Decomposable Nanoagonists Enable NIR-Elicited cGAS-STING Activation for Tandem-Amplified Photodynamic-Metalloimmunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcome of immunotherapy. However, the "constantly active" mode of current delivery strategies for STING agonists typically leads to off-target toxicity and hyperimmunity. To solve this critical issue, we herein construct a metal organic frameworks (MOF)-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enables mitochondria-targeted reactive oxygen species generation under NIR irradiation to specifically release mitochondrial DNA (mtDNA), as well as the inhibition of the repair of nuclear DNA (ncDNA) via hypoxia-responsive drugs. The oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern to activate the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhances the cGAS enzymatic activity via metallo-immune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitates the maturation of dendritic cells and the infiltration of cytotoxic T lymphocytes for primary tumors eradication, which also establishes a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enables NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, offering a distinct paradigm of photodynamic-metalloimmunotherapy. This article is protected by copyright. All rights reserved.