A Nanomedicine‐Enabled Ion‐Exchange Strategy for Enhancing Curcumin‐Based Rheumatoid Arthritis Therapy

Curcumin (Cur) has been clinically used for rheumatoid arthritis treatment by the means of reactive oxygen species (ROS) scavenging and immune microenvironment regulation. However, this compound has a poor water solubility and moderate antioxidative activity, favoring no further broadened application. Metal complexes of curcumin such as zinc-curcumin (Zn-Cur) features enhanced water solubilities, while copper-curcumin (Cu-Cur) shows a higher antioxidant activity but lower solubility than Zn-Cur. Based on their inherent biological properties, this work proposes a nanomedicine-based ion-exchange strategy to enhance the efficacy of Cur for rheumatoid arthritis treatment. Copper silicate nanoparticles with hollow mesoporous structure were prepared to load water-soluble Zn-Cur for constructing a composite nanomedicine, which can degrade in acidic microenvironment of arthritic region, releasing Cu²⁺ and Zn-Cur. Cu²⁺ then substitute for Zn²⁺ in Zn-Cur to form Cu-Cur with a significantly enhanced antioxidative effect, capable of efficiently scavenging ROS in M1 macrophages, promoting their transition to an anti-inflammatory M2 phenotype. In addition, the silicate released after nanocarrier degradation and the Zn²⁺ released after ion exchange reaction synergistically promote the biomineralization of osteoblasts. This work provides a new approach for enhancing the antiarthritic effect of Cur via an ion-exchange strategy.