Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.
Acta Biomater. 2023 Aug;166:552-566. doi: 10.1016/j.actbio.2023.05.037. Epub 2023 May 24.
Immune checkpoint blockade (ICB) therapy has shown great potential in the treatment of malignant tumors, but its therapeutic effect on glioblastoma (GBM) is unsatisfactory because of the low immunogenicity and T cell infiltration, as well as the presence of blood-brain barrier (BBB) that blocks most of ICB agents to the GBM tissues. Herein, we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted photothermal therapy (PTT) and ICB synergistic therapy by loading immune checkpoint inhibitor CLP002 into the allomelanin nanoparticles (AMNPs) and followed by coating cancer cell membranes (CCM). The resulting AMNP@CLP@CCM can successfully cross the BBB and deliver CLP002 to GBM tissues due to the homing effect of CCM. As a natural photothermal conversion agent, AMNPs are used for tumor PTT. The increased local temperature by PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells. Importantly, PTT can effectively stimulate immunogenic cell death to induce tumor-associated antigen exposure and promote T lymphocyte infiltration, which can further amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Therefore, AMNP@CLP@CCM has great potential for the treatment of orthotopic GBM by PTT and ICB synergistic therapy. STATEMENT OF SIGNIFICANCE: The effect of ICB therapy on GBM is limited by the low immunogenicity and insufficient T-cell infiltration. Here we developed a biomimetic nanoplatform of AMNP@CLP@CCM for GBM-targeted PTT and ICB synergistic therapy. In this nanoplatform, AMNPs are used as both photothermal conversion agents for PTT and nanocarriers for CLP002 delivery. PTT not only enhances BBB penetration but also upregulates the PD-L1 level on GBM cells by increasing local temperature. Additionally, PTT also induces tumor-associated antigen exposure and promotes T lymphocyte infiltration to amplify the antitumor immune responses of GBM cells to CLP002-mediated ICB therapy, resulting in significant growth inhibition of the orthotopic GBM. Thus, this nanoplatform holds great potential for orthotopic GBM treatment.
免疫检查点阻断 (ICB) 疗法在恶性肿瘤治疗中显示出巨大潜力，但由于免疫原性低和 T 细胞浸润不足，以及血脑屏障 (BBB) 的存在阻止了大多数 ICB 药物进入 GBM 组织，其对 GBM 的治疗效果并不理想。在此，我们通过将免疫检查点抑制剂 CLP002 装载到黑色素纳米颗粒 (AMNPs) 中，并随后涂覆癌细胞膜 (CCM)，开发了一种用于 GBM 靶向光热治疗 (PTT) 和 ICB 协同治疗的仿生纳米平台 AMNP@CLP@CCM。由于 CCM 的归巢效应，所得的 AMNP@CLP@CCM 可以成功穿越 BBB 并将 CLP002 递送至 GBM 组织。作为一种天然光热转换剂，AMNPs 用于肿瘤 PTT。PTT 引起的局部温度升高不仅增强了 BBB 渗透，还上调了 GBM 细胞上的 PD-L1 水平。重要的是，PTT 可以有效地刺激免疫原性细胞死亡，诱导肿瘤相关抗原暴露并促进 T 淋巴细胞浸润，从而进一步放大 GBM 细胞对 CLP002 介导的 ICB 治疗的抗肿瘤免疫反应，导致原位 GBM 的显著生长抑制。因此，AMNP@CLP@CCM 具有通过 PTT 和 ICB 协同治疗治疗原位 GBM 的巨大潜力。
ICB 疗法对 GBM 的疗效受到免疫原性低和 T 细胞浸润不足的限制。在这里，我们开发了一种用于 GBM 靶向 PTT 和 ICB 协同治疗的仿生纳米平台 AMNP@CLP@CCM。在这个纳米平台中，AMNPs 既用作 PTT 的光热转换剂，也用作 CLP002 递送的纳米载体。PTT 通过增加局部温度不仅增强了 BBB 渗透，还上调了 GBM 细胞上的 PD-L1 水平。此外，PTT 还诱导肿瘤相关抗原暴露并促进 T 淋巴细胞浸润，从而放大 GBM 细胞对 CLP002 介导的 ICB 治疗的抗肿瘤免疫反应，导致原位 GBM 的显著生长抑制。因此，该纳米平台在治疗原位 GBM 方面具有巨大潜力。
