MSA-2 Loaded Three-Dimensional Metal Covalent Organic Framework for Synergistic Radiosensitization and Innate Immune Activation

Radiotherapy (RT) remains a cornerstone of cancer treatment but is often limited by tumor radioresistance and an immune-suppressive microenvironment. An effective strategy that combines radiosensitization with innate immune activation provides opportunities to overcome the limitations faced by traditional RT. However, traditional STING agonists face challenges of instability, rapid clearance, poor tumor delivery, and systemic toxicity. To address these limitations, we developed a three-dimensional iridium-based metal-covalent organic framework (3D Ir-MCOF) loaded with 4-(5,6-dimethoxybenzo[b]thiophen-2-yl)-4-oxobutanoic acid (MSA-2) that simultaneously enables radiosensitization and tumor-specific innate immune activation. The framework incorporates high-Z iridium for enhanced X-ray energy deposition and ROS generation, while its porous architecture allows efficient loading and pH-responsive release of MSA-2 in the acidic tumor microenvironment. By synchronizing DNA damage with innate immune activation, 3D Ir-MCOFs induce dendritic cell maturation, type I interferon signaling, and T-cell infiltration, effectively converting "cold" tumors into "hot" ones. This work highlights 3D MCOFs as a multifunctional nanoplatform enabling concurrent next-generation radiosensitization and precise immune agonist delivery.