In situ generation of hybrid alginate hydrogels for enhanced breast tumor ferrotherapy through multiplex magnifying redox imbalances

Ferroptosis has drawn great attention to tumor treatments over the past decade. However, how to specifically boost tumoral redox imbalance by simultaneously superimposing iron-mediated reactive oxygen species and undermining antioxidative pathways at the tumor site is still a significant challenge in ferroptosis-based tumor ferrotherapy. In this study, we designed an in situ generable hydrogel that contains paclitaxel/chlorin e6-loaded iron-based metal-organic framework (Fe-MOF) nanoparticles for enhanced breast tumor ferrotherapy by multiplex magnifying redox imbalance. The polysaccharide sodium alginate can crosslink with tumoral calcium ions to generate a hydrogel patch, which promotes the retention of Fe-MOF and therapeutic molecules. The Fe-MOF holds peroxidase/glutathione oxidase mimicking properties, resulting in OH generation via the Fenton reaction and glutathione consumption. Local ultrasound treatment facilitates the release of therapeutics and stimulates the generation of signet oxygen by activating the sonosensitizer chlorin e6. In the meanwhile, the low-dose paclitaxel reduces tumoral pH value by downregulating the glutaminolysis-related gene (SLC7A11) which in turn enhances the catalytic activity of Fe-MOF and inhibits antioxidative pathways, respectively. Both in vivo and in vitro experiments show that our designed hybrid hydrogels can induce significant ferrotherapeutic effects by augmenting the tumoral oxidative stresses.