Hyaluronic acid-based core-shell microneedles for staged local delivery of psoralen toward anti-inflammatory and cartilage-protective therapy of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction, which requires local therapeutic strategies capable of regulating inflammation and cartilage homeostasis. Herein, we report a hyaluronic acid polymer-based core-shell microneedle patch (Mi@PSO/HPA MN) for localized RA treatment with spatially separated payloads and different release profiles. The shell is constructed from crosslinked hyaluronic acid methacrylate (HAMA) and a brush-like hyaluronic acid-based polymer (HPA), while the core is composed of hyaluronic acid (HA) encapsulating psoralen-loaded mPEG-PCL micelles (Mi@PSO). This compartmentalized design integrates the structural advantages of HA-based polymers with potentially complementary therapeutic effects. The outer shell was designed to release HPA earlier, while the core was designed to provide more prolonged Mi@PSO release. In vitro and in vivo results showed that Mi@PSO/HPA MNs reduced inflammatory marker expression, modulated macrophage polarization-related markers toward an anti-inflammatory profile, preserved cartilage matrix-related markers, and alleviated joint damage in CIA mice under the tested treatment regimen. Overall, this work presents a hyaluronic acid-based polymer-engineered core-shell microneedle platform that combines minimally invasive administration, staged local delivery, inflammation control, and cartilage protection, offering a promising strategy for RA management.