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

## TL;DR

This study shows that targeting mutant p53 and SNRPD2 with engineered exosomes can suppress ovarian cancer growth and improve chemotherapy response.

## Contribution

The novel approach of co-targeting mutant p53 and SNRPD2 via engineered exosomes to modulate splicing in ovarian cancer is introduced.

## Key findings

- SNRPD2 is a binding partner of mutant p53 and promotes ovarian cancer progression.
- Co-targeting mutant p53 and SNRPD2 with engineered exosomes restores tumor-suppressive mRNA isoforms and enhances chemotherapy sensitivity.
- Engineered exosomes effectively suppress ovarian cancer growth in vivo.

## 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 pre‐mRNAs. 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.

Mutant p53 drives oncogenic splicing to promote the progression of ovarian cancer by partnering with the spliceosome factor SNRPD2. Therefore, it is engineered iRGD‐exosomes to co‐deliver siRNAs against both targets. This approach restored tumor‐suppressive mRNA isoforms, effectively enhanced sensitivity to cisplatin, and ultimately blocked tumor progression.