三阴性乳腺癌（TNBC）缺乏靶向治疗，导致患有这种侵袭性疾病的患者临床预后不佳。治疗干预的一个有希望的目标是 Wnt 信号通路，当细胞外 Wnt 配体与过度表达的 Frizzled7 (FZD7) 跨膜受体结合时，该通路在 TNBC 细胞中被激活。这可以稳定细胞内的 β-连环蛋白，从而促进癌基因的转录，从而驱动肿瘤生长和转移。为了抑制 TNBC 细胞中的 Wnt 信号传导，我们开发了用 FZD7 抗体和 β-连环蛋白小干扰 RNA (siRNA) 功能化的治疗性纳米粒子 (NP)。这些抗体能够实现 TNBC 细胞特异性结合，并通过将 FZD7 受体锁定在配体无反应状态来抑制 Wnt 信号传导，而 siRNA 通过 RNA 干扰抑制 β-连环蛋白。与单独包被抗体或 siRNA 的 NP 相比，包被两种试剂的 NP 更有效地降低 TNBC 细胞中几种 Wnt 相关基因的表达，从而更大程度地抑制细胞增殖、迁移和球体形成。在两个转移性 TNBC 小鼠模型中，双抗体/siRNA 纳米载体在抑制肿瘤生长、转移和复发方面优于对照。这些发现表明，通过抗体/siRNA 纳米载体在受体和 mRNA 水平抑制 Wnt 信号传导是对抗 TNBC 的一种有前途的方法。

The paucity of targeted therapies for triple-negative breast cancer (TNBC) causes patients with this aggressive disease to suffer a poor clinical prognosis. A promising target for therapeutic intervention is the Wnt signaling pathway, which is activated in TNBC cells when extracellular Wnt ligands bind overexpressed Frizzled7 (FZD7) transmembrane receptors. This stabilizes intracellular β-catenin proteins that in turn promote transcription of oncogenes that drive tumor growth and metastasis. To suppress Wnt signaling in TNBC cells, we developed therapeutic nanoparticles (NPs) functionalized with FZD7 antibodies and β-catenin small interfering RNAs (siRNAs). The antibodies enable TNBC cell-specific binding and inhibit Wnt signaling by locking FZD7 receptors in a ligand unresponsive state, while the siRNAs suppress β-catenin through RNA interference. Compared to NPs coated with antibodies or siRNAs individually, NPs coated with both agents more potently reduce the expression of several Wnt related genes in TNBC cells, leading to greater inhibition of cell proliferation, migration, and spheroid formation. In two murine models of metastatic TNBC, the dual antibody/siRNA nanocarriers outperformed controls in terms of inhibiting tumor growth, metastasis, and recurrence. These findings demonstrate suppressing Wnt signaling at both the receptor and mRNA levels via antibody/siRNA nanocarriers is a promising approach to combat TNBC.