# Functional properties of skeletal myotube-derived extracellular vesicles based on microRNA profiles: a comparative analysis with mesenchymal stem cell-derived extracellular vesicles

## TL;DR

This study compares the functional properties of skeletal muscle and mesenchymal stem cell-derived extracellular vesicles using miRNA profiles to identify their potential therapeutic applications.

## Contribution

A novel miRNA–target-based framework is introduced to benchmark extracellular vesicles at the pathway level using miRNA profiles.

## Key findings

- SkM-EVs show predicted repression in pathways related to muscle atrophy and metabolism.
- MSC-EVs exhibit repression in immune signaling pathways.
- The framework provides a general strategy for comparing EV sources based on miRNA profiles.

## Abstract

Skeletal muscle-derived extracellular vesicles (SkM-EVs) are promising candidates for non-invasive, systemically delivered therapies, but their functional specificity relative to clinically advanced mesenchymal stem cell-derived EVs (MSC-EVs) remains unclear. We reanalyzed public miRNA-seq datasets of SkM-EVs and MSC-EVs and integrated validated miRNA–mRNA interactions to infer pathway-level repression potential of EV miRNA cargo. Two complementary approaches were used: a differential-expression-based relative evaluation with RBiomirGS, and an abundance-weighted absolute evaluation that converts miRNA profiles into gene-level Impact Scores followed by preranked KEGG enrichment. Despite their different formulations, both approaches converged on a shared pattern. SkM-EV miRNAs showed a predicted repression bias in FoxO, TGF-β and ErbB signaling pathways linked to muscle atrophy, metabolic homeostasis and pro-proliferative signaling. By contrast, MSC-EV miRNAs showed a predicted repression bias in immune signaling pathways. These source-dependent pathway signatures provide hypothesis-generating evidence that SkM-EVs may be better suited for muscle-, metabolic-, and cancer-related indications, whereas MSC-EVs may be more appropriate for immunomodulatory indications, pending experimental validation. Our miRNA–target-based framework provides a general strategy to benchmark EV sources at the pathway level directly from miRNA profiles.

The online version contains supplementary material available at 10.1038/s41598-026-38076-8.