Hyaluronic Acid-Modified Celecoxib-Loaded Nanostructured Lipid Carriers Combined with Dissolving Microneedles for Targeted Sustained-Release Therapy in Osteoarthritis.

BACKGROUND: Rapid local drug clearance and poor sustained retention pose challenges to the treatment of osteoarthritis. Therefore, a local delivery system that prolongs intra-articular drug retention and achieves efficient targeted delivery holds significant clinical promise. METHODS: Hyaluronic acid-modified celecoxib nanostructured lipid carriers (HA-Cxb-NLCs) were prepared and encapsulated in dissolving microneedles to form a composite delivery system (HA-Cxb-NLCs-DMNs). The system was characterised in terms of its physicochemical properties, in vitro drug release profiles, transdermal permeation behaviour, cellular compatibility, and uptake mechanisms. Subsequently, a sodium iodoacetate-induced rat osteoarthritis model was used to evaluate the therapeutic efficacy in vivo. RESULTS: HA-Cxb-NLCs-DMNs exhibit a uniform particle size (113.93 ± 1.66 nm) and a zeta potential of (-39.16 ± 3.00 mV). In vitro release persisted for 72 hours, with a cumulative permeation of 62.74 ± 1.40 μg·cm-2 and a skin retention of 3.20 ± 0.62 μg·cm-2. HA modification enhances cellular uptake of the nanocarriers via the CD44 receptor. Animal studies demonstrated that it reduces joint swelling, improves cartilage damage, and inhibits MMP-13 expression. CONCLUSION: This study presents a promising microneedle-nanoparticle synergistic delivery strategy for the local targeted therapy of osteoarthritis.