The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the “immune-cold” environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.

中文翻译：

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自噬抑制剂与免疫佐剂和抗 PD-L1 抗体在多功能纳米粒子中的组合用于增强乳腺癌免疫治疗

由于肿瘤特异性药物递送不佳和远隔效应，联合疗法在癌症治疗中的应用受到限制。在这里，使用聚乙烯亚胺和油酸 (PEI-OA) 的聚合物复合物开发了对 PD-L1 和 CD44 响应的多功能纳米粒子，并装载了两种化疗药物（紫杉醇和氯喹）、抗原（卵清蛋白）、免疫增强剂（CpG ) 和免疫检查点抑制剂（抗 PD-L1 抗体）。PEI-OA 极大地提高了纳米平台的载药能力和封装效率，而与其他治疗制剂相比，抗 PD-L1 抗体显着增加了其细胞摄取。药效学实验证实，抗 PD-L1 抗体可强烈抑制原发性乳腺癌，并提高肿瘤部位 CD4+ 和 CD8+ T 细胞的水平。此外，氯喹逆转了“免疫寒冷”环境，提高了化疗药物和免疫检查点抑制剂的抗肿瘤作用，同时增强了免疫记忆，防止了肺转移。我们的策略是合理设计纳米递送系统的一种有前景的方法，用于同时进行主动靶向、自噬抑制和化疗，可以与免疫检查点抑制剂结合以增强乳腺癌治疗。