Cuprotosis在肺转移治疗中显示出巨大的应用前景。然而，糖酵解、铜外流机制和肺部药物积累不足严重限制了铜凋亡的功效。在此，构建了一种可吸入的聚（2-（N-氧化物-N,N-二乙基氨基）乙基甲基丙烯酸酯）（OPDEA）包被的铜基金属有机框架，封装了丙酮酸脱氢酶激酶1 siRNA（siPDK），用于介导铜凋亡，随后促进肺转移的免疫疗法，即OMP。吸入后，OMP 显示出高效的肺部积聚和长期保留，这归因于 OPDEA 介导的肺粘膜渗透。在肿瘤细胞内，OMP在酸性条件下降解释放出Cu2+，Cu2+在谷胱甘肽（GSH）的调节下被还原为有毒的Cu，诱导铜凋亡。同时，OMP释放的siPDK抑制细胞内糖酵解和5'-三磷酸腺苷（ATP）的产生，然后阻断Cu流出蛋白ATP7B，从而使肿瘤细胞对OMP介导的铜凋亡更加敏感。此外，OMP 介导的铜凋亡会触发免疫原性细胞死亡 (ICD)，从而促进树突状细胞 (DC) 成熟和 CD8 T 细胞浸润。值得注意的是，OMP 诱导的铜凋亡上调膜相关程序性细胞死亡配体 1 (PD-L1) 的表达并诱导可溶性 PD-L1 分泌，从而与抗 PD-L1 抗体 (aPD-L1) 协同作用以重新编程免疫抑制肿瘤微环境，最终提高免疫治疗效果。总体而言，OMP 可以作为一种高效的可吸入纳米平台，通过诱导铜凋亡并与 aPD-L1 结合，提供更好的抗肺转移功效。© 2024 作者。

Cuproptosis shows enormous application prospects in lung metastasis treatment. However, the glycolysis, Cu+ efflux mechanisms, and insufficient lung drug accumulation severely restrict cuproptosis efficacy. Herein, an inhalable poly (2-(N-oxide-N,N-diethylamino)ethyl methacrylate) (OPDEA)-coated copper-based metal-organic framework encapsulating pyruvate dehydrogenase kinase 1 siRNA (siPDK) is constructed for mediating cuproptosis and subsequently promoting lung metastasis immunotherapy, namely OMP. After inhalation, OMP shows highly efficient lung accumulation and long-term retention, ascribing to the OPDEA-mediated pulmonary mucosa penetration. Within tumor cells, OMP is degraded to release Cu2+ under acidic condition, which will be reduced to toxic Cu+ to induce cuproptosis under glutathione (GSH) regulation. Meanwhile, siPDK released from OMP inhibits intracellular glycolysis and adenosine-5'-triphosphate (ATP) production, then blocking the Cu+ efflux protein ATP7B, thereby rendering tumor cells more sensitive to OMP-mediated cuproptosis. Moreover, OMP-mediated cuproptosis triggers immunogenic cell death (ICD) to promote dendritic cells (DCs) maturation and CD8+ T cells infiltration. Notably, OMP-induced cuproptosis up-regulates membrane-associated programmed cell death-ligand 1 (PD-L1) expression and induces soluble PD-L1 secretion, and thus synergizes with anti-PD-L1 antibodies (aPD-L1) to reprogram immunosuppressive tumor microenvironment, finally yielding improved immunotherapy efficacy. Overall, OMP may serve as an efficient inhalable nanoplatform and afford preferable efficacy against lung metastasis through inducing cuproptosis and combining with aPD-L1.© 2024 The Authors.