通过劫持巨胞饮作用的工程化溶酶体靶向蛋白质降解
Engineered Lysosome-Targeted Protein Degradation via Hijacking Macropinocytosis.
摘要(中文译文)
近年来，靶向蛋白质降解（TPD）策略已成为生物医学研究和制药行业中解决不可成药靶点的有效工具，其通过选择性结合目标蛋白并将其靶向至细胞内降解机器进行降解。然而，利用现有降解工具靶向细胞外蛋白需要基于细胞表面受体内吞运输的繁琐且需针对具体案例进行选择和设计的过程。在此，我们介绍了巨胞饮靶向嵌合体（MapTACs），这是一种利用巨胞饮作用——一种不依赖受体的内吞过程——将细胞外蛋白递送至溶酶体进行降解的TPD平台。利用葡聚糖作为多功能支架偶联蛋白结合适配体或抗体，我们证明MapTACs能以时间、剂量和巨胞饮依赖的方式高效降解单核细胞趋化蛋白-1（MCP-1）。重要的是，无需受体特异性修饰，MapTACs对多种细胞类型和细胞外蛋白靶点（MCP-1、肿瘤坏死因子-α和干扰素-γ）表现出广泛适用性。靶向TNF-α的MapTACs在LPS诱导的急性炎症模型中有效且特异性地降低TNF-α水平，减轻肺损伤，其半衰期约为0.72小时，主要蓄积于肝脏和肺部，其中F4/80阳性单核细胞/巨噬细胞为主要摄取细胞。通过克服基于受体的TPD策略的局限性，MapTAC为细胞外蛋白质降解提供了一个通用、经济高效且可扩展的平台，促进了靶向蛋白质降解工具的开发，并为癌症、炎症和其他疾病的治疗干预开辟了机会。
Abstract
Recently, targeted protein degradation (TPD) strategies have emerged as an effective tool for addressing undruggable targets in both biomedical research and the pharmaceutical industry, selectively binding proteins of interest and targeting them to the intracellular degradation machinery for degradation. However, the targeting of extracellular proteins with current degradation tools requires a tedious, case-specific selection and design process based on lysosomal trafficking of cell surface receptors. Here, we introduce Macropinocytosis-Targeting Chimeras (MapTACs), a TPD platform that exploits macropinocytosis, a receptor-independent endocytic process, to deliver extracellular proteins to lysosomes for degradation. Using dextran as a versatile scaffold conjugated to protein-binding aptamers or antibodies, we demonstrate that MapTACs efficiently degrade monocyte chemotactic protein-1 (MCP-1) in a time-, dose-, and macropinocytosis-dependent manner. Importantly, without the need for receptor-specific modifications, MapTACs exhibit broad applicability to a variety of cell types and extracellular protein targets (MCP-1, tumor necrosis factor-α, and interferon-γ). , TNF-α-targeting MapTACs effectively and specifically reduce the levels of TNF-α in an LPS-induced acute inflammation model, attenuating lung injury, with a half-life of approximately 0.72 h and predominant accumulation in the liver and lung, where F4/80-positive monocytes/macrophages serve as the primary uptake cells. By overcoming the limitations of the receptor-based TPD strategy, MapTAC provides a universal, cost-effective, and scalable platform for extracellular protein degradation, facilitating the development of targeted protein degradation tools and opening opportunities for therapeutic intervention in cancer, inflammation, and other diseases.
如何引用
AMA
Wen Xu, Henggong Pan, Yalan Han, Ling-Yan Su, Hejiang Zhou. Engineered Lysosome-Targeted Protein Degradation via Hijacking Macropinocytosis.. ACS nano. 2026; doi:10.1021/acsnano.6c07737.
APA
Wen Xu, Henggong Pan, Yalan Han, Ling-Yan Su, Hejiang Zhou (2026). Engineered Lysosome-Targeted Protein Degradation via Hijacking Macropinocytosis.. ACS nano. https://doi.org/10.1021/acsnano.6c07737
GB/T 7714
Wen Xu, Henggong Pan, Yalan Han, Ling-Yan Su, Hejiang Zhou. Engineered Lysosome-Targeted Protein Degradation via Hijacking Macropinocytosis.[J]. ACS nano, 2026 doi:10.1021/acsnano.6c07737.
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