Background
Extracellular vesicles (EV) mediate cellular communication locally in tissue microenvironments [1], distally from their cell source following sterile injury such as stroke [2], acute myocardial infarction [3, 4] brain injury [5] and in isolated cells in vitro [6]. The ability of EV to modulate the behaviour and phenotype in recipient cells poises them as an attractive therapeutic. EV therapeutic responses are driven by EV-specific cargo, such as proteins [6], lipids [7], small noncoding RNAs [4], mRNA, transcription factors [8], DNA, metabolites, and enzymes encased within the EV or decorated on the EV surface. For this reason, bioengineering approaches may allow the modification of EV-surface proteins and lipids to enable cellular targeting and strategies to load EV with specific RNA, DNA and pharmacological agents to enable EV as vectors for therapeutics [9]. Thereby, functionally manipulating recipient cells, for example to perturb pro-inflammatory signalling, inhibit cellular proliferation, differentiation and to promote regeneration and repair in a broad range of pathological tissues. There are important considerations when designing EV-therapeutics, such as biodistribution profiles in appropriate disease models and exploration of different methods of delivery, which are possibly, overlooked in current EV research investigations.
There has been tremendous success in the use of lipid nanoparticles in the administration of the mRNA SARs-CoV-2 vaccine internationally for COVID-19 [10]. Ionised lipids bind to negatively charged mRNA, supported by pegylated lipids, phospholipids, and cholesterol molecules to enable trafficking across the plasma membrane, delivering a payload of mRNA to cells for therapeutic effects. Advances, which enabled lipid nanoparticle technologies for drug/mRNA delivery were developed over several decades [11] but there are limitations. Unmodified lipid nanoparticles are not specific and therefore do not allow targeting of individual cells. When administered intravenously lipid nanoparticles are rapidly delivered to tissues, including the liver and spleen where they can show toxicity. The lipid nanoparticles used for the SARs-CoV-2 vaccine delivery are also not universal. Delivery of new mRNA vaccines will require alterations in the carbon tails of the lipids and ester linkages to enable similarly effective delivery and to prohibit toxicity. However, these modifications alter the lipid nanoparticle biodegradability and biodistribution patterns in vivo [12].
Naturally targeting vectors such as EV, can localise to specific cells, penetrate deep within tissues, easily pass through the cell membrane to deliver therapeutic molecules such as RNA and show no toxicity or immunogenicity [13]. EV have a net negative charge (zeta potential) and therefore are stable in physiological buffers and as they transit in the blood. Their inability to divide and replicate mitigates potential tumourgenic effects and they are stable for prolonged periods of time, which may facilitate practical limitations of lipid nanoparticle drug deliver systems, which require precise storage, such as the storage concerns with the COVID-19 mRNA vaccine Pfizer BioNTech (tozinameran). These EV strengths open new and important opportunities for EV-based therapeutics, with potential to generate autologous EV for personalised medical therapy, which would circumvent issues in biocompatibility and capitalise on EV naturally occurring receptors for targeted effects. However, there are concerns on EV heterogeneity, composition, characterization, and the consequences of functional manipulation of EV for targeted effects. Here, I will briefly discuss the need for more stringent assessment of EV-therapeutic biodistribution profiles in appropriate pathological models and highlight the need to explore appropriate routes of EV administration depending on the target organs with a focus on the vasculature (Figure 1 and Table 1).
