Enhanced ferroptosis by a nanoparticle mimicking hemoglobin coordinate pattern with self-supplying hydrogen peroxide

Abstract

Insufficient endogenous H₂O₂ for generation of hydroxyl radicals (^•OH) has strikingly compromised anti-tumor benefits of ferroptosis. Herein, we develop a H₂O₂ self-supplying nanoparticle based on a pH-responsive lipopeptide C₁₈-pHis₁₀. Inspired by the coordinate pattern of hemoglobin binding heme, Fe²⁺ and tetrakis(4-carboxyphenyl)porphyrin (TCPP) were delicately encapsulated by formation of coordination compounds with His. Ascorbgyl palmitate (AscP) was also incorporated into the nanoparticles for generation of H₂O₂ by reduction ¹O₂ produced from TCPP, meanwhile prevented Fe²⁺ from being oxidized. The protonation of pHis in acidic endo-lysosome induced the breakage of Fe²⁺/His/TCPP coordinate interactions, leading to accelerated release of payloads and the following escape to cytoplasm. Upon laser irradiation, TCPP produces excessive ¹O₂ followed by conversion to H₂O₂ in the presence of AscP, which is further catalyzed to lethal ^•OH by Fe²⁺ via Fenton reaction. The self-supplying H₂O₂ was found to result significantly higher accumulation of lipid peroxides and more effective tumor inhibition. Overall, this work sheds new a light on H₂O₂ self-supplying strategy to enhance ferroptosis by taking advantage of ¹O₂ generated by photodynamic therapy (PDT).