BRCA1 Mutation-Recognizing Tetrahedral Framework Nucleic Acid Nanoplatform Enables Coordinated PARP/WEE1 Inhibition and STING-Associated Antitumor Immunity in Ovarian Cancer.
5 affiliations
- 1Laboratory of Gynecologic Oncology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical University, Fuzhou, China.
- 2Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, China.
- 3Fujian Key Laboratory of Women and Children's Critical Diseases Research, Fuzhou, China.
- 4School of Medicine, Fuzhou University, Fuzhou, China.
- 5MOE Key Laboratory For Analytical Science of Food Safety and Biology, Fujian Key Laboratory of Analysis and Testing Technology For Food Safety and Health, College of Chemistry, Fuzhou University, Fuzhou, China.
Abstract
Improving therapeutic efficacy and antitumor immune responsiveness in BRCA1-mutant ovarian cancer remains challenging. Here, we developed a BRCA1 mutation-guided tetrahedral framework nucleic acid nanosystem, FBOA-tFNA, for coordinated intracellular delivery of the PARP inhibitor olaparib and the WEE1 inhibitor adavosertib. After folate receptor-mediated uptake, FBOA-tFNA recognizes BRCA1 mutant RNA through toehold-mediated strand displacement, enabling mutation-selective beacon activation, while drug release is independently regulated by reduction-responsive disulfide cleavage. Coordinated PARP/WEE1 inhibition amplified DNA damage, impaired G2/M checkpoint protection, and promoted tumor-cell killing in BRCA1-mutant ovarian cancer models. Resulting DNA damage-associated intracellular dsDNA signals activated STING-associated signaling, type I interferon responses, immunogenic cell death (ICD)-associated stress, dendritic-cell maturation, and CD8⁺ T-cell activation. Engineered patient-derived ovarian cancer organoids expressing a BRCA12594delC-containing transcript further supported the mutation-selective recognition and therapeutic potential of FBOA-tFNA ex vivo. In vivo, FBOA-tFNA showed tumor-associated fluorescence accumulation, BRCA1 mutant-transcript recognition-associated beacon activation, enhanced antitumor efficacy, and preliminary repeated-dose tolerability. Moreover, FBOA-tFNA enhanced antitumor immune responses and improved the response to anti-PD-1 therapy, accompanied by increased effector and memory-like T-cell populations. This programmable DNA nanoplatform provides a personalized combination strategy for coordinated DNA-damage therapy and immunomodulation in BRCA1-mutant ovarian cancer.
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BibTeX
@article{wang2026brca1,
title = {{BRCA1 Mutation-Recognizing Tetrahedral Framework Nucleic Acid Nanoplatform Enables Coordinated PARP/WEE1 Inhibition and STING-Associated Antitumor Immunity in Ovarian Cancer.}},
author = {Chenyi Wang and Mengying Yao and Jinhui Xie and Dingjie Wang and Yashi Shi and Xiaodan Mao and Chunhua Lu and Pengming Sun},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.78457},
url = {https://europepmc.org/article/MED/42952168},
note = {CC BY},
}
RIS
TY - JOUR
TI - BRCA1 Mutation-Recognizing Tetrahedral Framework Nucleic Acid Nanoplatform Enables Coordinated PARP/WEE1 Inhibition and STING-Associated Antitumor Immunity in Ovarian Cancer.
AU - Chenyi Wang
AU - Mengying Yao
AU - Jinhui Xie
AU - Dingjie Wang
AU - Yashi Shi
AU - Xiaodan Mao
AU - Chunhua Lu
AU - Pengming Sun
PY - 2026
DA - 2026/10/28
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.78457
UR - https://europepmc.org/article/MED/42952168
AB - Improving therapeutic efficacy and antitumor immune responsiveness in BRCA1-mutant ovarian cancer remains challenging. Here, we developed a BRCA1 mutation-guided tetrahedral framework nucleic acid nanosystem, FBOA-tFNA, for coordinated intracellular delivery of the PARP inhibitor olaparib and the WEE1 inhibitor adavosertib. After folate receptor-mediated uptake, FBOA-tFNA recognizes BRCA1 mutant RNA through toehold-mediated strand displacement, enabling mutation-selective beacon activation, while drug release is independently regulated by reduction-responsive disulfide cleavage. Coordinated PARP/WEE1 inhibition amplified DNA damage, impaired G2/M checkpoint protection, and promoted tumor-cell killing in BRCA1-mutant ovarian cancer models. Resulting DNA damage-associated intracellular dsDNA signals activated STING-associated signaling, type I interferon responses, immunogenic cell death (ICD)-associated stress, dendritic-cell maturation, and CD8⁺ T-cell activation. Engineered patient-derived ovarian cancer organoids expressing a BRCA12594delC-containing transcript further supported the mutation-selective recognition and therapeutic potential of FBOA-tFNA ex vivo. In vivo, FBOA-tFNA showed tumor-associated fluorescence accumulation, BRCA1 mutant-transcript recognition-associated beacon activation, enhanced antitumor efficacy, and preliminary repeated-dose tolerability. Moreover, FBOA-tFNA enhanced antitumor immune responses and improved the response to anti-PD-1 therapy, accompanied by increased effector and memory-like T-cell populations. This programmable DNA nanoplatform provides a personalized combination strategy for coordinated DNA-damage therapy and immunomodulation in BRCA1-mutant ovarian cancer.
SN - 2198-3844
ER -