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

Zhang, ZZ (Zhang, Zhanzhan)^[ 1 ] ; Gu, Y (Gu, Yu)^[ 1 ] ; Liu, Q (Liu, Qi)^[ 1 ] ; Zheng, CX (Zheng, Chunxiong)^[ 1 ] ; Xu, LF (Xu, Lifeng)^[ 1 ] ; An, YL (An, Yingli)^[ 1 ] ; Jin, X (Jin, Xin)^[ 2 ] ; Liu, Y (Liu, Yang)^[ 1 ] ; Shi, LQ (Shi, Linqi)^[ 1 ]

SMALL, 2018, 14(33): 文献号: 1801865

DOI: 10.1002/smll.201801865

 WOS:000441760000017

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 H2O2. 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 H2O2 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.