Engineered Exosomes for Delivery of Mir-423-5p to Improve Radiation Sensitivity by Inhibiting MAP7D1 in Esophageal...

Radiation therapy is a common treatment for patients with esophageal cancer (EC). Local recurrence after radiotherapy is one of the main reasons for treatment failure. Exosomal microRNA (miRNA) is associated with the initiation and progression of EC. However, the efficacy of exosomal miRNA in sensitivity to radiotherapy in EC remains unknown.

This study exploited engineered exosomes to deliver miR-423-5p mimic oligonucleotide simultaneously to EC cells. We cocultured EC cell lines by constructing engineered exosomes overexpressing miR-423-5p. Radiotherapy was given concomitantly. The CCK8 and flow cytometric assays were used to detect proliferation and apoptosis, respectively. The dual-luciferase reporter was used to verify MAP7D1 as a putative target of miR-423-5p. The expression levels of MAP7D1 in patients with EC were analyzed to study the clinical value of this parameter.

The results demonstrated that the upregulation of miR-423-5p reduced tumor proliferation (P < 0.01) and increased apoptosis (P < 0.01) during radiotherapy. Notably, cotreatment with Exo-miR-423-5p enhanced both early apoptotic and necrotic cell populations, suggesting potential immunogenic cell death. The luciferase reporter demonstrated that miR-423-5p targeted MAP7D1 3'UTR. Moreover, MAP7D1 expression was lower in EC cancer tissues than adjacent tissues (P < 0.001). In vivo, xenograft studies in nude mice revealed that systemic administration of Exo-miR-423-5p combined with radiation significantly inhibited tumor growth, improved survival, and exhibited favorable biodistribution with minimal toxicity.

The strategy of delivering miR-423-5p via exosomes foreshadows a potential approach for improving EC radiotherapy sensitivity and, consequently, the efficacy of cancer treatment.