Superoxide Anion (O₂^–•) Leading to Pulmonary Toxicity of Metal–Organic Frameworks (MOFs)

Metal–organic frameworks (MOFs) have attracted significant attention for their versatility in therapeutic and diagnostic roles, yet their potential impact on pulmonary toxicity remains largely unexplored. There is an urgent necessity to comprehensively investigate their biological impacts. Herein, we examined the cytotoxicity, oxidative stress, and pulmonary injury after UIO-66, ZIF-8, and MOF-199 stimulation, with a focus on their impact on lung cells and tissue. Crucially, our mechanistic investigations definitively elucidated that the pulmonary toxicity of MOF-199 is primarily driven by the excessive generation of superoxide anion (O 2 –• ). This superoxide-driven ROS cascade subsequently underlies the observed cellular damage, including calcium dysregulation and apoptosis, and instigates the inflammatory response leading to lung tissue injury. Conversely, UIO-66 and ZIF-8 generated the minimal superoxide level. This study provides crucial insights into the safety of MOFs and stresses the need for careful design to optimize both their functionality and biocompatibility for safe biomedical use.