Targeting extracellular vesicles to injured tissue using membrane cloaking and surface display

Abstract

BackgroundExtracellular vesicles (EVs) and exosomes are nano-sized, membrane-bound vesicles shed by most eukaryotic cells studied to date. EVs play key signaling roles in cellular development, cancer metastasis, immune modulation and tissue regeneration. Attempts to modify exosomes to increase their targeting efficiency to specific tissue types are still in their infancy. Here we describe an EV membrane anchoring platform termed “cloaking” to directly embed tissue-specific antibodies or homing peptides on EV membrane surfaces ex vivo for enhanced vesicle uptake in cells of interest. The cloaking system consists of three components: DMPE phospholipid membrane anchor, polyethylene glycol spacer and a conjugated streptavidin platform molecule, to which any biotinylated molecule can be coupled for EV decoration.ResultsWe demonstrate the utility of membrane surface engineering and biodistribution tracking with this technology along with targeting EVs for enhanced uptake in cardiac fibroblasts, myoblasts and ischemic myocardium using combinations of fluorescent tags, tissue-targeting antibodies and homing peptide surface cloaks. We compare cloaking to a complementary approach, surface display, in which parental cells are engineered to secrete EVs with fusion surface targeting proteins.ConclusionsEV targeting can be enhanced both by cloaking and by surface display; the former entails chemical modification of preformed EVs, while the latter requires genetic modification of the parent cells. Reduction to practice of the cloaking approach, using several different EV surface modifications to target distinct cells and tissues, supports the notion of cloaking as a platform technology.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0388-4) contains supplementary material, which is available to authorized users.

Advances in Analysis of Biodistribution of Exosomes by Molecular Imaging

“…In addition to natural cell-targeting abilities, it is also possible to engineer exosomes to target specific tissues or cells [102]. PEGylation of exosomes resulted in targeted accumulation of exosomes derived from cardiosphere-derived cells in ischemic myocardium in mice [111]. Targeted delivery of exosomes by genetic modification of their surface proteins has been also been reported: (1) brain targeting by rabies viral glycoprotein (RVG) peptide or RGD motif [19,112]; and (2) tumor targeting by EGFR-specific nanobodies or HER2-specific single-chain variable fragments [113].…”

Altered adrenergic response in myocytes bordering a chronic myocardial infarction underlies in vivo triggered activity and repolarization instability

“…Our study highlights the role of myocyte remodelling for both the triggers and functional substrate of the arrhythmia. Therefore, targeting the myocytes through local approaches such as targeted gene therapy (Sasano et al 2006) and exosome targeting (Antes et al 2018) may offer alternative, non-destructive strategies to treat post-MI arrhythmia.…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…Several studies have been lately reported suggesting alternative strategies to functionalise EVs for more accurate targeting of the damaged heart [220,221]. These include: lentiviral vector-based engineering of secreting cells to upregulate the expression of cardiomyocyte-specific binding peptides fused to the murine transmembrane protein Lamp2b, in order to enrich the targeting epitope on the exosomal surface [222]; overexpression of exosomal CXCR4 to push their bioavailability towards the ischaemic heart [156]; membrane anchoring systems to directly dock tissue-specific antibodies or homing antigens on the EV surface [223,224].…”