Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two main mechanisms, the classical and trans-signalling pathways. While signalling associated with anti-inflammatory activities cytokine, pathway mediates chronic therefore for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, potential as targeted delivery vehicles macromolecules. Here, we engineered EVs express signal transducer (IL6ST) decoy receptors selectively inhibit pathway. potency IL6ST receptor was optimized inclusion GCN4 dimerization domain peptide sequence derived from syntenin-1 which targets EVs. resulting were able efficiently activation in reporter cells, while having no effect on signalling. EVs, also capable blocking C2C12 myoblasts myotubes, thereby inhibiting phosphorylation STAT3 partially reversing anti-differentiation effects observed when treating IL6/IL6R complexes. Treatment Duchenne muscular dystrophy mouse model resulted reduction quadriceps gastrocnemius muscles these mice, demonstrating vivo activity therapy. Taken together, this study reveals promising DMD, demonstrates