三阴性乳腺癌（TNBC）是乳腺癌中最具侵袭性和致命性的亚型，其治疗效果令人失望且死亡率很高。肿瘤微环境（TME）通过多个复杂过程在TNBC的侵袭和转移中发挥着重要作用。大多数抗转移疗法仅关注癌细胞本身或干扰转移过程的单一因素，这通常与不良结果有关。因此，有效的 TNBC 治疗依赖于调节 TME 的多个关键转移相关方面。在此，设计了一种自靶向金属有机框架（MOF）纳米平台（命名为MTX-PEG@TPL@ZIF-8），旨在通过肿瘤微环境重塑和化疗增强来改善TNBC的治疗。自靶向 MOF 纳米平台由负载雷公藤内酯醇 (TPL) 的 ZIF-8 纳米颗粒组成，然后涂有甲氨蝶呤-聚乙二醇缀合物 (MTX-PEG)。由于MTX对肿瘤细胞表面过度表达的叶酸受体的亲和力，MTX-PEG@TPL@ZIF-8通过MTX介导的自靶向策略能够在肿瘤区域有效积累和深度渗透。由于 pH 触发的降解，这种 MOF 纳米平台可以在穿透肿瘤细胞后迅速释放药物。其抗转移机制是通过下调Vimentin、MMP-2和MMP-9的表达，增加E-cadherin的表达，上调cleaved caspase-3和cleaved caspase-9蛋白的表达来抑制肿瘤侵袭和转移。促进肿瘤细胞凋亡，从而减少其迁移。它还下调VEGF和CD31蛋白的表达，抑制新生血管的产生。总体而言，这些研究结果表明，自靶向 MOF 纳米平台为通过 TME 重塑和增强化疗治疗转移性 TNBC 提供了新见解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer with disappointing treatment and high mortality. Tumor microenvironment (TME) plays an important role in the invasion and metastasis of TNBC through multiple complex processes. Most anti-metastatic therapies only focus on cancer cells themselves or interfering with single factors of the metastasis process, which is often related to poor outcomes. Thus, effective TNBC treatment relies on regulating multiple key metastasis-related aspects of the TME. Herein, a self-targeting Metal-Organic Frameworks (MOFs) nanoplatform (named as MTX-PEG@TPL@ZIF-8) was designed to improve treatment of TNBC through tumor microenvironment remodeling and chemotherapy potentiation. The self-targeting MOF nanoplatform is consist of ZIF-8 nanoparticles loaded triptolide (TPL) and followed by the coating with methotrexate-polyethylene glycol conjugates (MTX-PEG). Due to MTX's affinity for the overexpressed folate receptor on tumor cell surfaces, MTX-PEG@TPL@ZIF-8 enables effective accumulation and deep penetration in the tumor area by an MTX-mediated self-targeting strategy. This MOF nanoplatform could promptly release the medication after penetrating the tumor cell, due to pH-triggered degradation. Its anti-metastasis mechanism is to inhibit tumor invasion and metastasis by down-regulating the expression of Vimentin, MMP-2 and MMP-9 and increasing the expression of E-cadherin, upregulation of cleaved caspase-3 and cleaved caspase-9 protein expression promote the apoptosis of tumor cells, thereby reducing their migration. It also downregulated the expression of VEGF and CD31 protein to inhibit the generation of neovascularization. Overall, these findings suggest the self-targeting MOF nanoplatform offers new insights into the treatment of metastatic TNBC by TME remodeling and potentiating chemotherapy.Copyright © 2024 Elsevier B.V. All rights reserved.