Nattokinase: A multifunctional food-derived enzyme for thrombophilia management.

A thrombophilic tendency (thrombophilia) is a hypercoagulable state that significantly increases the risk of thromboembolic events. Although conventional anticoagulant therapy is effective, the inherent risk of bleeding limits its long-term use, creating an urgent need for safer and more effective alternatives. Nattokinase (NK)- a serine protease derived from the fermentation of natto by Bacillus subtilis- exerts its antithrombotic effects through multiple mechanisms and targets, including direct degradation of fibrin, inhibition of platelet aggregation, and antioxidant/anti-inflammatory actions, while offering oral bioavailability and potential for long-term prevention. However, bottlenecks such as insufficient pH and thermal stability, limited clinical evidence, and a lack of standardization hinder its translation into clinical practice. This review systematically integrates the multifunctional mechanisms and pharmacokinetic characteristics of NK, proposing a 'dynamic equilibrium model of thrombolysis and haemostasis' as a theoretical framework to guide end-to-end optimization from molecular modification to personalized therapy. We first compare and evaluate the therapeutic advantages of NK against traditional and novel antithrombotic drugs. And then we critically analyze the technical maturity and clinical feasibility of engineering modifications (surface charge regulation, regional stiffening, AI-assisted design) and delivery systems (polysaccharide encapsulation, liposomes, nanocarriers). Finally, we identify priority research areas such as standardized production, genotype-guided dosing and trials in high-risk populations, thereby providing a roadmap for the translation of NK from functional foods to clinical drugs.