共同递送多种药物或规避药物流出机制可以显着降低多药耐药性（MDR），这是癌症治疗失败的主要原因。在这项研究中，我们使用计算机辅助策略设计并制造了一种通用的“三合一”自我递送系统，用于协同癌症治疗。首先，我们设计了两种谷胱甘肽 (GSH) 响应性异二聚体，ERL-SS-CPT（厄洛替尼 [ERL] 通过二硫键 [SS] 与喜树碱 [CPT] 连接）和 CPT-SS-ERI（CPT 与毛兰素 [ERI 缀合） ]），既可用作货物又可用作载体材料。接下来，分子动力学模拟表明，多种非共价分子力，包括π-π堆积、氢键、疏水相互作用和硫键，驱动这些异二聚体的自组装过程。然后，我们探索了异二聚体的普遍性，并开发了包含 40 种变体的“三元”药物递送平台。随后，我们对负载多西紫杉醇（DTX）的ERL-SS-CPT纳米颗粒（表示为DTX@ERL-SS-CPT NP）和负载姜黄素（CUR）的ERL-SS-CPT纳米颗粒（表示为CUR@CPT）进行了案例研究。 -SS-ERI NPs）全面研究其自组装机制、理化性质、储存稳定性、GSH响应性药物释放、细胞摄取、凋亡效应、生物相容性和细胞毒性。两种纳米颗粒均表现出清晰的球形结构、高载药量和优异的储存稳定性。 DTX@ERL-SS-CPT NPs 在 A549 细胞中表现出最强的细胞毒性，顺序为 DTX@ERL-SS-CPT NPs > ERL-SS-CPT NPs > CPT > DTX > ERL。相反，DTX@ERL-SS-CPT NPs 在正常人支气管上皮细胞系（BEAS-2B）中表现出可忽略不计的细胞毒性，表明其具有良好的生物相容性和安全性。对 CUR@CPT-SS-ERI NP 的生物相容性和细胞毒性也进行了类似的观察。内吞作用和遇到细胞内过表达的 GSH 时，二硫键接头被裂解，导致多功能纳米颗粒释放成三部分。球形纳米粒子增强了水溶性，减少了游离药物的所需剂量，增加了细胞药物积累，同时抑制了P-糖蛋白（P-gp）的表达，导致细胞凋亡。这项工作提供了一种计算机辅助通用策略——基于异二聚体的“三元”药物递送平台——以提高抗癌效率，同时减少多药耐药性。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Co-delivering multiple drugs or circumventing the drug efflux mechanism can significantly decrease multidrug resistance (MDR), a major cause of cancer treatment failure. In this study, we designed and fabricated a universal "three-in-one" self-delivery system for synergistic cancer therapy using a computer-aided strategy. First, we engineered two glutathione (GSH)-responsive heterodimers, ERL-SS-CPT (erlotinib [ERL] linked with camptothecin [CPT] via a disulfide bond [SS]) and CPT-SS-ERI (CPT conjugated with erianin [ERI]), which serve as both cargo and carrier material. Next, molecular dynamics simulations indicated that multiple noncovalent molecular forces, including π-π stacking, hydrogen bonds, hydrophobic interactions, and sulfur bonds, drive the self-assembly process of these heterodimers. We then explored the universality of the heterodimers and developed a "triadic" drug delivery platform comprising 40 variants. Subsequently, we conducted case studies on docetaxel (DTX)-loaded ERL-SS-CPT nanoparticles (denoted as DTX@ERL-SS-CPT NPs) and curcumin (CUR)-loaded ERL-SS-CPT NPs (identified as CUR@CPT-SS-ERI NPs) to comprehensively investigate their self-assembly mechanism, physicochemical properties, storage stability, GSH-responsive drug release, cellular uptake, apoptosis effects, biocompatibility, and cytotoxicity. Both NPs exhibited well-defined spherical structures, high drug loading rates, and excellent storage stability. DTX@ERL-SS-CPT NPs exhibited the strongest cytotoxicity in A549 cells, following the order of DTX@ERL-SS-CPT NPs > ERL-SS-CPT NPs > CPT > DTX > ERL. Conversely, DTX@ERL-SS-CPT NPs showed negligible cytotoxicity in normal human bronchial epithelium cell line (BEAS-2B), indicating good biocompatibility and safety. Similar observations were made for CUR@CPT-SS-ERI NPs regarding biocompatibility and cytotoxicity. Upon endocytosis and encountering intracellular overexpressed GSH, the disulfide-bond linker is cleaved, resulting in the release of the versatile NPs into three parts. The spherical NPs enhance water solubility, reduce the required dosage of free drugs, and increase cellular drug accumulation while suppressing P-glycoprotein (P-gp) expression, leading to apoptosis. This work provides a computer-aided universal strategy-a heterodimer-based "triadic" drug delivery platform-to enhance anticancer efficiency while reducing multidrug resistance.Copyright © 2024 Elsevier Inc. All rights reserved.