Engineering Extracellular Vesicles Restore the Impaired Cellular Uptake and Attenuate Intervertebral Disc Degeneration

Abstract

Extracellular vesicles (EVs) are potential alternatives for mesenchymal stem cells (MSCs) in the treatment of musculoskeletal degenerative diseases, including intervertebral disc degeneration (IDD). Usually, EVs are internalized and then deliver bioactive molecules that impart phenotypic changes in recipient cells. For effective utilization of EVs in the IDD therapy, understanding the mechanism of EV uptake is of vital importance. In this study, we found that EVs delivered antioxidant proteins to protect against pyroptosis of nucleus pulposus cells (NPCs). In particular, the therapeutic effect of EVs decreased in TNF-α-treated NPCs due to the impaired caveolae-mediated endocytosis pathway. Transcriptome sequencing and functional verification revealed that caveolae associated protein 2 (Cavin-2) played an important role in the uptake process of EVs. We then constructed the Cavin-2-modified engineering EVs via the gene-editing of parental MSCs. These kinds of modified EVs presented an improved uptake rate in TNF-α-treated NPCs, which effectively ameliorated the cell death of NPCs in a three-dimensional hydrogel culture model and retarded the progression of IDD in the ex vivo organ culture model. Collectively, these findings illustrate the mechanism of EV uptake in NPCs and explore the application of engineering EVs in the treatment of IDD.

The Proteolysis of ECM in Intervertebral Disc Degeneration

“…In recent studies, caveolae associated protein 2 (Cavin-2) modified engineered extracellular vesicles were used to treat disc degeneration. Cavin-2 modification significantly increased the extracellular vesicle uptake efficacy in degenerating NP cells compared to stem cell-derived extracellular vesicles alone [135]. Collectively, these studies demonstrate the great potential of bioactive materials in targeting IVD ECM degeneration, but more studies are needed to evaluate their long-term safety and efficacy (Table 1).…”

Oxidative Stress Aggravates Apoptosis of Nucleus Pulposus Cells through m6A Modification of MAT2A Pre-mRNA by METTL16

“…The stained sections were then observed under a microscope; the number of cells and the structure of NP tissue were observed to evaluate the severity of IVDD. The degenerative degree of discs was evaluated by a histological grading scale [ 27 – 29 ]. The scale was based on five categories of disc changes: with 0 points for a normal disc and 15 points for a severely degenerated disc.…”

Engineering Injectable Anti‐Inflammatory Hydrogels to Treat Acute Myocardial Infarction

“…Several studies have shown that injectable hydrogels can be used to load antioxidant drugs to regulate oxidative stress. [82][83][84][85][86] The antioxidants commonly used in the treatment of AMI include vitamins, [87,88] polyphenols, [89,90] and mitochondriatargeted drugs. [91] The therapeutic effect of vitamins has been studied and some advances have been reported in animal AMI models.…”