ABSTRACT

A long-term and huge challenge in nanomedicine is the substantial uptake and rapid clearance mediated by the mononuclear phagocyte system (MPS), which enormously hinders the development of nanodrugs. Inspired by the natural merits of extracellular vesicles, we therefore developed a combined “eat me/don’t eat me” strategy in an effort to achieve MPS escape and efficient drug delivery. Methodologically, cationized mannan-modified extracellular vesicles derived from DC2.4 cells were administered to saturate the MPS (eat me strategy). Then, nanocarriers fused to CD47-enriched exosomes originated from human serum were administered to evade phagocytosis by MPS (don’t eat me strategy). The nanocarriers were also loaded with antitumor drugs and functionalized with a novel homing peptide to promote the tumour tissue accumulation and cancer cell uptake (eat me strategy). The concept was proven in vitro as evidenced by the reduced endocytosis of macrophages and enhanced uptake by tumour cells, whereas prolonged circulation time and increased tumour accumulation were demonstrated in vivo. Specially, the strategy induced a 123.53% increase in tumour distribution compared to conventional nanocarrier. The study both shed light on the challenge overcoming of phagocytic evasion and provided a strategy for significantly improving therapeutic outcomes, potentially permitting active drug delivery via targeted nanomedicines.

摘要

纳米药物的一个长期而巨大的挑战是单核吞噬细胞系统（MPS）介导的大量摄取和快速清除，这极大地阻碍了纳米药物的发展。受细胞外囊泡天然优点的启发，我们开发了一种组合的“吃我/不吃我”策略，以努力实现 MPS 逃逸和有效的药物输送。在方法学上，施用源自DC2.4细胞的阳离子化甘露聚糖修饰的细胞外囊泡以使MPS饱和（吃我策略）。然后，将纳米载体与源自人血清的富含 CD47 的外泌体融合，以逃避 MPS 的吞噬作用（别吃我策略）。纳米载体还负载有抗肿瘤药物，并用新型归巢肽进行功能化，以促进肿瘤组织积累和癌细胞摄取（吃我策略）。这一概念在体外得到了证实，巨噬细胞内吞作用减少，肿瘤细胞摄取增强，而体内循环时间延长，肿瘤积累增加。特别是，与传统纳米载体相比，该策略使肿瘤分布增加了 123.53%。该研究既揭示了克服吞噬细胞逃避的挑战，又提供了一种显着改善治疗结果的策略，有可能允许通过靶向纳米药物进行主动药物输送。