Co-delivery of therapeutic protein and catalase-mimic nanoparticle using a biocompatible nanocarrier for enhanced therapeutic effect.

Therapeutic proteins are indispensable in the treatment of various human diseases. Despite the many benefits of therapeutic proteins, they also exhibit diverse side effects. Therefore, reducing unwanted side effects of therapeutic proteins as well as enhancing their therapeutic efficacy are very important in developing therapeutic proteins. Urate oxidase (UOX) is a therapeutic enzyme that catalyzes the conversion of uric acid (UA) into a soluble metabolite, and it is used clinically for the treatment of hyperuricemia. Since UA degradation by UOX generates H2O2 (a cytotoxic side product), UOX was co-delivered with catalase-mimic nanoparticles (AuNPs) using biocompatible pluronic-based nanocarriers (NCs) to effectively reduce H2O2-associated toxicity in cultured cells and to enhance UA degradation efficiency in vivo. Simple temperature-dependent size changes of NCs allowed co-encapsulation of both UOX and AuNPs at a high loading efficiency without compromising critical properties, resulting in efficient modulation of a mixing ratio of UOX and AuNPs encapsulated in NCs. Co-localizing UOX and AuNPs in the NCs led to enhanced UA degradation and H2O2 removal in vitro, leading to a great reduction in H2O2-associated cytotoxicity compared with UOX alone or a free mixture of UOX and AuNPs. Furthermore, we demonstrated that co-delivery of UOX and AuNPs using NCs significantly improves in vivo UA degradation compared to simple co-injection of free UOX and AuNPs. More broadly, we showed that biocompatible pluronic-based nanocarriers can be used to deliver a target therapeutic protein along with its toxicity-eliminating agent in order to reduce side effects and enhance efficacy.

Synergistic Degradation of a Hyperuricemia-Causing Metabolite Using One-Pot Enzyme-Nanozyme Cascade Reactions.

Multi-enzyme cascade reactions are frequently found in living organisms, in particular when an intermediate should be eliminated. Recently, enzyme-mimic nanomaterials (nanozymes) received much attention for various applications, because they are usually more stable and cost-effective than enzymes. However, enzyme-nanozyme cascade reations have not been yet extensively exploited. Therefore, in this study, we investigated one-pot enzyme-nanozyme cascade reactions using urate oxidase (UOX) and catalase-mimic gold nanoparticle nanozyme (AuNP) with the ultimate goal of treatment of hyperuricemia. UOX degrades hyperuricemia-causing uric acid, but also generates hydrogen peroxide raising several health concerns. We successfully demonstrated that one-pot UOX-AuNP cascade systems degrade uric acid more than five times faster than UOX alone, by eliminating potentially cytotoxic hydrogen peroxide, similar to enzyme-enzyme reactions.