The expanding role of protease therapeutics (2012-2026): from replacement therapies to immune system modulation and beyond.

Proteases are powerful therapeutic agents, offering unique advantages over conventional small molecules and biologics through their ability to directly and precisely cleave and (de)activate their protein targets. Since the early 1990s, FDA-approved protease therapeutics have served as replacement therapies for hematological disorders, as enzyme supplements for digestive disorders, and as treatments for neuromuscular disorders. Recent developments have expanded the use of native proteases to modulate antibody responses, improve transplant outcomes, and treat rare conditions with high unmet needs. Despite challenges such as immunogenicity and substrate specificity, the therapeutic landscape of proteases is being redefined by innovations in enzyme engineering and discovery. These advances, combined with targeted delivery strategies and improved stability, are reshaping proteases into precise and adaptable therapeutic agents. Rather than being limited to traditional uses, proteases are increasingly recognized for their potential to address complex conditions such as viral infections, neurodegeneration, and fibrosis, among others. With continued development, proteases are positioned to become a versatile and robust class of biologics with expanding clinical relevance. The present review explores the evolving landscape of protease therapeutics, focusing on their clinical applications, immune-modulatory capabilities, and future potential in precision medicine. This review provides a timely update to the comprehensive article "Proteases as Therapeutics" by Craik, Page, and Madison, published in the Biochemical Journal in 2011.