Xia Heming, Qin Mengmeng, Wang Zenghui, Wang Yaoqi, Chen Binlong, Wan Fangjie, Tang Mingmei, Pan Xingquan, Yang Ye, Liu Jianxiong, Zhao Ruiyang, Zhang Qiang, Wang Yiguang
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Nano Lett. 2022 Apr 13;22(7):2978-2987. doi: 10.1021/acs.nanolett.2c00185. Epub 2022 Mar 18.
Toll-like receptor (TLR) agonists are potent immune-stimulators that hold great potential in vaccine adjuvants as well as cancer immunotherapy. However, TLR agonists in free form are prone to be eliminated quickly by the circulatory system and cause systemic inflammation side effects. It remains a challenge to achieve precise release of TLR7/8 agonist in the native form at the receptor site in the endosomal compartments while keeping stable encapsulation and inactive in nontarget environment. Here, we report a pH-/enzyme-responsive TLR7/8 agonist-conjugated nanovaccine (TNV), which responds intelligently to the acidic environment and cathepsin B in the endosome, precisely releases TLR7/8 agonist to activate its receptor signaling at the endosomal membrane, stimulates DCs maturation, and provokes specific cellular immunity. In vivo experiments demonstrate outstanding prophylactic and therapeutic efficacy of TNV in mouse melanoma and colon cancer. The endosome-targeted responsive nanoparticle strategy provides a potential delivery toolbox of adjuvants to advance the development of tumor nanovaccines.
Toll样受体（TLR）激动剂是强大的免疫刺激剂，在疫苗佐剂以及癌症免疫治疗方面具有巨大潜力。然而，游离形式的TLR激动剂容易被循环系统迅速清除，并引发全身炎症副作用。在内体区室的受体部位以天然形式实现TLR7/8激动剂的精确释放，同时在非靶标环境中保持稳定包封且无活性，仍然是一个挑战。在此，我们报道了一种pH/酶响应性的TLR7/8激动剂偶联纳米疫苗（TNV），它能对内体中的酸性环境和组织蛋白酶B做出智能响应，精确释放TLR7/8激动剂以激活其在内体膜上的受体信号，刺激树突状细胞成熟，并激发特异性细胞免疫。体内实验证明了TNV在小鼠黑色素瘤和结肠癌中具有出色的预防和治疗效果。这种内体靶向响应性纳米颗粒策略为推进肿瘤纳米疫苗的开发提供了一个潜在的佐剂递送工具包。
