Fe-HCOF-PEG2000 as a Hypoxia-Tolerant Photosensitizer to Trigger Ferroptosis and Enhance ROS-Based Cancer Therapy

Background: The hypoxic tumor microenvironment and single mechanisms severely limit the photodynamic therapy (PDT) efficiency of covalent organic framework (COF) nanoparticles in cancer treatment. Purpose: Here, we propose an iron-loaded, hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)-modified hollow covalent organic framework (HCOF), Fe-HCOF-PEG 2000 , for use in hypoxic PDT and ferroptosis therapy owing to its type I and II photodynamic ability and iron nanoparticle loading property. Results: Fe-HCOF-PEG 2000 nanoparticles (Fe-HCOFs-PEG 2000 ) with semiconducting polymers and microporous skeletons allow efficient photophysical properties. Moreover, the iron nanoparticles on Fe-HCOF-PEG 2000 caused ferroptosis and further enhanced tumor elimination under normoxic and hypoxic conditions. DSPE-PEG 2000 endowed Fe-HCOF-PEG 2000 with hydrophilicity, allowing it to circulate and accumulate in organs rich in blood supply, especially tumors. 808 nm NIR activated Fe-HCOF-PEG 2000 aggregated in tumors and significantly inhibited tumor growth under hypoxia. Conclusion: To our knowledge, Fe-HCOF-PEG 2000 is the leading combination of type I/II PDT and ferroptosis. The strong antitumor effects of this nanomaterial suggest prospects for clinical translation as a tumor nanotherapy drug. Keywords: HCOFs, PDT, ROS, hypoxia, ferroptosis, cancer cells