ROS-responsive hydrogel loaded with capsaicin promotes tenogenic differentiation of tendon stem/progenitor cells and enhances tendon injury repair

Tendon injury repair remains challenging in sports medicine and orthopedics, partly due to limited endogenous regenerative capacity and sustained low-grade inflammation, which disrupt tendon stem/progenitor cells (TSPCs) homeostasis, impairing tenogenesis and enhancing osteogenesis, leading to complications like heterotopic ossification. Here, we engineered a reactive oxygen species (ROS)-responsive hydrogel loaded with capsaicin (CGT) and explored its role in tendon regeneration. <i>In vitro</i>, under IL-1β-induced inflammatory conditions, CGT ameliorated TSPCs dysfunction by upregulating tenogenic markers (Scx, Tnmd, Mkx) and collagen synthesis, while downregulating osteogenic markers (OCN, Runx-2), reducing ALP activity, and inhibiting calcium nodule formation. Mechanistically, CGT may suppress the PI3K-AKT-mTOR axis, attenuating proinflammatory cytokine secretion (IL-6, TNF-α, IL-1β). <i>In vivo</i>, local injection of CGT alone or with exogenous TSPCs into SD rat Achilles tendon defects promoted orderly collagen regeneration, reduced inflammation, and inhibited heterotopic ossification at 8 weeks postoperatively, with favorable biosafety. Tissue immunostaining suggested CGT enhanced tenogenesis-related and suppressed osteogenesis-related gene expression. These findings preliminarily indicate that CGT may modulate TSPCs differentiation and inflammatory microenvironments via the PI3K-AKT-mTOR axis, supporting tendon regeneration. This study offers insights into functional biomaterial design, with CGT showing potential for tendon injury management.