Injectable Nanocomposite Hydrogel System for miRNA‐Based Cartilage Repair in Knee Osteoarthritis

Abstract Knee osteoarthritis (KOA) is a common joint disorder characterized by progressive cartilage degeneration. MiR‐455‐3p has been identified as a promising therapeutic candidate to maintain cartilage homeostasis. However, clinical application of free miR‐455‐3p is limited by rapid degradation, poor targeting efficiency, and off‐target effects. To overcome these limitations, an injectable nanocomposite hydrogel‐based miRNA delivery system consisting of a cartilage affinity nanocarrier (CANC) encapsulated within a PCL‐b‐PEG‐b‐PCL hydrogel is developed. The CANC is formulated using 50% PEGylated G5 PAMAM dendrimers to load miR‐455‐3p and is further modified with chondrocyte‐affinity peptides (CAP) and minimal “self” peptides (MSP) to enhance cartilage targeting and evade macrophage uptake. In vitro studies demonstrated that it exhibited excellent stability, low cytotoxicity, superior cartilage penetration and chondrocyte targeting. Moreover, in vivo experiments in miR‐455‐3p knockout mice and a destabilization of the medial meniscus (DMM) induced KOA model confirmed that the sustained release and targeted delivery of miR‐455‐3p effectively rescued cartilage degeneration and prevent KOA progression. Notably, the nanocomposite hydrogel demonstrated high biocompatibility without observed cytotoxicity in major organs. This study highlights the therapeutic potential of the nanocomposite hydrogel miRNA delivery system in promoting cartilage regeneration and presents a promising approach for the development of disease‐modifying osteoarthritis drugs.