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A Self-amplifying ROS-sensitive prodrug-based nanodecoy for circumventing immune resistance in chemotherapy-sensitized immunotherapy.

Authors:
Jiulong Zhang Xiaoyan Sun Mengdan Xu Xiufeng Zhao Chunrong Yang Kexin Li Fan Zhao Haiyang Hu Mingxi Qiao Dawei Chen Xiuli Zhao

Acta Biomater 2022 Sep 25;149:307-320. Epub 2022 Jun 25.

School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang, 110016, P.R. China. Electronic address:

Circumventing immune resistance and boosting immune response is the ultimate goal of cancer immunotherapy. Herein, we reported a tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle for specifically inducing immunogenic cell death (ICD) in combination with TAM depletion. A versatile ROS-cleavable camptothecin (CPT) prodrug (DCC) was synthesized through a thioacetal linker between CPT and the ROS generator cinnamaldehyde (CA), which could self-assemble into a uniform prodrug nanoparticle to realize a positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." This DCC was further modified with the TAM membrane (abbreviated as [email protected]), which could not only target both primary tumors and lung metastasis nodules through VCAM-1/αβ integrin interaction but also absorb CSF-1 secreted by tumor cells to disturb the interaction between TAMs and cancer cells. Our nanodecoy could effectively induce ICD cascade and deplete TAMs for priming tumor-specific effector T cell infiltration for antitumor immune response activation, which represents a versatile approach for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A tumor-associated macrophage (TAM) membrane-camouflaged nanodecoy containing a self-amplifying reactive oxygen species (ROS)-sensitive prodrug nanoparticle was fabricated for the first time. This ROS-cleavable camptothecin (CPT)/cinnamaldehyde (CA) prodrug (DCC) could self-assemble into a uniform nanoparticle to realize the positive feedback loop of "ROS-triggered CA/CPT release and CA/CPT-mediated ROS generation." After TAM membrane coating, this system ([email protected]) could not only target both primary tumors and lung metastatic nodules but also scavenge CSF-1 secreted by tumor cells for TAM depletion for sufficient chemotherapy-sensitized immunotherapy.

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http://dx.doi.org/10.1016/j.actbio.2022.06.035DOI Listing
September 2022

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