Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments. Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood‒tumor barrier (BTB). BTB activates its Wnt signaling to maintain barrier properties, , Mfsd2a-mediated BTB low transcytosis. Here, we reported VCAM-1-targeting nano-wogonin (W@V-NPs) as an adjuvant of nano-orlistat (O@V-NPs) to intensify drug delivery and inhibit lipogenesis of brain metastases. W@V-NPs were proven to be able to inactivate BTB Wnt signaling, downregulate BTB Mfsd2a, accelerate BTB vesicular transport, and enhance tumor accumulation of O@V-NPs. With the ability to specifically kill cancer cells in a lipid-deprived environment with IC at 48 ng/mL, W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice. The combination did not induce brain edema, cognitive impairment, and systemic toxicity in healthy mice. Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

中文翻译：

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抑制血肿瘤屏障的 Wnt 信号传导以强化药物输送并抑制脑转移瘤的脂肪生成

乳腺癌脑转移瘤中的脂肪生成通常高度上调，以适应颅内低脂微环境。脂肪酶抑制剂具有治疗潜力，但其在肿瘤内的分布常常被血肿瘤屏障（BTB）阻断。 BTB 激活其 Wnt 信号传导以维持屏障特性，Mfsd2a 介导的 BTB 低转胞吞作用。在这里，我们报道了以 VCAM-1 为靶点的纳米汉黄芩素 (W@V-NPs) 作为纳米奥利司他 (O@V-NPs) 的佐剂，以强化药物输送并抑制脑转移瘤的脂肪生成。 W@V-NPs 被证明能够灭活 BTB Wnt 信号传导、下调 BTB Mfsd2a、加速 BTB 囊泡运输并增强 O@V-NPs 的肿瘤积累。 W@V-NPs 和 O@V-NPs 能够在 IC 为 48 ng/mL 的缺脂环境中特异性杀死癌细胞，从而抑制脑转移的进展，延长模型小鼠的存活时间。该组合不会引起健康小鼠的脑水肿、认知障碍和全身毒性。靶向 Wnt 信号传导可以安全地调节 BTB，以改善针对脑转移的药物输送和代谢治疗。