BRCA1 Mutation‐Recognizing Tetrahedral Framework Nucleic Acid Nanoplatform Enables Coordinated PARP/WEE1 Inhibition and STING‐Associated Antitumor Immunity in Ovarian Cancer

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 BRCA1 ^2594delC ‐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.