Topology-Controlled PEGylation Enhances Renal Accumulation of Therapeutic Peptide for Treating Ischemia–Reperfusion Injury

Ischemia-reperfusion injury (IRI) remains a major cause of graft dysfunction following kidney transplantation, driven in large part by mitochondrial oxidative stress and subsequent apoptotic cell death. Elamipretide (SS31), a mitochondria-targeted tetrapeptide, shows robust renoprotection in preclinical models but is constrained by rapid renal elimination and limited pharmacokinetic exposure. Here, we prepared multiarm PEG-SS31 conjugates with controlled arm number and total PEG molecular weight. A ROS-cleavable thioketal linker enabled SS31 release under oxidative stress. The lead topology self-assembles into nanoparticles, produces markedly enhanced renal accumulation relative to free SS31 and alternative architectures, and yields superior renoprotection in a murine IRI model with reduced tubular injury and apoptosis. These results identify PEG topology as a key design parameter for kidney-targeted peptide therapeutics.