Mild hyperthermia near-infrared-triggered urokinase release from CREKA-modified PLGA–PEG nanoparticles targeted to deep vein thrombosis

Owing to the short half-life, poor targeting ability, and high bleeding risk of conventional thrombolytic drugs, the treatment of deep vein thrombosis (DVT) remains challenging. In this study, a photothermal-responsive drug delivery platform was developed by combining the thrombolytic activity of urokinase (UK), the photothermal conversion property of copper sulfide (CuS) nanoparticles, and the fibrin-targeting ability of the peptide CREKA (Cys-Arg-Glu-Lys-Ala). The obtained UK@CuS@PLGA-PEG-CREKA (UK@CuS@PP-CREKA) nanoparticles have a particle size of 196.53 ± 10.99 nm and a zeta potential of -2.36 ± 0.83 mV, with good colloidal stability and prolonged circulation characteristics. Under 808 nm near-infrared (NIR) irradiation, the system achieves a photothermal conversion efficiency of 57.5% and a thrombolytic efficiency of 63.66%, which is much higher than that of free UK, with NIR-controlled release behavior. In a murine DVT model, the system increases the drug accumulation at the thrombus site 3.2-fold compared to the non-targeted control, and blood flow is restored within 5 h post-injection without causing detectable bleeding or systemic toxicity. Histopathological analysis further shows reduced P-selectin expression, indicating attenuated thrombus-associated inflammation, and no pathological damage to the major organs (heart, liver, spleen, lungs, kidneys). In summary, this targeted photothermal-controlled release strategy offers a promising approach for the treatment of DVT.