Breast-to-brain metastatic cells can interact with the surrounding cells, including astrocytes and microglia, to generate a pro-tumorigenic niche. Breast-to-brain metastasis can be treated using a dual strategy of eliminating metastatic tumor cells and normalizing their localized microenvironment. The effective accumulation of drugs at the action site of metastasis is crucial to realizing the above strategy, especially when dealing with the blood-brain barrier (BBB)-penetrating and tumor-targeting tactics. Here, we establish an in-situ microenvironment-tailored micelle (T-M/siRNA) to co-deliver therapeutic siRNA and paclitaxel (PTX) into the breast-to-brain metastasis. Anchored with a D-type cyclic peptide, T-M/siRNA can penetrate the BBB and subsequently target the brain metastases. Upon internalization by metastatic tumor cells, T-M/siRNA can release PTX in the high-level glutathione (GSH), resulting in killing cancer cells. Meanwhile, the micellar structure is dissociated, resulting in lowering the charge density to release the loaded siRNA that can targeted downregulate the expression of protocadherin 7 (PCDH7). Treatment of model mice revealed that T-M/siRNA can inhibit the abnormal activation of astrocytes and immunosuppressive activation of microglia, resulting in significantly enhanced synergistic anti-tumor efficacy. This study indicates that the micelle system can serve as a hopeful strategy to treat breast-to-brain metastasis.

乳房-脑转移细胞可以与周围的细胞相互作用，包括星形胶质细胞和小胶质细胞，以产生促肿瘤生态位。可以使用消除转移性肿瘤细胞和使其局部微环境正常化的双重策略来治疗乳房-脑转移。药物在转移作用部位的有效积累对于实现上述策略至关重要，尤其是在应对血脑屏障 (BBB) 穿透和肿瘤靶向策略时。在这里，我们建立了一种原位微环境定制胶束 (TM/siRNA)，以将治疗性 siRNA 和紫杉醇 (PTX) 共同递送到乳腺-脑转移瘤中。用D锚定型环肽，TM/siRNA 可以穿透 BBB 并随后靶向脑转移。在被转移性肿瘤细胞内化后，TM/siRNA 可以在高水平谷胱甘肽 (GSH) 中释放 PTX，从而杀死癌细胞。同时，胶束结构解离，导致电荷密度降低，释放负载的 siRNA，可以靶向下调 protocadherin 7 (PCDH7) 的表达。对模型小鼠的治疗表明，TM/siRNA可以抑制星形胶质细胞的异常激活和小胶质细胞的免疫抑制激活，从而显着增强协同抗肿瘤功效。这项研究表明，胶束系统可以作为治疗乳腺-脑转移的一种有希望的策略。