Dual Targeting of Mutant p53 and SNRPD2 via Engineered Exosomes Modulates Alternative Splicing to Suppress Ovarian Cancer

Sep 22, 2026

Mutation of the tumor suppressor gene TP53 promotes ovarian cancer progression and therapeutic resistance, yet whether mutant p53 controls alternative splicing and how to leverage this for treatment remains unclear. SNRPD2 is identified as a binding partner of mutant p53, is highly expressed and linked to poor prognosis, and functionally drives ovarian cancer cell growth and migration. Mechanistically, mutant p53 and SNRPD2 cooperate to assemble the Sm/SMN spliceosomal complex, shifting alternative splicing to reduce oncogenic transcripts and increase tumor suppressor counterparts. Engineered exosomes decorated with iRGD and loaded with siRNAs against mutant p53 and SNRPD2 suppress tumor cell growth and improve chemosensitivity in vivo. Overall, co-targeting these regulators via engineered exosomes provides a potential therapeutic strategy for ovarian cancer.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

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Abstract

Introduction

Ovarian cancer burden and TP53 mutations

Alternative splicing and cancer resistance

Mutant p53 and RNA splicing regulation

SNRPD2/SmD2 as a spliceosomal Sm protein component

Advanced Science [www.advancedscience.com](www.advancedscience.com) RESEARCH ARTICLE Dual Targeting of Mutant p53 and SNRPD2 via Engineered Exosomes Modulates Alternative Splicing to Suppress Ovarian Cancer Wei Zhao1, 2, 3 Qian Hao4, 5 Yu Gan4, 5 Jing Tong4, 5 Xiaodan Chen1, 2, 3 Shuran Tan1, 2, 3 Ruiwen Ruan6, 7 Yingdan Huang4, 5 Mingming Cao4, 5 Jun Deng6, 7 Tao Han8 Getao Shi9 Bo Gao9 Yu Zhang1, 2, 3 Xiang Zhou4, 5, 10 1 Department of Gynecology, Xiangya Hospital, Central South University, Changsha, China 2 Gynecological Oncology Research and Engineering Center of Hunan Province, Changsha, China 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China 4 Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, China 5 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 6 Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China 7Jiangxi Key Laboratory For Individual Cancer Therapy, Nanchang, Jiangxi, China 8Xinxiang Key laboratory For Molecular Oncology, Institutes of Health Central Plains, Xinxiang Medical University, Xinxiang, China 9Umibio Co. Ltd., Shanghai, China 10 Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China Correspondence: Bo Gao ([bogao@umibio.cn](bogao@umibio.cn)) Yu Zhang (xyzhangyu@csu.edu.cn) Xiang Zhou (xiangzhou@fudan.edu.cn) Received: 16 July 2025 Revised: 12 December 2025 Accepted: 6 January 2026 Keywords: alternative splicing | engineered exosomes | p53 | SNRPD2 | targeted therapy ABSTRACT Mutation of the tumor suppressor gene TP53 promotes ovarian cancer progression and therapeutic resistance. Whether mutant p53 (mtp53) regulates alternative splicing and how this regulation can be exploited for cancer therapy remain unclear. Here, small nuclear ribonucleoprotein D2 polypeptide (SNRPD2) as a binding partner of mtp53 is identified. SNRPD2 is highly expressed in ovarian cancer and associated with an unfavorable prognosis. The overexpression of SNRPD2 promotes, whereas its depletion inhibits, the growth and migration of ovarian cancer cells. Mechanistically, mtp53 cooperates with SNRPD2 to facilitate the assembly of the Sm/SMN protein complex, an essential component of the spliceosome, modulating alternative splicing of premRNAs. Specifically, the co-depletion of mtp53 and SNRPD2 reduces the level of OTUD3 oncogenic transcripts while increasing its tumor suppressor counterparts through an exon-skipping event. Moreover, therapeutic engineered exosomes are developed with their surfaces decorated with iRGD and their interiors loaded with siRNAs targeting mtp53 and SNRPD2 . These exosomes effectively suppress the growth of ovarian cancer cells and enhance their sensitivity to chemotherapy in vivo. Collectively, this study uncovers that mtp53 and SNRPD2 cooperatively regulate alternative splicing to drive ovarian cancer progression, and co-targeting these two molecules via engineered exosomes represents a potential therapeutic strategy for ovarian cancer. 1 Introduction Ovarian cancer, characterized by frequent relapse and inherent chemotherapy resistance, ranks among the most lethal gynecological malignancies [1] . Despite the continuous development of novel therapeutic strategies, clinical management remains severely challenged by the high relapse rate and chemotherapy resistance [2–4] . TP53 mutations represent a cornerstone molecular alteration in ovarian cancer (OC), particularly in high-grade serous ovarian carcinoma (HGSOC), with profound clinical and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is pr

FAQs

What role does mutant p53 play in ovarian cancer alternative splicing?

The study investigates whether mutant p53 regulates alternative splicing and proposes that mutant p53 cooperates with SNRPD2 to modulate spliceosome activity and splicing outcomes relevant to tumor progression.

How does SNRPD2 affect ovarian cancer cells?

SNRPD2 is highly expressed in ovarian cancer and is associated with an unfavorable prognosis; overexpression promotes, while depletion inhibits, ovarian cancer cell growth and migration.

How do engineered exosomes target mtp53 and SNRPD2 therapeutically?

Engineered exosomes are decorated with iRGD and loaded with siRNAs targeting mtp53 and SNRPD2, which suppress ovarian cancer cell growth and enhance chemosensitivity in vivo.

Sep 22, 2026

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