Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in degradation of low-density lipoprotein receptor (LDLR) and PCSK9 inhibition emerges as an attractive strategy for atherosclerosis management. In this study, extracellular vesicles (EVs) were engineered to nanosponges, which could efficiently adsorb and deliver PCSK9 into lysosomes for degradation. Briefly, nanosponges were engineered by modifying EVs with EGF-A/PTGFRN fusion protein (PCSK9 binding domain EGF-A from the mutant LDLR with higher affinity was fused to the C-terminus of Prostaglandin F2 Receptor Negative Regulator). The modification endowed the EVs with hundreds of EGF-A displayed on the surface and thus the capacity to adsorb PCSK9 efficiently. The adsorbed PCSK9 would thus be delivered into lysosomes for degradation when the nanosponges were endocytosed by liver cell, thus releasing endogenous LDLR from degradation. In ApoE-/- mouse model, tail vein injected nanosponges were able to degrade PCSK9, increase LDLR expression, lower LDL-C level, and thus alleviate atherosclerosis. In summary, we here not only develop a novel strategy for PCSK9 inhibition, but also propose a universal method for adsorption and degradation of circulating proteins for disease management.

中文翻译：

---

工程化的细胞外囊泡作为纳米海绵，用于 PCSK9 的溶酶体降解。


前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 （PCSK9） 在低密度脂蛋白受体 （LDLR） 的降解中起着至关重要的作用，PCSK9 抑制成为动脉粥样硬化管理的一种有吸引力的策略。在这项研究中，细胞外囊泡 （EV） 被改造成纳米海绵，纳米海绵可以有效地吸附并将 PCSK9 递送到溶酶体中进行降解。简而言之，通过使用 EGF-A/PTGFRN 融合蛋白修饰 EV 来设计纳米海绵（来自具有较高亲和力的突变 LDLR 的 PCSK9 结合域 EGF-A 与前列腺素 F2 受体负调节因子的 C 端融合）。这种修饰使 EV 表面显示数百个 EGF-A，从而能够有效吸附 PCSK9。因此，当纳米海绵被肝细胞内吞时，吸附的 PCSK9 将被递送到溶酶体中进行降解，从而释放出内源性 LDLR。在 ApoE-/- 小鼠模型中，尾静脉注射的纳米海绵能够降解 PCSK9，增加 LDLR 表达，降低 LDL-C 水平，从而缓解动脉粥样硬化。总之，我们在这里不仅开发了一种抑制 PCSK9 的新策略，还提出了一种用于疾病管理的循环蛋白质吸附和降解的通用方法。