The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side effects. RNA interference (RNAi) targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy, thus enable sustained and efficient immune checkpoint blockade (ICB) to active antitumor immune response. Herein, we designed a glutathione (GSH)-responsive camptothecin (CPT) prodrug-based hybrid micellar nanoparticles (siPD-L1@HM-CPT) to achieve synergistic antitumor chemoimmunotherapy by PD-L1 knockdown. siPD-L1@HM-CPT derived from the one-step loading PD-L1 siRNA (siPD-L1) into the CPT prodrug-based hybrid micelles (HM-CPT) which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP₁₅ and stabilizer DSPE-PEG, showed high loading efficiency, GSH-responsive drug release, and excellent stability and biosafety. siPD-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo, high accumulation at the tumor sites, and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy, inducing strong immunogenic cell death (ICD) and sustained ICB to improve intratumoral CD8⁺ T cells infiltration. In addition, the antitumor immunity response limited by the differentiated immunogenicity, intrinsic PD-L1 expression, and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16–F10 and 4T1 tumor models. Our study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.

化学免疫联合治疗作为一种新的治疗策略已被广泛研究并应用于临床，以提高抗肿瘤治疗效果并减轻副作用。通过抑制 PD-L1 从头产生来靶向 PD-L1 的 RNA 干扰 (RNAi) 将克服化疗期间先天性和适应性 PD-L1 表达，从而使持续有效的免疫检查点阻断 (ICB) 激活抗肿瘤免疫反应。在此，我们设计了一种谷胱甘肽 (GSH) 响应型喜树碱 (CPT) 前药混合胶束纳米粒子 (siPD-L1@HM-CPT)，通过 PD-L1 敲低实现协同抗肿瘤化学免疫治疗。siPD-L1@HM-CPT 源自一步将 PD-L1 siRNA (siPD-L1) 加载到基于 CPT 前药的混合胶束 (HM-CPT) 中，这些胶束由基于可生物降解的多磷酸酯的前药 CPT-ss 共同组装而成-PAEEP₁₅和稳定剂DSPE-PEG，表现出高负载效率，对GSH敏感的药物释放，以及优异的稳定性和生物安全性。siPD-L1@HM-CPT通过致敏CPT化疗，实现CPT和siPD-L1同时在体外和体内共递送，在肿瘤部位高积累，并在细胞内快速释放，以提高抗肿瘤功效，诱导强免疫原性细胞死亡(ICD) 和持续 ICB 改善肿瘤内 CD8 ⁺T细胞浸润。此外，在我们的实验性 B16-F10 和 4T1 肿瘤模型中，通过有效的 ICD 和 ICB 从沉默 PD-L1 和协同 CPT 化学增敏作用促进了受分化免疫原性、内在 PD-L1 表达和细胞内 GSH 水平限制的抗肿瘤免疫反应。我们的研究可能为通过方便可控的制备抗肿瘤化学免疫疗法设计新型共递送纳米颗粒提供一个视角。