美国威斯康星大学Quanyin Hu团队报道工程化血小板作为靶向蛋白降解剂，及其在乳腺癌模型中的应用。该项研究成果于2024年12月3日在线发表在《自然—生物技术》杂志上。

据悉，靶向蛋白降解的嵌合分子临床应用受限于不理想的药物特性，和系统给药后由于非特异性生物分布引发的生物安全性问题。

研究人员开发了一种工程化血小板的方法，通过共价标记血小板中的热休克蛋白90（HSP90）与目标蛋白配体，实现体内降解细胞内或细胞外的目标蛋白（POI）。降解血小板（DePLT）能够靶向伤口区域并激活。

根据连接的POI配体和预标记HSP90的运输机制，激活的DePLT可通过泛素-蛋白酶体机制或溶酶体，介导靶细胞中的目标蛋白降解。包装在血小板衍生微颗粒中的HSP90，利用泛素-蛋白酶体系统降解细胞内的POI，而释放的游离HSP90则将细胞外的POI引导至溶酶体进行降解。

在术后乳腺癌小鼠模型中，工程化的DePLT通过对应的POI配体，有效降解细胞内的溴域含量蛋白4或细胞外的程序性死亡配体1，从而抑制癌症复发或转移。

附：英文原文

Title: Engineered platelets as targeted protein degraders and application to breast cancer models

Author: Chen, Yu, Pal, Samira, Li, Wen, Liu, Fengyuan, Yuan, Sichen, Hu, Quanyin

Issue&Volume: 2024-12-03

Abstract: Clinical application of chimeric molecules for targeted protein degradation has been limited by unfavorable drug-like properties and biosafety concerns arising from nonspecific biodistribution after systemic administration. Here we develop a method to engineer platelets for degradation of either intracellular or extracellular proteins of interest (POIs) in vivo by covalently labeling heat shock protein 90 (HSP90) in platelets with a POI ligand. The degrader platelets (DePLTs) target wound areas and undergo activation. Depending on the tethered POI ligand and transport mechanism of the prelabeled HSP90, activated DePLTs can mediate targeted protein degradation in the target cell through the ubiquitin–proteasome machinery or the lysosome. HSP90 packaged into platelet-derived microparticles uses the ubiquitin–proteasome system to degrade intracellular POIs, whereas released free HSP90 redirects extracellular POIs to lysosomal degradation. In postsurgical breast cancer mouse models, DePLTs engineered with corresponding POI ligands effectively degrade intracellular bromodomain-containing protein 4 or extracellular programmed cell death ligand 1, thereby suppressing cancer recurrence or metastasis.

DOI: 10.1038/s41587-024-02494-8

Source: https://www.nature.com/articles/s41587-024-02494-8