Supramolecular dynamic hydrogels loaded with bevacizumab nanoparticles promote hyaline cartilage regeneration by inhibiting angiogenesis.

After joint cartilage injury, due to abnormal vascular invasion, the repaired tissue often forms fibrous cartilage with poor mechanical properties, not matching normal articular hyaline cartilage. The overexpression of vascular endothelial growth factor (VEGF) is considered a significant cause of hyaline cartilage repair failure, while bevacizumab, a commonly used clinical VEGF inhibitor, exhibits a potent anti-angiogenic effect. Therefore, this study combines bevacizumab-loaded nanoparticles with host-guest macromer dynamic hydrogels (HBN hydrogel) to form a composite system, delivering bevacizumab through sustained release to inhibit angiogenesis, improve the cartilage regeneration microenvironment, and thus promote in situ hyaline cartilage repair. The dynamic structure of the host-guest macromer hydrogel supports cell adhesion, aggregation, and spreading within a three-dimensional network, promoting stem cell chondrogenic differentiation under three-dimensional culture conditions. The HBN hydrogel effectively inhibits vascular ingrowth and promotes hyaline cartilage formation when implanted subcutaneously in nude mice. In the orthotopic rat knee defect model, the HBN hydrogel significantly enhanced the quality of in situ repair by promoting anti-inflammatory M2 macrophage polarization and suppressing catabolic enzymes, thereby regenerating hyaline cartilage that closely mirrors native tissue. Ultimately, by synergistically coupling an adaptive three-dimensional mechanical network with the sustained anti-angiogenic and immunomodulatory release of bevacizumab, this composite system provides a highly translational platform for joint repair. STATEMENT OF SIGNIFICANCE: Cartilage repair remains challenging because regenerating neotissue often turns into fibrocartilage due to abnormal blood vessel invasion. We introduce a dynamic host-guest macromer (HGM) hydrogel loaded with bevacizumab nanoparticles to block vascular invasion and promote true hyaline cartilage regeneration. Unlike traditional static hydrogels, this dynamic system supports cell adhesion and spreading in 3D, providing a more favorable environment for tissue formation. In vivo studies show that the HGM hydrogel induces smooth, cartilage-like tissue with minimal vascularization. This work offers a supramolecular materials-based strategy to regulate angiogenesis and inspire therapeutic approaches for hyaline cartilage repair.