State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, P. R. China.
College of Chemistry and Chemical Engineering, Donghua University, Shanghai 201620, P. R. China.
ACS Nano. 2024 Apr 9;18(14):10142-10155. doi: 10.1021/acsnano.3c13088. Epub 2024 Mar 25.
Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α and β integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.
充分调动多种免疫细胞的活性对于实现理想的肿瘤免疫治疗效果至关重要,但这仍然具有挑战性。在此,我们报告了一种基于磷树状大分子(命名为 AK128)/程序性死亡蛋白 1 抗体(aPD1)纳米复合物(NCs)的纳米药物制剂,该制剂被伪装成 M1 型巨噬细胞膜(M1m),用于增强原位脑胶质瘤的免疫治疗。构建的 AK128-aPD1@M1m NCs 的平均粒径为 160.3nm,具有良好的稳定性和细胞相容性。由于修饰的 M1m 具有 α 和 β 整合素,NCs 能够穿透血脑屏障,同时递送到原位脑胶质瘤中,具有延长的血液循环时间的 AK128 与内在免疫调节活性和 aPD1。我们表明,磷树状大分子 AK128 可以促进外周血单个核细胞中自然杀伤(NK)细胞的增殖,而递送到的 aPD1 能够进行免疫检查点阻断(ICB),以恢复细胞毒性 T 细胞和 NK 细胞,从而促进肿瘤细胞凋亡,同时大大减少肿瘤中调节性 T 细胞的分布,从而改善脑胶质瘤的免疫治疗。这种具有简单组成的纳米药物制剂通过利用纳米载体的免疫调节活性和抗体介导的 ICB 治疗,对免疫细胞进行了多种调节,为癌症免疫治疗提供了一种有效的策略。
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