Liao Kangsheng, Chen Ruihong, Zhang Jinwei, Ruan Yongdui, Huang Xueqin, Huang Yuhe, Xia Jiaojiao, Zhao Daina, Chen Lingming, Zhao Yi, Yang Fen, Xu Jun-Fa, Shen Ling, Pi Jiang
Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, School of Medical Technology, Guangdong Medical University, Dongguan 523808, PR China; Research Center of Nano Technology and Application Engineering, Dongguan Innovation Institute, School of Medical Technology, Guangdong Medical University, Dongguan 523808, PR China.
Department of Dermatology, Chongqing General Hospital, Chongqing 401147, PR China.
Acta Biomater. 2025 Apr;196:471-486. doi: 10.1016/j.actbio.2025.03.002. Epub 2025 Mar 3.
Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases. The pathogenesis hallmarks for TB are complex immune escape mechanisms of Mtb and low targeting effects of anti-TB drugs. cGAS signaling, which is responsible for triggering host antibacterial immunity against Mtb infection, has shown potentials to serve as targets for anti-TB immunotherapy. As cGAS agonist manganese ions (Mn) can activate cGAS-mediated autophagy to inhibit intracellular Mtb in macrophages, we constructed a functional nanoagonist targeting cGAS signaling based on manganese dioxide nanoparticles, naming Tuf-Rif@HA-MnO NPs, for synergistic macrophage-targeted drug delivery and anti-TB immuno-therapeutics. Tuf-Rif@HA-MnO NPs can actively target macrophages for rifampicin delivery and react with intracellular glutathione (GSH) to release Mn for cGAS-STING signaling activation, which further promote autophagy and antibacterial M1 polarization of Mtb infected macrophages to achieve synergistic intracellular Mtb clearance. Furthermore, Tuf-Rif@HA-MnO NPs can potentiate dendritic cell maturation, CD4+ Th1 cell and CD8+ cytotoxic T cell activation in vivo, which collectively attribute to reduced Mtb burdens and alleviated tissue inflammations in lung of Mtb-infected mice without systemic toxicity. This macrophage targeted drug delivery nanoagonist system is expected to develop rational immunotherapy strategy targeting cGAS signaling against TB and drug-resistant TB. STATEMENT OF SIGNIFICANCE: cGAS-mediated autophagy plays a critical role in Mtb clearance in macrophages. Tuf-Rif@HA-MnO NPs specifically deliver rifampicin into macrophage for Mtb clearance. Tuf-Rif@HA-MnO NPs activate cGAS-mediated macrophage autophagy for Mtb clearance. Tuf-Rif@HA-MnO NPs synergize cGAS-mediated immunotherapy with targeted drug delivery for more effective anti-TB treatment.
由结核分枝杆菌（Mtb）感染引起的结核病（TB）仍然是传染病中的主要杀手之一。结核病的发病机制特征是Mtb复杂的免疫逃逸机制以及抗结核药物的低靶向作用。负责触发宿主针对Mtb感染的抗菌免疫的cGAS信号通路，已显示出作为抗结核免疫治疗靶点的潜力。由于cGAS激动剂锰离子（Mn）可激活cGAS介导的自噬以抑制巨噬细胞内的Mtb，我们基于二氧化锰纳米颗粒构建了一种靶向cGAS信号通路的功能性纳米激动剂，命名为Tuf-Rif@HA-MnO NPs，用于协同巨噬细胞靶向药物递送和抗结核免疫治疗。Tuf-Rif@HA-MnO NPs可以主动靶向巨噬细胞以递送利福平，并与细胞内谷胱甘肽（GSH）反应释放Mn以激活cGAS-STING信号通路，进而促进自噬以及Mtb感染巨噬细胞的抗菌M1极化，以实现协同清除细胞内的Mtb。此外，Tuf-Rif@HA-MnO NPs可以增强体内树突状细胞成熟、CD4+ Th1细胞和CD8+ 细胞毒性T细胞的激活，这些共同作用导致Mtb感染小鼠肺部的Mtb负荷降低和组织炎症减轻，且无全身毒性。这种巨噬细胞靶向药物递送纳米激动剂系统有望开发针对cGAS信号通路的合理免疫治疗策略，用于治疗结核病和耐药结核病。意义声明：cGAS介导的自噬在巨噬细胞清除Mtb中起关键作用。Tuf-Rif@HA-MnO NPs特异性地将利福平递送至巨噬细胞以清除Mtb。Tuf-Rif@HA-MnO NPs激活cGAS介导的巨噬细胞自噬以清除Mtb。Tuf-Rif@HA-MnO NPs将cGAS介导的免疫治疗与靶向药物递送协同作用，以实现更有效的抗结核治疗。
