Little things make big things happen

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Science Translational Medicine  18 Nov 2020:
Vol. 12, Issue 570, eabf4689
DOI: 10.1126/scitranslmed.abf4689


Iron core nanoparticles can serve as vesicle shuttles and be guided by external magnetic fields to deliver therapeutic exosomes to injured tissue.

Emerging understanding of exosomes, nanoscale membrane–bound vesicles released by cells to provide extracellular signaling, yields insights into their vital role in regulation of homeostasis and host response to disease. Originating from multivesicular bodies, exosomes transport proteins, phospholipids, microRNA, and mRNA and function as mediators of cell-to-cell communication. Exosomes released by endothelial cells activate endothelial progenitor cells and promote angiogenesis, whereas exosomes produced by malignant cells increase cellular adhesion and promote metastasis. Further elucidation of their biological role motivates growing interest in their use as potential therapeutics or sites of intervention in disease.

Liu et al. describe an innovative approach in which they used an iron core nanoparticle as a “vesicle shuttle” to augment and manipulate exosome biodistribution in response to injury. Their shuttle consisted of a core of ferro-ferric oxide wrapped in a silica shell to protect against acidic degradation and an outer polyethylene glycol corona conjugated to two antibody types to bind to both an exosome of interest and the target tissue. Using a rat model of myocardial infarction, they isolated exosomes with therapeutic effects and identified surface markers for use in creating exosome-specific antibodies. Their vesicle shuttles successfully targeted and transported exosomes of interest and were directed to the heart through external application of a magnetic field. They further demonstrated that their exosome-loaded nanoparticles released their antibodies in the relatively acidic environment of the injured myocardium to achieve focal exosome delivery and uptake.

After confirmation of focal and directed delivery of the targeted exosome, Liu and colleagues assessed the efficacy of their approach in both rat and rabbit models of myocardial infarction. Animals were treated 2 weeks after ligature of the left anterior descending artery, and ventricular function and histology were compared 4 weeks later. Remarkably, infarct size of treated animals was substantially reduced with a concomitant increase in angiogenesis. Echocardiography demonstrated improved function after treatment, with near return to normal function in comparison with control animals whose function continued to decline.

Although substantial further work is required before translating these findings to clinical implementation, Liu et al. have shown the tremendous therapeutic potential of nanoparticles in harnessing the body’s response to injury. Because the current approach relies on use of host exosomes, it will be important to determine whether exosome production in older hosts with chronic disease is as robust as that observed in study animals. If the natural response lacks the required therapeutic efficacy, engineered exosomes coupled with nanoparticles to deliver the therapy may be an alternative approach able to prove the adage that the best things come in small packages.

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