Oral nanoarray hydrogel-mediated macrophage repolarization and ferroptosis suppression for inflammatory bowel disease treatment.

Inflammatory bowel disease (IBD) is closely associated with macrophage dysregulation, particularly insufficient anti-inflammatory M2 macrophages. However, current therapies mainly emphasize M2 polarization, with limited attention to the ferroptotic vulnerability of M2 macrophages under oxidative IBD conditions. Here, we developed an oral nanoarray hydrogel (BAN@Ca) designed to restore immune homeostasis via a synergistic strategy of blocking ferroptotic pathways and remodeling macrophage phenotypes. Constructed by crosslinking bilirubin-alginate self-assembled nanoparticles (BAN) with calcium ions (Ca2+), BAN@Ca features dual pH/enzyme-responsiveness, enabling colon-specific degradation and overcoming the diffusion barriers typical of conventional hydrogels to achieve rapid dissociation at the disease site. Mechanistically, the released BAN specifically targets M2 macrophages and leverages bilirubin to scavenge reactive oxygen species (ROS) and upregulate the GSH/GPX4 axis, thereby effectively blocking lipid peroxidation-driven ferroptosis and ensuring cell survival. Simultaneously, co-released Ca2+ activates the PI3K/AKT signaling pathway to robustly drive the reprogramming of pro-inflammatory M1 macrophages into the M2 phenotype, replenishing the M2 pool. Both in vitro and in vivo studies confirm that BAN@Ca significantly ameliorates colitis symptoms and promotes mucosal healing. This study demonstrates that the synergistic modulation of macrophage polarization and ferroptosis susceptibility represents a highly effective and novel therapeutic strategy for IBD.