State Key Laboratory of Pharmaceutical Biotechnology School of Life Sciences Nanjing University 163 Xianlin Avenue Nanjing 210093 China.
State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Taipa Macau SAR 999078 China.
Adv Sci (Weinh). 2021 May 4;8(13):2004929. doi: 10.1002/advs.202004929. eCollection 2021 Jul.
The blood-brain barrier (BBB) is the most restrictive and complicated barrier that keeps most biomolecules and drugs from the brain. An efficient brain delivery strategy is urgently needed for the treatment of brain diseases. Based on the studies of brain-targeting extracellular vesicles (EVs), the potential of using small apoptotic bodies (sABs) from brain metastatic cancer cells for brain-targeting drug delivery is explored. It is found that anti-TNF- antisense oligonucleotide (ASO) combined with cationic konjac glucomannan (cKGM) can be successfully loaded into sABs via a transfection/apoptosis induction process and that the sABs generated by B16F10 cells have an extraordinarily high brain delivery efficiency. Further studies suggest that ASO-loaded sABs (sCABs) are transcytosed by b. End3 (brain microvascular endothelial cells, BMECs) to penetrate the BBB, which is mediated by CD44v6, and eventually taken up by microglial cells in the brain. In a Parkinson's disease (PD) mouse model, sCABs dramatically ameliorate PD symptoms via the anti-inflammatory effect of ASO. This study suggests that sABs from brain metastatic cancer cells are excellent carriers for brain-targeted delivery, as they have not only an extraordinary delivery efficiency but also a much higher scale-up production potential than other EVs.
血脑屏障（BBB）是最具限制性和复杂性的屏障，可阻止大多数生物分子和药物进入大脑。对于脑部疾病的治疗，迫切需要一种有效的脑部递药策略。基于对脑靶向细胞外囊泡（EVs）的研究，探索了利用脑转移性癌细胞的小凋亡体（sAB）进行脑靶向药物递送的潜力。研究发现，通过转染/凋亡诱导过程，将抗 TNF-α 反义寡核苷酸（ASO）与阳离子魔芋葡甘露聚糖（cKGM）结合可以成功地装载到 sAB 中，并且由 B16F10 细胞产生的 sAB 具有极高的脑递送效率。进一步的研究表明，载有 ASO 的 sAB（sCAB）通过 b.End3（脑微血管内皮细胞，BMECs）被转胞吞以穿透 BBB，这是由 CD44v6 介导的，最终被脑内的小胶质细胞摄取。在帕金森病（PD）小鼠模型中，sCAB 通过 ASO 的抗炎作用显著改善 PD 症状。这项研究表明，脑转移性癌细胞的 sAB 是脑靶向递药的理想载体，因为它们不仅具有非凡的递药效率，而且与其他 EV 相比，具有更高的规模化生产潜力。
