Background and methods: Silica-coated magnetic nanoparticle (SiO 2 -MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO 2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO 2 surface, which provides abundant -NH 2 functional groups for conjugating with tPA. Results: The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO 2 -MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO 2 -MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO 2 -MNP (SiO 2 -MNP-tPA) did not alter blood component concentrations. After conjugating to SiO 2 -MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO 2 -MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO 2 -MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis. Conclusion: Biocompatible SiO 2 -MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.