A Single‐Atom Mn/MoO <sub>3−</sub> <i> <sub>x</sub> </i> Nanoagonist for Cascade cGAS/STING Activation in Tumor‐Specific Catalytic Metalloimmunotherapy
Xi Hu, Zhiyuan Ma, Bo Zhang, Jie Wang, Yanchun Zhou, Jun Li, Tianqi Liu, Jingxin Zhang, Bangzhen Hong, Mingjian Zhu, Fangyuan Li, Daishun Ling
Abstract
Abstract The cyclic GMP‐AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway plays a crucial role in initiating anti‐tumor immunity. Despite the development of various STING agonists, their effectiveness is often limited by suboptimal activation efficiency and poor sustainability. To address this, a Mn/MoO 3− x nanoagonist featuring Mn single‐atom sites is presented, designed for cascade cGAS/STING activation in tumor‐specific catalytic metalloimmunotherapy. The single‐atom nanoagonist (SANA) is meticulously crafted by doping Mn atoms into defective molybdenum oxide (MoO 3− x ), enabling robust peroxidase‐mimicking catalysis and inducing severe double‐stranded DNA (dsDNA) damage in tumors. Of note, Mn 2+ and MoO 4 2− can be responsively released from Mn/MoO 3− x SANA and enhance the sensitivity of cGAS to dsDNA. Importantly, MoO 4 2− with a relatively slow‐release profile and facile cellular accumulation compensates for Mn 2+ that has poor cellular accumulation due to continuous efflux, thus continuatively triggering the secretion of type I interferon for beyond 72 h. Remarkably, Mn/MoO 3− x SANA significantly inhibits tumor growth and metastasis without supplementary STING agonists or external stimulation. This study offers a promising cascade cGAS/STING activation approach to enhance the efficacy and sustainability of catalytic metalloimmunotherapy.