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

Abstract 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 FeCl 3 ‐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.