Fibrin‐Targeting Metal–Organic Framework Nanoagent for NIR‐Triggered Photothermal Thrombus Ablation

Thrombosis remains a leading cause of mortality worldwide; however, current thrombolytic therapies suffer from limited thrombus targeting, poor penetration, and systemic side effects. To address these challenges, a fibrin-targeting photothermal nanoassembly, GCREKA-Pd@MIL-100, is engineered by encapsulating ultrasmall palladium (Pd) nanoclusters into a MIL-100(Fe) metal-organic framework and grafting a stabilized peptide ligand Gly-Cys-Arg-Glu-Lys-Ala (GCREKA) onto its surface. The porous MIL-100 matrix provides spatial confinement for the Pd nanoclusters, yielding uniform localized surface plasmon resonance (LSPR) active domains with high near-infrared (NIR) photothermal conversion efficiency. Covalent functionalization with GCREKA enhances colloidal stability and thrombus affinity. In vitro studies demonstrate that GCREKA-Pd@MIL-100 exhibits excellent cytocompatibility and hemocompatibility while achieving a clot mass reduction of over 50% under NIR irradiation. In a FeCl₃-induced mouse mesenteric thrombosis model, GCREKA-Pd@MIL-100 accumulates selectively at the thrombotic site accompanied by localized heat (>60 °C) generation and achieves ≈60% thrombus clearance without off-target tissue damage. These findings highlight that GCREKA-Pd@MIL-100 is a potent site-specific nanoagent for minimally invasive thrombolysis, offering a promising alternative to conventional thrombolytic therapies.