Nanocarriers for Protein Delivery to the Cytosol: Assessing the Endosomal Escape of Poly(Lactide-co-Glycolide)-Poly(Ethylene Imine) Nanoparticles
Nanocarriers for Protein Delivery to the Cytosol: Assessing the Endosomal Escape of Poly(Lactide-co-Glycolide)-Poly(Ethylene Imine) Nanoparticles
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DOI：
10.3390/nano9040652
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发表时间：
2019-04-01
期刊：
影响因子：
5.3
通讯作者：
Signore, Giovanni
中科院分区：
文献类型：
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作者：
Galliani, Marianna;Tremolanti, Chiara;Signore, Giovanni
治疗性蛋白质和酶是一组有趣的候选药物，可用于治疗多种疾病，但它们通常需要载体以避免体内降解和快速清除。为此，有机纳米颗粒（NP）因其生物相容性而成为绝佳选择，而负载交联酶聚集体（CLEA）的聚（丙交酯-乙交酯）（PLGA）NP最近作为靶向酶递送的多功能工具而引起了人们的关注。然而，PLGA NP 通过内吞作用被细胞摄取，并且通常被运输到溶酶体中，而许多治疗性蛋白质和酶应该到达细胞胞质溶胶以发挥其活性。在这里，我们设计了一个基于 CLEA 的系统，使用阳离子内体逃逸剂（聚（乙烯亚胺），PEI）实施，以将 CLEA NP 的用途扩展到胞质酶。我们证明我们的系统可以通过两种不同的机制在细胞质水平上传递蛋白质有效负载：内体逃逸和直接易位。最后，我们将该系统应用于体外治疗相关酶（超氧化物歧化酶，SOD）的细胞质递送。
Therapeutic proteins and enzymes are a group of interesting candidates for the treatment of numerous diseases, but they often require a carrier to avoid degradation and rapid clearance in vivo. To this end, organic nanoparticles (NPs) represent an excellent choice due to their biocompatibility, and cross-linked enzyme aggregates (CLEAs)-loaded poly (lactide-co-glycolide) (PLGA) NPs have recently attracted attention as versatile tools for targeted enzyme delivery. However, PLGA NPs are taken up by cells via endocytosis and are typically trafficked into lysosomes, while many therapeutic proteins and enzymes should reach the cellular cytosol to perform their activity. Here, we designed a CLEAs-based system implemented with a cationic endosomal escape agent (poly(ethylene imine), PEI) to extend the use of CLEA NPs also to cytosolic enzymes. We demonstrated that our system can deliver protein payloads at cytoplasm level by two different mechanisms: Endosomal escape and direct translocation. Finally, we applied this system to the cytoplasmic delivery of a therapeutically relevant enzyme (superoxide dismutase, SOD) in vitro.