Delivering Antisense Oligonucleotides across the Blood‐Brain Barrier by Tumor Cell‐Derived Small Apoptotic Bodies

Abstract

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.

Antisense oligonucleotides for Alzheimer's disease therapy: from the mRNA to miRNA paradigm

“…Such methods are reviewed in the section 3.1. ASO modifications and delivery strategies for therapeutic applications and elsewhere [ [8] , [9] , [10] , 16 ].

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Tumor-derived extracellular vesicles as messengers of natural products in cancer treatment

“…Wang et al . 181 combined cationic konjac glucomannan (cKGM) with anti-TNF-α antisense oligonucleotide. Load drugs in the apoptotic bodies (sABs) of brain metastatic cancer cells.…”

“…B) Analysis of brain delivery efficiency, fluorescence microscopy images of a brain section, and the representative images from fluorescence microscopy. Adapted with permission from 181 . Copyright Year 2021, Wiley-VCH GmbH.…”

Anti‐MicroRNA‐21 Oligonucleotide Loaded Spermine‐Modified Acetalated Dextran Nanoparticles for B1 Receptor‐Targeted Gene Therapy and Antiangiogenesis Therapy

“…Endosomal escape may be achieved via the "proton sponge" effect of the amine moieties and increased endosomal osmotic pressure by degradation of the SpAcDex material. [41,42] Thus, the endosomal escape of NPs in U87MG cells was carefully studied to elucidate the underlying mechanism. The colocalization ratio between endosomes and ATMO-21 was analyzed by CLSM, which was used as a negative control of the endosomal escape efficacy of B1L@SpAcDex-ATMO-21 NPs.…”