Semiconducting Polymer Nanoparticles with Surface-Mimicking Protein Secondary Structure as Lysosome-Targeting Chimaeras for Self-Synergistic Cancer Immunotherapy,Advanced Materials

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Semiconducting Polymer Nanoparticles with Surface-Mimicking Protein Secondary Structure as Lysosome-Targeting Chimaeras for Self-Synergistic Cancer Immunotherapy
Advanced Materials ( IF 27.4 ) Pub Date : 2022-06-15 , DOI: 10.1002/adma.202203309
Ji Qi ₁ , Shaorui Jia ₁ , Xiaoying Kang ₁ , Xinying Wu ₁ , Yuning Hong ₂ , Ke Shan ₃ , Xianglong Kong ₃ , Zhiming Wang ₄ , Dan Ding _{1,

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Affiliation

Immunotherapy has received tremendous attention for tumor treatment, but the efficacy is greatly hindered by insufficient tumor-infiltration of immune cells and immunosuppressive tumor microenvironment. The strategy that can efficiently activate cytotoxic T lymphocytes and inhibit negative immune regulators will greatly amplify immunotherapy outcome, which is however very rare. Herein, a new kind of semiconducting polymer (SP) nanoparticles is developed, featured with surface-mimicking protein secondary structure (SPSS NPs) for self-synergistic cancer immunotherapy by combining immunogenic cell death (ICD) and immune checkpoint blockade therapy. The SPs with excellent photodynamic property are synthesized by rational fluorination, which can massively induce ICD. Additionally, the peptide antagonists are introduced and self-assembled into β-sheet protein secondary structures on the photodynamic NP surface via preparation process optimization, which function as efficient lysosome-targeting chimaeras (LYTACs) to mediate the degradation of programmed cell death ligand-1 (PD-L1) in lysosome. In vivo experiments demonstrate that SPSS NPs can not only elicit strong antitumor immunity to suppress both primary tumor and distant tumor, but also evoke long-term immunological memory against tumor rechallenge. This work introduces a new kind of robust immunotherapy agents by combining well-designed photosensitizer-based ICD induction and protein secondary structures-mediated LYTAC-like multivalence PD-L1 blockade, rendering great promise for synergistic immunotherapy.

中文翻译：

具有表面模拟蛋白质二级结构的半导体聚合物纳米颗粒作为溶酶体靶向嵌合体用于自协同癌症免疫治疗

免疫疗法在肿瘤治疗中受到了极大的关注，但由于免疫细胞的肿瘤浸润不足和免疫抑制肿瘤微环境，极大地阻碍了疗效。能够有效激活细胞毒性T淋巴细胞并抑制负性免疫调节因子的策略将大大放大免疫治疗的效果，但这种情况非常罕见。在此，我们开发了一种新型的半导体聚合物（SP）纳米粒子，该纳米粒子具有表面模拟蛋白二级结构（SPSS NPs），用于结合免疫原性细胞死亡（ICD）和免疫检查点阻断疗法进行自我协同癌症免疫治疗。通过合理氟化合成具有优异光动力学性能的SPs，可大量诱导ICD。此外，通过制备工艺优化，将肽拮抗剂引入光动力纳米粒子表面并自组装成β-折叠蛋白二级结构，作为有效的溶酶体靶向嵌合体（LYTACs）介导程序性细胞死亡配体-1（PD）的降解-L1) 在溶酶体中。体内实验表明，SPSS NPs不仅可以引发强大的抗肿瘤免疫来抑制原发性肿瘤和远处肿瘤，而且还可以唤起针对肿瘤再攻击的长期免疫记忆。这项工作通过结合精心设计的基于光敏剂的 ICD 诱导和蛋白质二级结构介导的 LYTAC 样多价 PD-L1 阻断，引入了一种新型的强效免疫治疗药物，为协同免疫治疗带来了巨大希望。

更新日期：2022-06-15

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