Natural product-integrated microneedle patch for rheumatoid arthritis treatment through anti-inflammation and angiogenesis suppression

Synovitis and angiogenesis are two essential pathological factors that synergistically aggravate rheumatoid arthritis (RA), in which the highly inflammatory environment promotes new blood vessel formation while constant angiogenesis renders recruitment of more inflammatory macrophages. Herein, we developed a micelle-embedded dissolvable microneedle to realize both anti-inflammation and anti-angiogenesis effects for enhanced anti-arthritis therapy. Anti-arthritis natural products, berberine (Ber) and sinomenine (Sin), were encapsulated in the reactive oxygen species (ROS)-responsive micelles (B/S-TMs) and self-assembled using thioketal-modified amphiphilic copolymer PLGA-TK-PEG, followed by their integration into a carboxymethyl cellulose-based microneedle to achieve effective transdermal delivery and rapid cargo release. B/S-TMs were accumulated in the RA joint <i>via</i> passive targeting, and they released Ber and Sin through thioketal bond cleavage under a high ROS level environment. Interestingly, Ber or Sin individually exerted anti-inflammatory effect <i>via</i> simultaneously promoting M2 macrophage polarization and anti-angiogenesis effect by decreasing the endothelial cell migration and tube formation. The combined Ber and Sin further amplified these effects. The therapeutic microneedle patch (B/S-TM@MN) significantly decreased the expression of CD68-positive macrophages and CD31-stained blood vessel, attaining improved anti-arthritis efficacy compared with monotherapies in the collagen-induced arthritis (CIA) mouse model. Our work represents a promising strategy for targeting multiple pathological factors for enhanced anti-RA therapy.