Xiao Yuchen, Zhu Tianchuan, Zeng Qi, Tan Qingqin, Jiang Guanmin, Huang Xi
Center for Infection and Immunity, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, Guangdong 519000, China.
Center for Infection and Immunity, Guangdong Provincial Key Laboratory of Biomedical Imaging, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519000, China.
Acta Biomater. 2023 Feb;157:451-466. doi: 10.1016/j.actbio.2022.11.043. Epub 2022 Nov 25.
Immune checkpoint blockade therapy targeting programmed death-1 (PD-1) or its major ligand programmed death-ligand 1 (PD-L1) has achieved remarkable success in the treatment of several tumors, including colorectal cancer. However, the efficacy of PD-1/PD-L1 inhibitors is limited in some colorectal cancers within the immunosuppressive tumor microenvironment (such as when there is a lack of immune cell infiltration). Herein, anti-PD-L1 functionalized biomimetic polydopamine-modified gold nanostar nanoparticles (PDA/GNS@aPD-L1 NPs) were developed for synergistic anti-tumor treatment by combining PD-1/PD-L1 blockade with photothermal ablation. PDA/GNS@aPD-L1 NPs were prepared by encapsulating photothermal nanoparticles (polydopamine-modified gold nanostar, PDA-GNS) with cell membrane isolated from anti-PD-L1 single-chain variable fragment (scFv) over-expressing cells. In addition to disrupting PD-1/PD-L1 immunosuppressive signals, the anti-PD-L1 scFv on the membrane of PDA/GNS@aPD-L1 NPs was conducive to the accumulation of PDA-GNS at tumor sites. Importantly, the tumor photothermal ablation induced by PDA-GNS could reverse the immunosuppressive tumor microenvironment, thereby further improving the efficiency of PD-1/PD-L1 blockade therapy. In this study, the synthetized PDA/GNS@aPD-L1 NPs exhibited good biocompatibility, efficient photothermal conversion ability, and enhanced tumor-targeting ability. In vivo studies revealed that a PDA/GNS@aPD-L1 NP-based therapeutic strategy significantly inhibited tumor growth, and prolonged overall survival by further promoting the maturation of dendritic cells (DCs), increasing the infiltration of CD8T cells, and decreasing the number of immunosuppressive cells (such as regulatory T cells and myeloid-derived suppressive cells). Collectively, the developed PDA/GNS@aPD-L1 NP-based therapeutic strategy combines PD-1/PD-L1 blockade with photothermal ablation, which could remodel the tumor microenvironment for effective clinical colorectal cancer therapy. STATEMENT OF SIGNIFICANCE: Immunosuppressive tumor microenvironment is the main challenge facing programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade therapy. By encapsulating photothermal nanoparticles (polydopamine-modified gold nanostar, PDA-GNS) with cell membrane over-expressing anti-PD-L1 single-chain variable fragment, we constructed anti-PD-L1 functionalized biomimetic nanoparticles (PDA/GNS@aPD-L1 NPs). By specific binding to the PD-L1 present on tumor cells, PDA/GNS@aPD-L1 NPs could disrupt PD-1/PD-L1 immunosuppression signaling, and effectively deliver PDA-GNS targeting to tumor sites. Additionally, PDA-GNS-mediated local photothermal ablation of tumors promoted the release of tumor-associated antigens and thus activated anti-tumor immune responses. Meanwhile, hyperthermia facilitates immune cell infiltration by increasing tumor vascular permeability. Therefore, PDA/GNS@aPD-L1 NPs could sensitize tumors to PD-1/PD-L1 blockade therapy by remodeling the immunosuppressive tumor microenvironment, which provides a new strategy for tumor treatment.
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