Xi Tan1, Hong Zhou1, Chenhui Wang1,2, Xuhan Liu3, Xiangliang Yang1,4, Wei Liu1,4()
College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 611731, China
Department of Emergency Medicine, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen 518060, China
National Engineering Research Center for Nanomedicine, Huazhong University of Science and Technology, Wuhan 430074, China
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In this work, we successfully constructed a novel GSH-responsive and biodegradable prodrug-based hybrid micellar nanoparticles (siPD-L1@HM-CPT) by convenient and controllable preparation for co-delivery of PD-L1 siRNA (siPD-L1) and camptothecin (CPT). Moreover, siPD-L1@HM-CPT could silence PD-L1 expression to sensitize CPT chemotherapy and relieve tumor immunosuppressive microenvironment (TME) strengthened by adaptive PD-L1 upregulation, and so as to facilitate cytotoxic T cells infiltration for antitumor chemo-immunotherapy.
Abstract
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 chemo-immunotherapy 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.
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