A Ferroptosis‐Inhibitive Polypeptosome for Synergistic Management of Acute Kidney Injury Through Antioxidation and Iron Binding

Abstract Acute kidney injury (AKI) is a critical condition with a wide range of triggers that cause heavy burden on public health. Despite its high incidence and mortality, the treatment of AKI still highly relies on hemodialysis, which is costly and usually accompanied by severe complications. Therefore, development of new therapeutic targets and methods for AKI is urgently needed. Herein, a ferroptosis‐targeting strategy for AKI treatment by rationally designed ferroptosis‐inhibitive polypeptide‐based polymersomes (polypeptosomes, FIPs) is proposed. Such FIPs are self‐assembled from poly(glutamic acid)‐ block ‐poly(methionine‐ stat ‐tyrosine) [PGA 9 ‐ b ‐P(Met 8 ‐ stat ‐PTyr 13 )]. The ferroptosis‐inhibition function of the FIPs arises from the rationally‐selected amino acid composition: P(Met‐ stat ‐Tyr) endows the FIPs with a high scavenging efficiency of over 90% toward different reactive oxygen species (ROS); while the glutamate and tyrosine residues, as well as the amide groups, can bind iron ions, thus blocking iron overload and lipid peroxide in cells. In vivo experiments confirm that the FIPs can effectively alleviate oxidative stress, inhibit ferroptosis, and restore kidney functions. Transcriptome sequencing further reveals the therapeutic mechanisms of FIPs. Overall, such polypeptosomes capable of blocking multiple pathways of ferroptosis open a new avenue for AKI treatment and provide fresh insights into the development of generalized therapies for inflammation.