovarian cancer.
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