Strategies that selectively bind proteins of interest and target them to the intracellular protein recycling machinery for targeted protein degradation have recently emerged as powerful tools for undruggable targets in biomedical research and the pharmaceutical industry. However, targeting any new protein of interest with current degradation tools requires a laborious case-by-case design for different diseases and cell types, especially for extracellular targets. Here we observe that nanoparticles can mediate specific receptor-independent internalization of a bound protein and further develop a general strategy for degradation of extracellular proteins of interest by making full use of clinically approved components. This extremely flexible strategy aids in targeted protein degradation tool development and provides knowledge for targeted drug therapies and nanomedicine design.

选择性结合目标蛋白质并将其靶向细胞内蛋白质回收机制以进行靶向蛋白质降解的策略最近已成为生物医学研究和制药行业中不可成药靶标的强大工具。然而，使用当前的降解工具靶向任何感兴趣的新蛋白质需要针对不同的疾病和细胞类型进行费力的逐案设计，尤其是细胞外靶标。在这里，我们观察到纳米颗粒可以介导结合蛋白的特异性受体非依赖性内化，并通过充分利用临床批准的成分进一步开发降解感兴趣的细胞外蛋白的一般策略。这种极其灵活的策略有助于靶向蛋白质降解工具的开发，并为靶向药物治疗和纳米药物设计提供知识。