Rhodiola rosea-derived exosome-like nanovesicles inhibit vascular endothelial pyroptosis in the treatment of limb skeletal muscle ischemic injury through the TXNIP/NLNP3 pathway

Abstract Skeletal muscle ischemia, resulting from impaired blood flow, is a prevalent clinical issue and a leading cause of amputation. Plant-derived exosome-like nanovesicles (ELNs) have emerged as promising candidates due to their diverse bioactive components with antioxidant, anti-inflammatory and regenerative properties. In this study, exosome-like nanovesicles (RhELNs) extracted from the root of Rhodiola rosea, a traditional Chinese medicine, were proved to have a good ability to promote the regeneration of vascular endothelial cells under hypoxia by EdU experiment and transwell experiment in vitro. After the treatment of mice with RhELNs injected into the tail vein, it was found that the inflammation level of the skeletal muscle of the mice was decreased, the degree of fibrosis was alleviated, the blood flow was restored, skeletal muscle atrophy and limb gangrene were improved. These results indicate that RhELNs can promote the recovery of ischemic skeletal muscle and angiogenesis. Furthermore, we identified a novel microRNA (novel-mirNA-115-5p) in RhELNs, which plays an important role in RhELNs. It protects vascular endothelial cells from mitochondrial damage by targeting TXNIP and it promotes vascular regeneration by reducing cellular pyroptosis under hypoxia conditions through inhibition of the TXNIP- NLRP3 pathway. These results suggest that RhELNs represent a promising new approach for treating lower limb skeletal muscle ischemic diseases.