Exosome-Mediated Small RNA Delivery: A Novel Therapeutic Approach for Inflammatory Lung Responses

Abstract

Exosomes (EXOs) are a type of extracellular nanovesicles released from living cells. Accumulating evidence suggests that EXOs are involved in the pathogenesis of human diseases, including lung conditions. In recent years, the potential of EXO-mediated drug delivery has gained increasing interest. In this report, we investigated whether inhaled EXOs serve as an efficient and practical delivery vehicle to activate or inhibit alveolar macrophages (AMs), subsequently modulating pulmonary immune responses. We first identified the recipient cells of the inhaled EXOs, which were labeled with PKH26. We found that only lung macrophages efficiently take up intratracheally instilled EXOs in vivo. Using modified calcium chloride-mediated transformation, we manipulated small RNA molecules in serum-derived EXOs, including siRNAs, microRNA (miRNA) mimics, and miRNA inhibitors. Via intratracheal instillation, we successfully delivered siRNA and miRNA mimics or inhibitors into lung macrophages using the serum-derived EXOs as vehicles. Furthermore, EXO siRNA or miRNA molecules are functional in modulating LPS-induced lung inflammation in vivo. Beneficially, serum-derived EXOs themselves do not trigger lung immune responses, adding more favorable features to serve as drug delivery agents. Collectively, we developed a novel protocol using serum-derived EXOs to deliver designated small RNA molecules into lung macrophages in vivo, potentially shedding light on future gene therapy of human lung diseases.

Mesenchymal Stem Cells Reduce Corneal Fibrosis and Inflammation via Extracellular Vesicle-Mediated Delivery of miRNA

“…These results suggest a role for miRNA in the anti‐inflammatory/regenerative function displayed by the CSSC EVs. Such a function is consistent with a number of recent studies that have linked miRNA delivery by EVs to regenerative, antifibrotic, and immune suppressive properties of the vesicles . Some authors have suggested that the small amount of miRNA in EVs makes it more likely that a protein cargo is involved in their biological properties .…”

Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model

“…Increasing data indicate that macrophages may create an optimal microenvironment for reducing inflammation through a paracrine mechanism [16][17][18], and exosomes secreted by macrophages play an important role in communicating with neighboring cells via regulating levels of cytokines and miRNAs to ameliorate the inflammatory response in recipient cells [19,20]. It has been reported that macrophage-derived exosomes attenuated thermal hyperalgesia in a murine model of inflammatory pain, suggesting their role in dysregulated inflammation [21].…”

3D cell culture stimulates the secretion of in vivo like extracellular vesicles

“…EVs play important roles in cell-to-cell communications via cross-transferring of important signaling components [11][12][13][14] . For instance, EVs can carry and transmit mRNAs and miRNAs for promoting tumor growth, which has been identified as the diagnostic biomarkers for lung cancer 15 , breast cancer 16 and ovarian cancer 17,18 . The mRNAs found in smaller EVs (exosomes) can be transferred and translated to functional proteins after uptake by other cells 19 .…”