Nanotechnology-enabled M2 macrophage polarization and ferroptosis inhibition for targeted inflammatory bowel disease treatment.

Transforming macrophages into the anti-inflammatory M2 phenotype could markedly strengthen inflammatory bowel disease (IBD) treatment, which is considered as a promising strategy. However, the high ferroptosis sensitivity of M2 macrophages, which decreases their activity, is a major stumbling block to this strategy. Therefore, promoting M2 polarization while simultaneously inhibiting ferroptosis to tackle this challenge is indispensable. Herein, a calcium‑carbonate (CaCO 3) mineralized liposome encapsulating a ferroptosis inhibitor (Fer-1) was developed (CaCO 3 @Lipo@Fer-1, CLF). The CaCO 3 mineralized coating shields the liposomes to prevent the release of Fer-1 in circulation, while releasing Ca2+ in the acidic-inflammatory environment. This released Ca2+ promotes M2 polarization through the CaSR/AKT/β-catenin pathway. The subsequently released Fer-1 effectively upregulates GSH and GPX4, scavenges reactive oxygen species, and inhibits ferroptosis in M2 macrophages. In vivo, CLF improved the targeting efficiency of IBD lesions (about 4.17-fold) through the epithelial enhanced permeability and retention (eEPR) effect and enhanced IBD therapy by increasing the M2/M1 macrophage ratio and inhibiting ferroptosis. We demonstrate that the synergistic regulation of macrophage polarization and ferroptosis sensitivity by this mineralized nanoinhibitor is a viable strategy for IBD therapy. Schematic diagram of the preparation of CaCO 3 @Lipo@Fer-1 (CLF) mineralized-liposome and therapeutic mechanisms in inflammatory bowel disease (IBD). (A) Preparation of CLF mineralized liposome. (B) CLF treats IBD by regulating macrophage polarization and inhibiting ferroptosis. (C) Mechanism of CLF promoting polarization and inhibiting ferroptosis of M2 macrophages. [Display omitted] [ABSTRACT FROM AUTHOR]