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引用次数: 0
摘要
现有策略使用双功能嵌合体来介导细胞外蛋白质降解。然而,这些策略依赖于特定的溶酶体捕获受体来促进溶酶体递送,这可能会因细胞间受体表达的内在差异以及受体的突变或下调而引发耐药性问题。另一个挑战是建立一个适用于多种情况的通用平台。在这里,我们开发了一种即插即用的单功能降解平台--MONOTAB(MOdified NanOparticle with TArgeting Binders),它能将细胞外靶标拖入溶酶体进行降解。MONOTAB 利用某些纳米粒子固有的溶酶体靶向能力,避免了对特定受体的依赖性和钩状效应。为了实现高度模块化和可编程的靶向特异性,我们利用链霉亲和素与生物素的相互作用,通过抗体安装方法或直接结合,将抗体或其他靶向分子固定在纳米粒子上。我们的研究表明,MONOTAB 能诱导高效降解各种治疗靶标,包括膜蛋白、分泌蛋白甚至细胞外囊泡。
A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles.
Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.