A rationally designed injury kidney targeting peptide library and its application in rescuing acute kidney injury.

Acute kidney injury (AKI) has high incidence and mortality rates. Present treatments are mostly symptomatic and cause side effects due to systemic distribution; thus, targeted kidney drug delivery is desired. Transmembrane kidney injury molecule-1 (KIM1) is expressed at low levels in normal kidneys but markedly up-regulated following injury, making it an ideal marker/target for injured kidneys. Here, assisted by AlphaFold, we constructed a library of 1885 peptides that target the extracellular Ig V domain of KIM1 based on interacting fragments from 47 potential KIM1 binding proteins followed by systemic optimization according to their binding energies with KIM1. Experimental validation of top candidates (TKP 1-5) demonstrated that TKP 4 efficiently targeted injured renal cells/kidneys, with its specificity demonstrated in KIM1 knockout cells/mice. TKP 4-decorating liposomes were loaded with nystatin, a renal-protective compound with systemic side effects, and efficiently targeted injured mouse kidneys and alleviated AKI. This work establishes a virtual platform to screen/identify drug delivery candidates with broad research/therapeutic potentials.