三阴性乳腺癌 (TNBC) 含有高比例的乳腺癌干细胞样细胞 (BCSC)，这会导致疾病的不良预后、转移和复发。因此，针对 BCSC 可能是对抗 TNBC 的一种有前途的方法。在此背景下，我们研究了印楝内酯 (Nim)，这是一种柠檬苦素三萜类化合物，具有有效的抗癌特性，但较差的药代动力学和低生物利用度限制了其治疗应用。因此，为了增强 Nim 的治疗潜力，我们配制了 Nim 封装的聚乳酸-乙醇酸 (PLGA) 纳米颗粒 (Nim NP)，并在体外和体内评估了抗癌干细胞 (CSC) 效果。体外研究表明，与天然 Nim 相比，Nim NP 显着抑制 BCSC 的几个固有特征，例如干性、自我更新性、化疗耐药性、上皮间质转化 (EMT) 和迁移。接下来，探讨了 Nim 抗 CSC 作用背后的机制。从机制上讲，我们发现 Nim 通过下调 DNA 甲基转移酶 (DNMT) 来表观遗传恢复肿瘤抑制基因分泌型卷曲相关蛋白 1 (SFRP1) 的表达，从而抑制 Wnt/β-catenin 信号传导。此外，体内结果表明，在两个临床前模型中，与天然 Nim 相比，Nim NP 表现出增强的抗肿瘤和抗转移作用，且没有任何全身毒性。总体而言，这些发现提供了概念证明，即基于 Nim 的植物纳米药物可以通过 DNMTs-SFRP1-Wnt/β-catenin 信号轴的表观遗传重编程来抑制 BCSC。© 2023 作者。

Triple-negative breast cancer (TNBC) harbors a high percentage of breast cancer stem-like cells (BCSCs) that significantly contribute to poor prognosis, metastasis, and relapse of the disease. Thus, targeting BCSCs could be a promising approach to combat TNBC. In this context, we investigated nimbolide (Nim), a limonoid triterpenoid that has potent anticancer properties, but poor pharmacokinetics and low bioavailability limit its therapeutic application. So, to enhance the therapeutic potential of Nim, Nim-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Nim NPs) were formulated and the anticancer stem cell (CSC) effects evaluated in vitro and in vivo. In vitro studies suggested that Nim NPs significantly inhibited several inherent characteristics of BCSCs, such as stemness, self-renewability, chemoresistance, epithelial-to-mesenchymal transition (EMT), and migration in comparison to native Nim. Next, the mechanism behind the anti-CSC effect of Nim was explored. Mechanistically, we found that Nim epigenetically restores tumor suppressor gene secreted frizzled-related protein 1 (SFRP1) expression by downregulating DNA methyltransferases (DNMTs), leading to Wnt/β-catenin signaling inhibition. Further, in vivo results demonstrated that Nim NPs showed enhanced anti-tumor and anti-metastatic effects compared to native Nim in two preclinical models without any systemic toxicity. Overall, these findings provide proof of concept that Nim-based phytonanomedicine can inhibit BCSCs by epigenetic reprogramming of the DNMTs-SFRP1-Wnt/β-catenin signaling axis.© 2023 The Authors.