A Metalloporphyrin Nanosystem Enables Non‐Invasive Visualization and Specific Treatment for Thrombosis and Ischemic Stroke

Abstract Thrombotic ischemic stroke (IS) is a severe neurological disease of the brain, with high global mortality and disability rates. The significant temporal disconnect and lack of coordination between thrombolysis (≥15% hemorrhage risk from short half‐life thrombolytics) and IS treatment results in limited clinical efficacy. Innovative strategies are required to: 1) resolve stereochemical conflicts in single‐molecule multifunctional materials; 2) enable spatiotemporal functions for effective diagnosis and treatment; 3) establish unambiguous structure‐property relationships. Herein, 4IrMn nanoparticles (NPs), with a dual transition metal core exhibit an endogenous peroxynitrite (ONOO ⁻ ) response, which triggers near‐infrared chemiluminescence (NIR‐CL) signals for the precise location of lesion sites. Under laser irradiation, 4IrMn NPs initiate synergistic photothermal therapy (PTT) and photodynamic therapy (PDT) in mouse thrombus models to achieve effective thrombolysis (the relative volume of clots decreased by ≈60%) with no observed hemorrhagic complications or recurrent embolism. After thrombolysis, 4IrMn NPs effectively scavenge excess cytotoxic reactive oxygen/nitrogen species (RONS) and suppresses pro‐inflammatory cytokines such as tumor necrosis factor‐alpha/interleukin‐6 (TNF‐α and IL‐6). Ultimately, 4IrMn NPs enhance neuronal survival in the ischemic penumbra and reduce the extent of cerebral tissue death. This single‐molecule‐based multifunctional nanosystem integrates diagnostic‐therapeutic‐prognosis features, realizing a significant advance in addressing the constraints of current thrombosis and IS treatment.