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

• Published in: ChemMedChem Vol. 17; no. 19; pp. e202200384 - n/a
• Main Authors: Chauhan, Kanchan, Olivares‐Medina, Cindy N., Villagrana‐Escareño, Maria V., Juárez‐Moreno, Karla, Cadena‐Nava, Rubén D., Rodríguez‐Hernández, Ana G., Vazquez‐Duhalt, Rafael
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 06.10.2022; John Wiley and Sons Inc
• Subjects: Blood circulation; Catalytic activity; Chemical modification; Encapsulation; Enzyme Replacement Therapy; Enzymes; Gaucher disease; Gaucher Disease - drug therapy; Gaucher Disease - genetics; Gaucher's disease; Genetic disorders; glucocerebrosidase; Glucosylceramidase; Glucosylceramidase - genetics; Humans; Internalization; Intravenous administration; Macrophages; Mannose; Nanoparticles; nanoreactors; Nanotechnology; Stability; Therapy; virus-like particles; Viruses; VLP; virus-like particles; Gaucher disease; nanoparticles; VLP; glucocerebrosidase; nanoreactors
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202200384

Gaucher disease is a genetic disorder and the most common lysosomal disease caused by the deficiency of enzyme β‐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 β‐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 (KM=0.29 mM) and the functionalized nanoreactors (KM=0.32 mM) were similar even after chemical modification. Importantly, the stability of enzymes under physiological conditions (pH 7.4, 37 °C) was enhanced by ≈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. Fewer jabs, decreased cost: Gaucher disease is caused by a deficiency in β‐glucocerebrosidase (GCase). Although enzyme replacement therapy can be applied using mannose‐exposed conjugated GCase, the low stability of the enzyme in blood demands periodic intravenous administration, adding to the high cost of treatment. In this work, GCase was encapsulated inside virus‐like nanoparticles, and their surface was functionalized with mannose groups for targeting to macrophages. These nanoreactors showed significant GCase activity. Importantly, the enzymes were found to be 11‐fold more stable under physiological conditions after encapsulation, which could decrease the cost of therapy by reducing the number of required intravenous injections.