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Eudragit L100-55-halloysite nanotubes (EL100-55, HNTs) nanocomposite microcapsules were introduced to release nattokinase (NK) and avoid the limitations of oral and systemic administration of NK while increasing the entrapment efficiency and stability of NK. The drug loading capacity, stability, and shapes of the NK microcapsules (NK@HNTs-EL) were characterized with Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). The maximum loading rate of NK was 82.63%, and the encapsulation efficiency of NK was 31.6%. The formulation conditions did not adversely affect the NK tertiary structure. The maximum in vitro drug release in the simulated small intestine buffer was 93.3%, and the NK@HNTs-EL exhibited pH-dependent drug release. The drug release data were analyzed with different kinetic models, which showed that the NK@HNTs-EL drug-release mechanism involved erosion and osmotic pressure on the EL100-55. After 90 days of storage, the NK@HNTs-EL maintained an enzymatic activity greater than 95%. Hemolysis analyses indicated that NK@HNTs-EL was not cytotoxic at concentrations below 500 FU/mL. These findings indicate that NK@HNTs-EL is a promising oral thrombolytic agent. [ABSTRACT FROM AUTHOR]