ROS-Responsive, Water-Oil Biphasic Hydrogel-Based Separable Microneedle System for Intra-Articular Delivery in Osteoarthritis Therapy.

Osteoarthritis (OA) is characterized by a chronic inflammatory microenvironment with excessive reactive oxygen species (ROS) and progressive cartilage degeneration. To address these challenges, we developed a ROS-responsive, water-oil biphasic separable microneedle patch (CKCA MN) for transdermal therapy. This microneedle utilizes hyaluronic acid (HA) as a rapidly dissolving substrate, and its needle tip comprises a coordination-crosslinked hydrogel formed by Ce3+ and alendronate (Aln), loaded with cinnamaldehyde (CM) as the oil-phase carrier encapsulating kartogenin (KGN). The needle tip can rapidly dissociate from the base and selectively remain in the dermis, enabling localized therapeutic delivery for OA. Within the needle tip, the aqueous phase degrades under the trigger of ROS. Ce3+ efficiently scavenges ROS via the Ce3+/Ce4+ redox cycle, while Aln binds to the bone surface and suppresses osteoclast activity. Concurrently, the oil phase can directly neutralize ROS and facilitate sustained release of KGN, which drives chondrogenic differentiation of endogenous progenitor cells. Critically, the oil phase can precisely regulate the degradation kinetics of the Ce-Aln hydrogel, thereby establishing a dual-phase release curve: Ce3+-driven anti-inflammatory effects followed by KGN-mediated cartilage matrix synthesis and structural restoration. The presence of the oil phase can reduce the degradation rate of the needle tip, from 24 to 120 h of degradation release. The treatment with the CKCA MN resulted in a 3-4-fold decrease in inflammatory factors and cartilage remodeling. Collectively, the CKCA MN leverages ROS-responsive degradation to spatiotemporally regulate drug release, thereby achieving a synergistic therapeutic cascade of "anti-inflammation, subchondral bone protection, and cartilage regeneration," which addresses the interconnected pathological mechanisms underlying OA progression.