GSH-responsive camptothecin prodrug-based hybrid micellar nanoparticles enable antitumor chemo-immunotherapy by PD-L1 knockdown
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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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GSH-responsive camptothecin prodrug-based hybrid micellar nanoparticles enable antitumor chemo-immunotherapy by PD-L1 knockdown
)
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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