State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, P. R. China.
Biomater Sci. 2024 Jun 11;12(12):3175-3192. doi: 10.1039/d4bm00490f.
The tumor immunosuppressive microenvironment (TIME) and uncontrollable release of antigens can lower the efficacy of nanovaccine-based immunotherapy (NBI). Therefore, it is necessary to develop a new strategy for TIME reshaping and controllable release of antigens to improve the NBI efficacy. Herein, an acidity-responsive Schiff base-conjugated polyphenol-coordinated nanovaccine was constructed for the first time to realize bidirectional TIME reshaping and controllable release of antigens for activating T cells. In particular, an acidity-responsive tannic acid-ovalbumin (TA-OVA) nanoconjugate was prepared a Schiff base reaction. Fe was coordinated with TA-OVA to produce a Fe-TA-OVA nanosystem, and 1-methyltryptophan (1-MT) as an indoleamine 2,3-dioxygenase inhibitor was loaded to form a polyphenol-coordinated nanovaccine. The coordination between Fe and TA could cause photothermal ablation of primary tumors, and the acidity-triggered Schiff base dissociation of TA-OVA could controllably release OVA to realize lysosome escape, initiating the body's immune response. More importantly, oxidative stress generated by a tumor-specific Fenton reaction of Fe ions could promote the polarization of tumor-associated macrophages from the M2 to M1 phenotype, resulting in the upregulation of cytotoxic T cells and helper T cells. Meanwhile, 1-MT could downregulate immunosuppressive regulatory T cells. Overall, such skillful combination of bidirectional TIME reshaping and controllable antigen release into one coordination nanosystem could effectively enhance the NBI efficacy of tumors.
肿瘤免疫抑制微环境（TIME）和抗原的不可控释放会降低基于纳米疫苗的免疫疗法（NBI）的疗效。因此，有必要开发一种新的策略来重塑 TIME 和可控释放抗原，以提高 NBI 的疗效。本文首次构建了一种酸响应型席夫碱偶联多酚配位的纳米疫苗，以实现双向 TIME 重塑和可控释放抗原，从而激活 T 细胞。具体而言，通过席夫碱反应制备了一种酸响应性单宁酸-卵清蛋白（TA-OVA）纳米复合物。Fe 与 TA-OVA 配位生成 Fe-TA-OVA 纳米系统，并负载 1-甲基色氨酸（1-MT）作为吲哚胺 2,3-双加氧酶抑制剂，形成多酚配位的纳米疫苗。Fe 与 TA 之间的配位作用可引起原发性肿瘤的光热消融，而 TA-OVA 的酸触发席夫碱解离可实现 OVA 的可控释放，从而引发机体的免疫反应。更重要的是，Fe 离子的肿瘤特异性芬顿反应产生的氧化应激可促进肿瘤相关巨噬细胞从 M2 向 M1 表型极化，导致细胞毒性 T 细胞和辅助性 T 细胞的上调。同时，1-MT 可下调免疫抑制性调节性 T 细胞。总之，这种双向 TIME 重塑和可控抗原释放的巧妙结合到一个配位纳米系统中，可以有效地增强肿瘤的 NBI 疗效。
