酶反应性聚合体改善GM1神经节脂质病细胞模型中的自噬失败

IF 2.5 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Frontiers in chemical engineering Pub Date : 2022-10-12 DOI:10.3389/fceng.2022.997607
Bipin Chakravarthy Paruchuri, Sarah Smith, Jessica Larsen
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引用次数: 1

摘要

GM1神经节苷脂病是由β-半乳糖苷酶(βgal)缺乏和随后GM1神经节苷在溶酶体中的积累引起的溶酶体储存障碍。GM1神经节脂质病和其他储存障碍的病理方面之一是自噬受损,即自噬体和溶酶体降解细胞废物的融合减少。酶替代疗法(ERT)可有效治疗全身性缺乏症,但受静脉注射酶的免疫原性和半衰期缩短的限制。在本文中,我们报道了一种透明质酸-b聚乳酸(HA-PLA)聚合体递送系统,该系统可以实现酶响应和持续递送βgal,以促进细胞自噬的自修复过程。HA-PLA聚合体平均直径为138.0±17.6 nm,包封βgal的效率为77.7±3.4%。在模型酶透明质酸酶存在的情况下,HA-PLA聚合体的包封剂释放量比没有酶的高两倍。我们还发现,与健康细胞相比,GM1神经节脂质病(GM1SV3)细胞模型中的自噬减少。据报道,在GM1SV3细胞中,负载βgal的聚合体增强了自噬。最值得注意的是,在聚合体处理24小时后,GM1SV3细胞中溶酶体和自噬体的融合恢复到健康细胞的正常水平。本文描述的HA-PLA聚合体可以提供一种治疗GM1神经节脂质中毒的有希望的递送系统。
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Enzyme-responsive polymersomes ameliorate autophagic failure in a cellular model of GM1 gangliosidosis
GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of β-galactosidase (βgal) and subsequent accumulation of GM1 ganglioside in lysosomes. One of the pathological aspects of GM1 gangliosidosis, and other storage disorders, is impaired autophagy, i.e., a reduced fusion of autophagosomes and lysosomes to degrade cellular waste. Enzyme replacement therapy (ERT) can effectively treat systemic deficiency but is limited by immunogenicity and shortened half-life of intravenously administered enzyme. In this paper, we report a hyaluronic acid-b-polylactic acid (HA-PLA) polymersome delivery system that can achieve an enzyme-responsive and sustained delivery of βgal to promote the cell’s self-healing process of autophagy. HA-PLA polymersomes have an average diameter of 138.0 ± 17.6 nm and encapsulate βgal with an efficiency of 77.7 ± 3.4%. In the presence of model enzyme Hyaluronidase, HA-PLA polymersomes demonstrate a two-fold higher release of encapsulant than without enzyme. We also identified reduced autophagy in a cellular model of GM1 Gangliosidosis (GM1SV3) compared to healthy cells, illustrated using immunofluorescence. Enhanced autophagy was reported in GM1SV3 cells treated with βgal-loaded polymersomes. Most notably, the fusion of lysosomes and autophagosomes in GM1SV3 cells returned to normal levels of healthy cells after 24 h of polymersome treatment. The HA-PLA polymersomes described here can provide a promising delivery system to treat GM1 Gangliosidosis.
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