From Permeation Enhancer to Therapeutic Enabler: Advances, Applications, and Translational Perspectives in Hyaluronidase-Based Drug Delivery

Hyaluronidase is a carbohydrate-active enzyme that cleaves glycosaminoglycans, particularly hyaluronic acid. By transiently degrading the extracellular matrix, it facilitates reliable subcutaneous delivery of high-dose protein therapeutics. Despite its proven utility, challenges remain in preserving enzyme stability and ensuring consistent catalytic performance across formulations. Recent efforts have therefore focused on excipient and pH optimization to maintain protein integrity while sustaining enzymatic activity, device engineering to enhance injectability and patient usability, and pharmacokinetic modeling to correlate local tissue dispersion with systemic exposure. In oncology, hyaluronidase is increasingly incorporated into anticancer regimens to remodel the tumor microenvironment, alleviate stromal resistance, and promote immune-cell infiltration, thereby enabling synergistic antitumor effects across multiple therapeutic modalities. This review first classifies hyaluronidases by their biological sources and catalytic mechanisms, then summarizes advances in drug delivery with particular emphasis on recombinant human hyaluronidase in clinical use. Finally, it highlights mechanistic and translational insights that guide the rational design of safer, more effective, and clinically adaptable hyaluronidase-enabled delivery systems for both subcutaneous and tumor-targeted applications. Hyaluronidase transiently remodels the extracellular matrix to enhance drug permeability and dispersion. This review outlines advances in recombinant human hyaluronidase (rHuPH20) for subcutaneous and tumor-targeted delivery, highlighting formulation stabilization, injectability optimization, and pharmacokinetic modeling.