奥拉帕尼是一种聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂，已在携带乳腺癌基因（BRCA）突变的三阴性乳腺癌（TNBC）患者中表现出良好的疗效。然而，它对 BRCA 野生型 (BRCAwt) TNBC 的影响有限。因此，使 BRCAwt TNBC 细胞对奥拉帕尼敏感对于有效的临床实践至关重要。 Novobiocin 是一种 DNA 聚合酶 theta (POLθ) 抑制剂，对已对 PARP 抑制剂产生耐药性的 BRCA 突变癌细胞表现出敏感性。尽管这两种 DNA 修复抑制剂都显示出对 BRCA 突变癌症的治疗功效，但它们的纳米药物制剂对野生型癌症的抗肿瘤作用仍不清楚。此外，确保药物在癌症部位的有效积累和释放对于奥拉帕尼的临床应用至关重要。在此，我们设计了一种逐步拆卸的DNA修复抑制剂纳米系统，作为增强奥拉帕尼在BRCAwt TNBC中的有效性的新策略。该纳米系统能够在通过二硫键互连的超薄二氧化硅框架内协同递送两种DNA修复抑制剂奥拉帕尼和新生霉素。所设计的纳米系统表现出卓越的功能，包括长期分子存储和由肿瘤微环境触发的特定药物释放。此外，该纳米系统对 BRCAwt TNBC 细胞的细胞活力、增强 DNA 损伤的积累和促进细胞凋亡表现出有效的抑制作用。此外，该纳米系统在 BRCAwt TNBC 内有效积累，导致显着的生长抑制，并通过磁共振成像 (MRI) 评估显示出血管调节能力。我们的结果提供了首个证据，展示了逐步拆卸的 DNA 修复抑制剂纳米系统的潜力，如治疗 BRCA 野生型三阴性乳腺癌的一种有前景的策略。© 2023 Fang 等人。

Olaparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor has demonstrated promising efficacy in patients with triple-negative breast cancer (TNBC) carrying breast cancer gene (BRCA) mutations. However, its impact on BRCA wild-type (BRCAwt) TNBC is limited. Hence, it is crucial to sensitize BRCAwt TNBC cells to olaparib for effective clinical practice. Novobiocin, a DNA polymerase theta (POLθ) inhibitor, exhibits sensitivity towards BRCA-mutated cancer cells that have acquired resistance to PARP inhibitors. Although both of these DNA repair inhibitors demonstrate therapeutic efficacy in BRCA-mutated cancers, their nanomedicine formulations' antitumor effects on wild-type cancer remain unclear. Furthermore, ensuring effective drug accumulation and release at the cancer site is essential for the clinical application of olaparib.Herein, we designed a progressively disassembled nanosystem of DNA repair inhibitors as a novel strategy to enhance the effectiveness of olaparib in BRCAwt TNBC. The nanosystem enabled synergistic delivery of two DNA repair inhibitors olaparib and novobiocin, within an ultrathin silica framework interconnected by disulfide bonds.The designed nanosystem demonstrated remarkable capabilities, including long-term molecular storage and specific drug release triggered by the tumor microenvironment. Furthermore, the nanosystem exhibited potent inhibitory effects on cell viability, enhanced accumulation of DNA damage, and promotion of apoptosis in BRCAwt TNBC cells. Additionally, the nanosystem effectively accumulated within BRCAwt TNBC, leading to significant growth inhibition and displaying vascular regulatory abilities as assessed by magnetic resonance imaging (MRI).Our results provided the inaugural evidence showcasing the potential of a progressively disassembled nanosystem of DNA repair inhibitors, as a promising strategy for the treatment of BRCA wild-type triple-negative breast cancer.© 2023 Fang et al.