Lv Mingchen, Xu Jiaxi, Chen Ran, Hu Wei, Zhou Yuxiao, Sun Min, Fan Zhen, Du Jianzhong
Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai, 201804, China.
Department of Gynaecology and Obstetrics, Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine, Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, 200434, China.
Small. 2025 Apr;21(14):e2412612. doi: 10.1002/smll.202412612. Epub 2025 Mar 3.
Hyperuricemia, characterized by elevated uric acid levels, is the primary cause of gout. Recombinant uricase is one of the last-resort therapies but generates unwanted pro-inflammatory HO and anti-uricase antibodies. In this work, we developed an albumin corona-coated enzyme-loaded zeolitic imidazolate framework (UCZIF) to sustainably maintain low blood uric acid level without producing HO. The corona coating not only preserves loaded enzymes but also reduces macrophage phagocytosis by 73.4% compared to free uricase. In addition, the uptake level of UCZIF by dendritic cells is reduced by 74.1%, and the maturation of dendritic cells is inhibited by 35.4% compared to free uricase. Animal experiments demonstrate that albumin corona-coated UCZIF effectively lowers blood uric acid level in both acute and diet-induced chronic hyperuricemia models with significantly increasing the half-life of uricase. Furthermore, compared to the generation of anti-uricase antibodies during standalone uricase treatment, the levels of anti-uricase immunoglobulins are significantly reduced by 65.5% (immunoglobulin M) and 76.3% (immunoglobulin G) with repeated administration of albumin corona-coated UCZIF. Overall, this albumin corona-coated nanoscale metal-organic framework offers a promising approach to minimize the immunogenicity induced by exogenous enzymes and further safely reduce uric acid levels in the treatment of hyperuricemia.
高尿酸血症以尿酸水平升高为特征，是痛风的主要病因。重组尿酸酶是最后的治疗手段之一，但会产生不良的促炎物质HO和抗尿酸酶抗体。在这项工作中，我们开发了一种白蛋白冠层包被的载酶沸石咪唑框架（UCZIF），以可持续地维持低血尿酸水平而不产生HO。冠层包被不仅能保护负载的酶，而且与游离尿酸酶相比，还能使巨噬细胞吞噬作用降低73.4%。此外，与游离尿酸酶相比，UCZIF被树突状细胞的摄取水平降低了74.1%，树突状细胞的成熟受到35.4%的抑制。动物实验表明，白蛋白冠层包被的UCZIF在急性和饮食诱导的慢性高尿酸血症模型中均能有效降低血尿酸水平，并显著延长尿酸酶的半衰期。此外，与单独使用尿酸酶治疗期间产生抗尿酸酶抗体相比，重复给药白蛋白冠层包被的UCZIF后，抗尿酸酶免疫球蛋白水平显著降低，免疫球蛋白M降低65.5%，免疫球蛋白G降低76.3%。总体而言，这种白蛋白冠层包被的纳米级金属有机框架为最小化外源性酶诱导的免疫原性并在高尿酸血症治疗中进一步安全降低尿酸水平提供了一种有前景的方法。
