Engineered synthetic eukaryotic vesicles as anti-inflammatory drug delivery system to target Myd88

ABSTRACT: Mesenchymal stem cells (MSC) secrete naturally extracellular vesicles (EV) with a regenerative profile, and an increasing number of studies have focused on the employment of EV for therapeutic drug delivery. However, EV are usually produced by the cells at low quantities and packed with unnecessary cytoplasmic components that are unfavorable for further drug loading. In this study, we developed a simple vesicle generation process from the cell membranes directly, after which they are called synthetic eukaryotic vesicles (SyEV or reNV). We hypothesized that MSC-derived SyEV can be efficiently loaded with an anti-inflammatory drug and the loaded vesicles can strongly suppress bacterial outer membrane vesicle (OMV)-induced sepsis. SyEV were generated from MSC membranes through serial extrusion, ionic stress and subsequent revesiculation, leading to high yield and purity with very few cytosolic contaminants. When these SyEV were given to macrophages and mice exposed to OMV, the release of pro-inflammatory cytokines was significantly inhibited comparable to natural EV. Then, we encapsulated SyEV with a peptide targeting Myd88 and showed the enhanced therapeutic potential of the loaded vesicles in OMV-induced macrophages. Further, in vivo study indicated that the peptide-encapsulated SyEV could dramatically suppress cytokine release into the systemic circulation via a synergistic way. Taken together, these data suggest that SyEV-based therapeutics is a highly interesting platform to deliver an advanced therapeutic drug for the treatment of inflammatory diseases without severe side effects.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mesenchymal Stem Cell, Stem Cell

SUBMITTER: Evelin Berger  

LAB HEAD: Carina Sihlbom

PROVIDER: PXD033512 | Pride | 2023-03-11

REPOSITORIES: Pride