Spatial Confined Synergistic Enzymes with Enhanced Uricolytic Performance and Reduced Toxicity for Effective Gout Treatment

Abstract

Confinement of urate oxidase with detoxifying enzymes into multienzyme architecture is an appealing approach for gout treatment due to its capability to decompose serum uric acid without generation of H O . However, most of these strategies involve chemical modifications to the enzymes and barely consider enhancing the stability of the multienzyme architectures particularly against proteolysis, which significantly dampened its catalytic activity and in vivo stability. Herein, a novel strategy to prepare multienzyme nanoclusters with highly uricolytic activity and enhanced stability is demonstrated. With the close proximation, catalase can effectively decompose the H O generated by uricase during uricolysis. Moreover, with a shell structure constructed with polyethylene glycol, the nanocluster achieves great performance in reducing the nonspecific serum protein adsorptions and proteases digestion, leading to an enhanced circulation time after the intravenous administration. Such complementary multienzyme nanoclusters realize the long-term therapeutic effect in the management of serum uric acid level, without any toxicity or undesired immune responses in vivo. This work mimics the synergistic effect of protein complex in nature and can be further developed to a general method for the construction of multienzyme nanoclusters, which provides new opportunities for utilizing therapeutic enzymes for the treatment of metabolic diseases.

In Situ Modification of the Tumor Cell Surface with Immunomodulating Nanoparticles for Effective Suppression of Tumor Growth in Mice

“…To prepare IMN, BSA was first encapsulated into nBSA via in situ polymerization as reported previously . The nBSA was then subsequently conjugated with PBA using 2,5‐dioxopyrroliding [(4‐dihydroboran)phenyl]amide propionate (PBA‐NHS, Figures S1a and S2a, Supporting Information) to obtain nBSA‐PBA.…”

Advanced functional polymer materials

“…43). [275][276][277][278] A prolonged plasma circulation time can be observed (as high as 7 days) with low level of immunogenicity. This in situ polymerization technique can be universally applied to a library of proteins, with different sizes, surface charges, and structures.…”

Cargo‐Templated Crosslinked Polymer Nanocapsules and Their Biomedical Applications

“…The particle size of CT‐CPNCs can be varied from 10–200 nm depending on the cargoes and synthesis conditions. [ 15 ] For example, single‐protein CT‐CPNCs with a small particle size (10–30 nm) usually have a long circulation half life in vivo, showing the potential for the treatment of metabolic diseases such as hyperuricemia [29b,50] . Blood–brain barrier (BBB) is a highly regulated brain endothelial structure, which provides shelter to the brain.…”

“…[ 94 ] Recently, Liu and co‐workers developed another multiple‐enzyme CT‐CPNC. [ 50 ] As shown in Figure 7 a, UOx and CAT were first encapsulated into n(UOx) and n(CAT), respectively, using APM ( A2 ) as a monomer. Adamantane‐terminated polyethylene glycol (PEG‐Ad) and cyclodextrin‐terminated PEG (CD‐PEG) were conjugated to the amine groups on the surface of n(UOx) and n(CAT), respectively, to prepare n(UOx)‐PEG‐Ad and n(CAT)‐PEG‐CD.…”