Zhang Tingting, Yin Weimin, Zhao Yuge, Huang Li, Gu Jingjing, Zang Jie, Zheng Xiao, Chang Jiao, Sun Jiuyuan, Dong Haiqing, Li Yongyong, Li Yan
Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education, Tongji Hospital, The Institute for Biomedical Engineering and Nano Science (iNANO), School of Medicine, Tongji University, 389 Xincun Road, Shanghai, 200065, China.
Adv Healthc Mater. 2024 Aug;13(20):e2302387. doi: 10.1002/adhm.202302387. Epub 2024 May 29.
Macrophages, capable of both direct killing and antigen presentation, are crucial for the interplay between innate and adaptive immunity. However, strategies mainly focus on polarizing tumor-associated macrophages (TAMs) to M1 phenotype, while overlooking the inefficient antigen cross-presentation due to hyperactive hydrolytic protease within lysosomes which leads to antigen degradation. In light of the significant influence of reactive oxygen species (ROS) on TAMs' polarization and the inhibition of phagosomal proteolysis, a novel nanosystem termed OVA-Fe-GA (OFG) is engineered, drawing inspiration from the NOX2 enzyme's role. OFG integrates ovalbumin (OVA) and a network composed of Fe-gallic acid (GA), emulating the NOX2 enzyme's sequential ROS generation process ("O to O to HO/•OH"). Furthermore, it elucidates a biological mechanism that augments antigen cross-presentation by suppressing the expression of cysteine proteases. OFG restores the innate anti-tumor functionality of TAMs and significantly amplifies their antigen cross-presentation (4.5-fold compared to the PBS control group) in B16-OVA tumor-bearing mice. Notably, the infiltration and activity of intratumoral CD8 T cells are enhanced, indicating an adaptive immune response. Moreover, OFG exhibits excellent photothermal properties, thereby fostering a system antitumor immune response. This study provides a promising strategy for initiating both innate and adaptive immunity via TAMs activation.
巨噬细胞既能直接杀伤又能呈递抗原，对固有免疫和适应性免疫之间的相互作用至关重要。然而，目前的策略主要集中于将肿瘤相关巨噬细胞（TAM）极化为M1表型，却忽略了溶酶体内水解蛋白酶活性过高导致抗原降解，进而使抗原交叉呈递效率低下的问题。鉴于活性氧（ROS）对TAM极化的显著影响以及对吞噬体蛋白水解的抑制作用，受NOX2酶作用的启发，设计了一种新型纳米系统OVA-Fe-GA（OFG）。OFG整合了卵清蛋白（OVA）和由铁-没食子酸（GA）组成的网络，模拟了NOX2酶的ROS连续生成过程（“O₂到O₃到HO•/•OH”）。此外，它还阐明了一种通过抑制半胱氨酸蛋白酶的表达来增强抗原交叉呈递的生物学机制。在荷B16-OVA肿瘤小鼠中，OFG恢复了TAM的固有抗肿瘤功能，并显著增强了它们的抗原交叉呈递能力（与PBS对照组相比提高了4.5倍）。值得注意的是，肿瘤内CD8⁺ T细胞的浸润和活性增强，表明产生了适应性免疫反应。此外，OFG具有优异的光热性能，从而促进了系统性抗肿瘤免疫反应。本研究为通过激活TAM启动固有免疫和适应性免疫提供了一种有前景的策略。
