Huilan Zhuang,Panpan Xue,Sijie Shao,Xuemei Zeng,Shuangqian Yan
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 .
Development of ferroptosis-inducible nanoplatforms with high efficiency and specificity is highly needed and challenging in tumor ferrotherapy. Here, we demonstrate highly effective tumor ferrotherapy using iron (II)-based metal-organic framework (Fe ss MOF) nanoparticles, assembled from disulfide bonds and ferrous ions. The as-prepared Fe ss MOF nanoparticles exhibit peroxidase-like activity and pH/glutathione-dependent degradability, which enables tumor-responsive catalytic therapy and glutathione depletion by the thiol/disulfide exchange to suppress glutathione peroxidase 4, respectively. Upon PEGylation and Actinomycin D (ActD) loading, the resulting Fe ss MOF/ActD-PEG nanoplatform induces marked DNA damage and lipid peroxidation. Concurrently, we found that ActD can inhibit Xc − system and elicit ferritinophagy, which further boosts the ferrotherapeutic efficacy of the Fe ss MOF/ActD-PEG. In vivo experiments demonstrate that our fabricated nanoplatform presents excellent biocompatibility and a high tumor inhibition rate of 91.89%.
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