A Microneedle Platform Co-loaded with Eugenol, Chlorogenic Acid, and Allopurinol for In Vivo Modulation of Pathological Crystal Formation in Experimental Gouty Arthritis

Abstract Gouty arthritis arises from pathological deposition of monosodium urate (MSU) crystals, whose interactions with surrounding tissues initiate and amplify inflammation. Here, we developed a nanoengineered microneedle (MN) platform for localized modulation of pathological crystallization. The MN system spatially compartmentalizes chlorogenic acid (CGA), eugenol (EUG), and allopurinol (AP) and was designed to provide a rapid-release EUG/CGA phase and a sustained-release polymeric CGA/AP phase: a fraction of CGA is dissolved in EUG for rapid self-emulsification and early interaction with MSU crystal surfaces, while the remainder is embedded in a biodegradable polymer matrix for sustained release. Fluorescence tracing confirmed the penetration of the labeled EUG-associated phase into periarticular tissues, while CGA delayed MSU nucleation, suppressed crystal growth, and remodeled crystal habit from needle-like morphologies toward less sharp petal-like forms. The polymer matrix enabled sustained release of CGA and AP, supporting prolonged crystallization inhibition and urate control. In vivo, the intra-articular MSU crystal-covered area at 144 h was 0.82 ± 0.04% in the MN-treated group versus 7.23 ± 0.84% in the untreated model group (n = 3, P < 0.001). Serum uric acid levels at 144 h were 4.35 ± 0.43 and 10.00 ± 0.31 μg/mL, respectively (n = 6, P < 0.0001), while joint swelling rates at 96 h were 3.80 ± 1.71% and 21.06 ± 1.78%, respectively (n = 6, P < 0.0001). Synovial IL-1β, IL-6, and TNF-α positive areas were all below 5% in the MN-treated group and were significantly lower than those in untreated rats (n = 3, all P < 0.0001), accompanied by improved synovial tissue integrity. This study provides in vivo experimental evidence that pathological MSU crystallization can be locally modulated through an interfacial-engineered MN platform, offering a new strategy for gout therapy by integrating crystal regulation, anti-inflammatory intervention, and urate-lowering treatment.