The intracellular retention of nanotherapeutics is essential for their therapeutic activity. The immobilization of nanotherapeutics inside target cell types can regulate various cell behaviors. However, strategies for the intracellular immobilization of nanoparticles are limited. Herein, a cisplatin prodrug was synthesized and utilized as a glutathione (GSH)-activated linker to induce aggregation of the cisplatin prodrug/IR820/docetaxel nanoassembly. The nanoassembly has been reprogrammed with peptide-containing moieties for tumor-targeting and PD-1/PD-L1 blockade. The aggregation of the nanoassemblies is dependent on GSH concentration. Evaluations in vitro and in vivo revealed that GSH-induced intracellular aggregation of the nanoassemblies enhances therapeutic activity in primary tumors by enhancing the accumulation and prolonging the retention of the chemotherapeutics in the tumor site and inducing reactive oxygen species (ROS) generation and immunogenic cell death. Moreover, the nanoassemblies reinvigorate the immunocytes, especially the systemic immunocytes, and thereby alleviate pulmonary metastasis, even though the population of immunocytes in the primary tumor site is suppressed due to the enhanced accumulation of chemotherapeutics. This strategy provides a promising option for the intracellular immobilization of nanoparticles in vitro and in vivo.

纳米治疗药物的细胞内滞留对其治疗活性至关重要。将纳米治疗剂固定在靶细胞类型内可以调节各种细胞行为。然而，纳米颗粒的细胞内固定化策略是有限的。在此，合成了顺铂前药并用作谷胱甘肽（GSH）激活的接头以诱导顺铂前药/IR820/多西他赛纳米组装体的聚集。该纳米组装体已用含肽部分重新编程，用于肿瘤靶向和 PD-1/PD-L1 阻断。纳米组件的聚集取决于 GSH 浓度。体外和体内评估揭示了 GSH 诱导的纳米组件的细胞内聚集通过增强积聚和延长化疗药物在肿瘤部位的保留时间和诱导活性氧 (ROS) 生成和免疫原性细胞死亡来增强原发性肿瘤的治疗活性。此外，即使由于化学治疗剂的积累增强，原发肿瘤部位的免疫细胞群受到抑制，纳米组装体也能重新激活免疫细胞，尤其是全身免疫细胞，从而减轻肺转移。该策略为体外和体内纳米粒子的细胞内固定提供了一个有前途的选择。