Dual-targeted hybrid nanovesicles coordinated bone-muscle regeneration via regulating the DUSP4/p38 MAPK pathway to reverse osteosarcopenia

Osteosarcopenia (OSP), a degenerative syndrome characterized by concurrent osteoporosis and sarcopenia, exhibits persistently high global prevalence due to aging and disuse, yet lacks targeted therapies. p38 MAPK plays a key regulatory role in musculoskeletal degeneration. Increased expression of DUSP4, a key inhibitor of the Mitogen-Activated Protein Kinase (MAPK) pathway, inhibits the phosphorylation of p38 MAPK. Thus, targeted delivery of microRNAs that inhibit DUSP4 expression can activate the p38 MAPK pathway and promote osteogenic and myogenic differentiation. However, the therapeutic efficacy of nucleic acid drugs critically depends on delivery systems with targeted specificity, stability, and biocompatibility. Therefore, we engineered a hybrid nanovesicle (miR@DT/iMNV) by fusing bone-muscle dual-targeting peptide-modified liposomes (miR@DT-Lipo) and iPSC-derived MSC-EVs (iMSC-EVs). The miR@DT/iMNV enables the dual-tissue targeted delivery of miR-206-5p (which is downregulated in OSP and can target and inhibit DUSP4) and exhibits excellent biocompatibility. Results demonstrated that miR@DT/iMNV enhances osteogenic/myogenic capacities of stem cells, modulates macrophage phenotypes, restores mitochondrial function, and increases bone/muscle mass in a disused OSP murine model. This dual-targeted, multi-mechanistic strategy presents an innovative therapeutic approach for OSP.