Microneedle‐Delivered PDA@Exo for Multifaceted Osteoarthritis Treatment via PI3K‐Akt‐mTOR Pathway

Abstract Osteoarthritis (OA) is marked by cartilage deterioration, subchondral bone changes, and an inflammatory microenvironment. The study introduces the Microneedle‐Delivered Polydopamine‐Exosome (PDA@Exo MN), a therapeutic that not only preserves cartilage and promotes bone regeneration but also improves localized drug delivery through enhanced penetration capabilities. PDA@Exo MN shows strong reactive oxygen species (ROS) scavenging abilities and high biocompatibility, fostering osteogenesis and balancing anabolic and catabolic processes in cartilage. It directs macrophage polarization from M0 to the anti‐inflammatory M2 phenotype. RNA sequencing of treated chondrocytes demonstrates restored cellular function and activated antioxidant responses, with modulated inflammatory pathways. The PI3K‐AKT‐mTOR pathway's activation, essential for PDA@Exo's effects, is confirmed via bioinformatics and Western blot. In vivo assessments robustly validate that PDA@Exo MN prevents cartilage degradation and OA progression, supported by histological assessments and micro‐CT analysis, highlighting its disease‐modifying impact. The excellent biocompatibility of PDA@Exo MN, verified through histological (H&E) and blood tests showing no organ damage, underscores its safety and efficacy for OA therapy, making it a novel and multifunctional nanomedical approach in orthopedics, characterized by organ‐friendliness and biosecurity.