Catalpol-Loaded Silk Fibroin Nanoparticle/GelMA Hydrogels Promote Autophagy-Mediated Angiogenesis for Vascular Regeneration in Limb Ischemia

Limb ischemia is a severe manifestation of peripheral arterial disease with limited therapeutic options. Induction of therapeutic angiogenesis represents a promising strategy to restore blood perfusion. Natural bioactive compounds, particularly when integrated with biomaterial engineering, offer therapeutic potential with favorable biosafety profiles. Here, we demonstrate that catalpol (CTP), a bioactive compound from Rehmannia glutinosa, exerts pro-angiogenic effects by enhancing endothelial cell viability, proliferation, migration, and vascular sprouting in vitro. Catalpol upregulates angiogenesis-related markers and promotes angiogenesis via autophagy activation, which is validated using 3-methyladenine (3-MA). To improve local retention and sustained delivery, CTP-loaded silk fibroin nanoparticles (CTP/SFNP) are self-assembled via mild desolvation and incorporated into gelatin methacryloyl hydrogel (CTP/SFNP/GelMA). In a mouse hind limb ischemia model, this hydrogel promotes neovascularization, restores blood perfusion, alleviates tissue injury, and exhibits favorable biocompatibility. These findings highlight the therapeutic potential of CTP/SFNP/GelMA for ischemic diseases and identify autophagy activation as a potential mechanism underlying catalpol-mediated angiogenesis, providing insights into nanocarrier design for natural bioactive compounds.