Platelet pharmacytes for the hierarchical amplification of anti‐tumor immunity in response to self‐generated immune signals
Platelet pharmacytes for the hierarchical amplification of anti‐tumor immunity in response to self‐generated immune signals
复制标题
血小板药细胞用于分层放大抗肿瘤免疫，以响应自身产生的免疫信号
DOI：
10.1002/adma.202109517
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发表时间：
2022
影响因子：
29.4
通讯作者：
Lichen Yin
中科院分区：
文献类型：
--
作者：
Jing Yan;Xun Liu;Fan Wu;Chenglong Ge;Huan Ye;Xingye Chen;Yuansong Wei;Renxiang Zhou;Shanzhou Duan;Rongying Zhu;Yiran Zheng;Lichen Yin
肿瘤源性外泌体介导的系统性免疫抑制是免疫检查点阻断（ICB）疗法耐药的重要原因。在此，自适应血小板（PLT）药细胞被设计为介导外泌体抑制siRNA和抗PD-L1（aPDL1）的级联递送，以实现协同抗肿瘤免疫。在药物细胞中，由 Rab27 siRNA (siRab) 和膜穿透多肽组装而成的聚阳离子纳米复合物 (NC) 封装在 PLT 的开放小管系统内，细胞毒性 T 淋巴细胞 (CTL) 响应的 aPDL1 纳米凝胶 (NG) 共价背包在 PLT 表面上。全身给药后，药细胞能够延长血液循环并主动积聚至肿瘤，其中PLT被激活以释放siRab NC，其有效转染肿瘤细胞、沉默Rab27a并抑制外泌体分泌。免疫抑制因此得到缓解，导致细胞毒性 T 细胞的激活、增殖和肿瘤浸润，从而触发潜在的 aPDL1 释放。因此，表达 PD-L1 的外泌体对 aPDL1 的竞争性耗竭被最小化，从而使 ICB 敏感。 siRab 和 aPDL1 协同诱导针对同基因小鼠黑色素瘤的强烈抗肿瘤免疫反应和记忆。本研究报道了一种仿生机制来解决聚阳离子siRNA递送系统的血液循环/细胞内化矛盾，并为抗肿瘤免疫的时空增强提供了一种启发性的方法。
Systemic immunosuppression mediated by tumor‐derived exosomes is an important cause for the resistance of immune checkpoint blockade (ICB) therapy. Herein, self‐adaptive platelet (PLT) pharmacytes are engineered to mediate cascaded delivery of exosome‐inhibiting siRNA and anti‐PD‐L1 (aPDL1) toward synergized antitumor immunity. In the pharmacytes, polycationic nanocomplexes (NCs) assembled from Rab27 siRNA (siRab) and a membrane‐penetrating polypeptide are encapsulated inside the open canalicular system of PLTs, and cytotoxic T lymphocytes (CTLs)‐responsive aPDL1 nanogels (NGs) are covalently backpacked on the PLT surface. Upon systemic administration, the pharmacytes enable prolonged blood circulation and active accumulation to tumors, wherein PLTs are activated to liberate siRab NCs, which efficiently transfect tumor cells, silence Rab27a, and inhibit exosome secretion. The immunosuppression is thus relieved, leading to the activation, proliferation, and tumoral infiltration of cytotoxic T cells, which trigger latent aPDL1 release. As such, the competitive aPDL1 exhaustion by PD‐L1‐expressing exosomes is minimized to sensitize ICB. Synergistically, siRab and aPDL1 induce strong antitumor immunological response and memory against syngeneic murine melanoma. This study reports a bioinspired mechanism to resolve the blood circulation/cell internalization contradiction of polycationic siRNA delivery systems, and renders an enlightened approach for the spatiotemporal enhancement of antitumor immunity.