Antiangiogenic therapy with bevacizumab while being interesting for metastatic triple-negative breast cancer (mTNBC) is restrained by tumor hypoxia elevation and cancer stem cell enrichment. Here, we find that neuropilin-1 (NRP-1)-targeted delivery of nucleus accumbens-associated protein-1 (NAC-1) siRNA mediated by tLyP-1 peptide-functionalized chimaeric polymersomes (tLyP-1-Ps) effectively sensitizes antiangiogenic therapy of mTNBC in vivo. tLyP-1-Ps showed good encapsulation (up to 14.4 wt. %) of siNAC-1, giving robust tLyP-1-Ps-siNAC-1 nanoformulation with a defined size of 48.5 nm (PDI = 0.13) and a surface charge of −9.2 mV, and mediated efficient cytoplasmic transportation of siNAC-1 in MDA-MB-231 TNBC cells, resulting in significant silencing of NAC-1 mRNA and the corresponding oncoprotein. Transwell invasion and wound healing assays revealed that tLyP-1-Ps-siNAC-1 potently inhibited MDA-MB-231 cell invasion and migration. Intriguingly, tLyP-1-Ps-siNAC-1 was shown to markedly improve the bevacizumab therapy of mTNBC, significantly curbing lung metastasis and prolonging the survival time of the MDA-MB-231 metastatic model. The combination of targeted NAC-1 gene silencing and antiangiogenic therapy appears to be an innovative treatment for mTNBC.

中文翻译：

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NAC-1 siRNA的神经纤维蛋白靶向的聚合物小体的系统性输送可提高转移性​​三阴性乳腺癌的抗血管生成治疗的敏感性。

贝伐单抗的抗血管生成治疗虽然对转移性三阴性乳腺癌（mTNBC）很有用，但它受肿瘤缺氧升高和癌干细胞富集的限制。在这里，我们发现由tLyP-1肽功能化的嵌合聚合物小体（tLyP-1-Ps）介导的伏安核相关蛋白1（NAC-1）siRNA的神经纤维蛋白1（NRP-1）靶向递送有效地使抗血管生成性mTNBC体内治疗。tLyP-1-Ps表现出良好的包封性（最高14.4 wt。％）的siNAC-1，可提供功能强大的tLyP-1-Ps-siNAC-1纳米制剂，定义的大小为48.5 nm（PDI = 0.13），表面电荷为-9.2 mV，并介导siNAC-1在细胞内的高效胞质转运MDA-MB-231 TNBC细胞，导致NAC-1 mRNA和相应癌蛋白的显着沉默。Transwell侵袭和伤口愈合实验表明，tLyP-1-Ps-siNAC-1有效抑制MDA-MB-231细胞的侵袭和迁移。有趣的是，tLyP-1-Ps-siNAC-1被证明可以显着改善mTNBC的贝伐单抗治疗，显着抑制肺转移并延长MDA-MB-231转移模型的生存时间。靶向NAC-1基因沉默和抗血管生成疗法的结合似乎是mTNBC的创新疗法。