Abstract：
The therapeutic efficacy of cuproptosis combined with phototheranostics is still hindered by easy copper efflux, nonspecific accumulation and limited light penetration depth. Here, a high-performance NIR-II semiconductor polymer was first synthesized through dual-donor engineering. Then a biomimetic cuproptosis amplifier (PCD@CM) was prepared by Cu(II)-mediated coordinative self-assembly of NIR-II ultrasmall polymer dots and the chemotherapeutic drug DOX, followed by camouflaging of tumor cell membranes. After homologous targeting delivery to tumor cells, overexpressed GSH in the tumor microenvironment (TME) triggers the disassembly of the amplifier and the release of therapeutic components through the reduction of Cu(II) to Cu(I), which enable NIR-II fluorescence/photoacoustic imaging-guided NIR-II photothermal therapy (PTT) and chemotherapy. The released Cu(I) induces the aggregation of lipoylated mitochondrial proteins accompanied by the loss of iron-sulfur proteins, leading to severe proteotoxic stress and eventually cuproptosis. NIR-II PTT and GSH depletion render tumor cells more sensitive to cuproptosis. The amplified cuproptosis sensitization provokes significant immune surveillance, triggering the immunogenic cell death (ICD) to promote cytotoxic T lymphocyte infiltration together with aPD-L1-mediated immune checkpoint blockade. This work proposes a new strategy to develop cuproptosis sensitization systems enhanced by NIR-II phototheranostics with homologous targeting and anti-tumor immune response capabilities.
摘要：
趋化联合光疗的治疗效果仍然受到容易的铜流出的阻碍，非特异性积累和有限的光穿透深度。这里,首先通过双供体工程合成了高性能的NIR-II半导体聚合物。然后通过Cu（II）介导的NIR-II超小聚合物点与化疗药物DOX的协同自组装制备了仿生角化放大器（PCD@CM），然后伪装肿瘤细胞膜.同源靶向递送至肿瘤细胞后，肿瘤微环境（TME）中过度表达的GSH通过将Cu（II）还原为Cu（I）触发放大器的分解和治疗成分的释放，这使得NIR-II荧光/光声成像引导的NIR-II光热治疗（PTT）和化疗成为可能。释放的Cu（I）诱导脂质化线粒体蛋白的聚集，伴随着铁硫蛋白的损失，导致严重的蛋白毒性应激和最终的角化。NIR-IIPTT和GSH耗竭使肿瘤细胞对角化更敏感。扩增的角化致敏引起显著的免疫监视，触发免疫原性细胞死亡（ICD）以促进细胞毒性T淋巴细胞浸润以及aPD-L1介导的免疫检查点阻断。这项工作提出了一种新的策略，以开发具有同源靶向和抗肿瘤免疫反应能力的NIR-II光疗增强的角化增敏系统。
