Muc1 drives tendon regeneration by activating an endothelial-to-tenocyte PDGFA signaling axis via extracellular vesicles

Tendon injuries pose significant clinical challenges because tendon tissue has limited intrinsic healing capacity, often resulting in poor functional recovery. In exploring novel therapeutic strategies, we found that Mucin 1 (Muc1), a key regulator of tissue repair, is transiently upregulated during the early stages of tendon injury. We therefore hypothesized that sustained activation of this naturally transient signal would promote tendon repair. To validate this hypothesis, we developed a nanoparticle-based gene delivery system to achieve sustained Muc1 expression in a rat model of tendon injury. This targeted intervention significantly improved tendon healing, primarily by creating a pro-regenerative microenvironment. Mechanistically, we demonstrated that Muc1 activation stimulates endothelial cells to secrete platelet-derived growth factor A (PDGFA), which promotes tendon cell proliferation, particularly when packaged within extracellular vesicles. Collectively, those findings support Muc1 as a potent therapeutic target. The nanoparticle-mediated Muc1 gene delivery strategy offers a highly promising regenerative approach for tendon injury treatment with direct translational potential.