Targeted Enzymatic VLP-Nanoreactors with β-Glucocerebrosidase Activity as Potential Enzyme Replacement Therapy for Gaucher's Disease

Gaucher disease is a genetic disorder and the most common lysosomal disease caused by the deficiency of enzyme beta-glucocerebrosidase (GCase). Although enzyme replacement therapy (ERT) is successfully applied using mannose-exposed conjugated glucocerebrosidase, the lower stability of the enzyme in blood demands periodic intravenous administration that adds to the high cost of treatment. In this work, the enzyme beta-glucocerebrosidase was encapsulated inside virus-like nanoparticles (VLPs) from brome mosaic virus (BMV), and their surface was functionalized with mannose groups for targeting to macrophages. The VLP nanoreactors showed significant GCase catalytic activity. Moreover, the Michaelis-Menten constants for the free GCase enzyme (K-M=0.29 mM) and the functionalized nanoreactors (K-M=0.32 mM) were similar even after chemical modification. Importantly, the stability of enzymes under physiological conditions (pH 7.4, 37 degrees C) was enhanced by approximate to 11-fold after encapsulation; this is beneficial for obtaining a higher blood circulation half-life, which may decrease the cost of therapy by reducing the requirement of multiple intravenous injections. Finally, the mannose receptor targeted enzymatic nanoreactors showed enhanced internalization into macrophage cells. Thus, the catalytic activity and cell targeting suggest the potential of these nanoreactors in ERT of Gaucher's disease.

Automated summary

Encapsulated enzyme nanoreactors showed significant GCase catalytic activity and enhanced stability under physiological conditions. Targeting to macrophages was achieved through mannose receptor functionalization, suggesting potential for enzyme replacement therapy in Gaucher's disease.