Self‐Assembling P38 Peptide Inhibitor Nanoparticles Ameliorate the Transition from Acute to Chronic Kidney Disease by Suppressing Ferroptosis

Accumulating evidence highlights p38 as a crucial factor highly activated during the process of acute kidney injury (AKI), but the application of p38 inhibitor in AKI is quite limited due to the low efficiency and poor kidney-targeting ability. Herein, a novel self-assembling peptide nanoparticle with specific p38-inhibiting activity is constructed, which linked mitogen-activated protein kinase kinase 3b (MKK3b), the functional domain of p38, with the cell-penetrating TAT sequence, ultimately self-assembling into TAT-MKK3b nanoparticles (TMNPs) through tyrosinase oxidation. Subsequent in vitro and in vivo studies demonstrated that TMNPs preferably accumulated in the renal tubular epithelial cells (RTECs) through forming protein coronas by binding to albumin, and strongly improved the reduced renal function of ischemia-reperfusion injury (IRI)-induced AKI and its transition to chronic kidney disease (CKD). Mechanically, TMNPs inhibited ferroptosis via its solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis-inducing capacity and synergistic potent antioxidant property in AKI. The findings indicated that the multifunctional TMNPs exhibited renal targeting, ROS-scavenging, and ferroptosis-mitigating capabilities, which may serve as a promising therapeutic agent for the treatment of AKI and its progression to CKD.