Self‐Healing Hyaluronic Acid‐based Hydrogel with miRNA140‐5p Loaded MON‐PEI Nanoparticles for Chondrocyte Regeneration: Schiff Base Self‐Assembly Approach

Articular cartilage defects present a significant therapeutic challenge due to the inherent avascular and aneural characteristics of cartilage tissue. Gene therapy has emerged as a promising strategy for cartilage regeneration, particularly through the use of functional RNA and biomaterial-assisted frameworks. In this study, an innovative gene-activated self-healing hydrogel is developed and fabricated for the controlled release of miR140-5p, a key regulator of cartilage regeneration. The hydrogel, crosslinked via UV radiation, is composed of aminated hyaluronic acid and a modified photosensitizer (NB). To enhance the scaffold's structural integrity and gene delivery efficiency, mineralized silk fibroin and miR140-5p-loaded MON-PEI nanoparticles are incorporated. These findings demonstrate that this novel hydrogel (miR140-5p-CaP@mSF-HA-NB) effectively encapsulates and releases miR140-5p, exhibits excellent biocompatibility, and promotes enhanced cartilage regeneration in both in vitro and in vivo models. Therefore, this gene-activated hydrogel holds significant potential for clinical applications in the treatment of articular cartilage defects.