Nanozyme-mediated drug ion-exchange strategy ameliorates inflammatory bowel disease by scavenging ROS and reprogramming proinflammatory macrophages

Simultaneously alleviating oxidative stress and remodeling inflammatory microenvironment holds great promise for treating inflammatory bowel disease (IBD). Nevertheless, the efficacy of conventional therapies remains limited by poor targeting, insufficient modulation of the inflammatory microenvironment and serious adverse effects. Here, inspired by the intrinsic biological properties of metal-curcumin (Cur) complexes, a nanozyme-mediated ion-exchange strategy was proposed to enhance the targeted therapeutic effect of Cur for IBD. Specifically, copper-doped mesoporous polydopamine nanoparticles (Cu-mPDA) with dual enzyme-like activities were served as drug carriers to encapsulate water-soluble zinc-curcumin (Zn-Cur) and further modified with hyaluronic acid (HA), yielding Zn-Cur/Cu-mPDA@HA. Encouragingly, Zn-Cur/Cu-mPDA@HA could degrade in inflammatory microenvironment, releasing Zn-Cur and Cu 2+ , which subsequently in situ generate Cu-Cur with high antioxidant activity by ion-exchange reaction. Notably, Zn-Cur/Cu-mPDA@HA not only exhibited favorable targeting specificity toward M1 macrophages in inflamed colon tissues, but also displayed enhanced abilities to scavenge ROS, inhibit pro-inflammatory factors secretion and promote macrophages repolarization from the pro-inflammatory M1 state to the anti-inflammatory M2 subtype. Mechanistically, Zn-Cur/Cu-mPDA@HA suppressed the TLR4/MyD88/NF-κB pathway, breaking the inflammation-free radical vicious cycle, thereby attenuating chronic inflammation and fostering a favorable microenvironment for intestinal barrier restoration. Such a nanozyme-mediated ion-exchange and in situ drug generation strategy offers a new insight for designing nanomedicines for the treatment of IBD and other inflammatory diseases.