Pioneering rheumatoid arthritis treatment: Magnesium ion-mediated natural multi-component hydrogel synergistically regulates macrophage polarization, pannus formation, and bone regeneration

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects millions of people worldwide. Current therapeutic drugs for RA are often limited by poor solubility, unresponsive to monotherapy, low bioavailability, and severe side effects. To address these challenges, we developed a pH-responsive, biodegradable, and multifunctional oral hydrogel delivery system (GTPM Gel) based on the major active ingredients (glycyrrhizic acid (GA), total alkaloids of FZ (TAC), pseudoephedrine (PE), Mg²⁺) from Mahuang Fuzi decoction for the treatment of RA in clinic. In this system, all four components synergistically contributed to gel formation and pharmacodynamics, making each component indispensable. Notably, Mg²⁺ in GTPM Gel promoted the gelation of GA via coordination bonds while exhibiting anti-inflammatory properties and facilitating osteochondral regeneration. Moreover, GTPM Gel enhanced the solubility of TAC and reduced its toxicity, leading to improved anti-RA effects. <i>In vitro</i> and <i>In vivo</i> studies demonstrated that GTPM Gel effectively inhibited the polarization of inflammatory macrophages, reduced pannus formation, and inhibited bone and cartilage erosion by downregulating the PI3K/AKT/NF-<i>κ</i>B signaling pathway. This study suggested that the magnesium ion-mediated natural multi-component hydrogel, with its remarkable efficacy and biocompatibility, holds promise as a potential therapeutic candidate for RA treatment.