Enhanced Renal Accumulation of Polyserine Synthesized from Unprotected Serine <i>N</i> -Carboxyanhydride

The development of renal-targeting delivery systems has shown great potential to improve the therapeutic efficacy to treat kidney diseases. However, current nanocarriers often exhibit poor targeting efficiency or short renal retention, limiting their use in drug delivery. Herein, we report the simplified preparation of poly(DL-serine) (PSer) bearing hydroxyl side chains, which showed enhanced accumulation in kidney in the first several hours post intravenous injection. Starting from unprotected amino acids, the hydrophilic polypeptides were prepared in a two-step synthesis without tedious protection/deprotection procedures. With the improved uptake by renal tubular epithelial cells, PSer outperformed its threonine analogue, with the kidney-to-liver ratio of up to 7.7 (∼9% injected dose in kidney). Finally, the conjugates of PSer with dexamethasone exhibited enhanced therapeutic efficacy than free drug in an animal model of acute kidney injury. We believe this work improves our understanding to design nanomedicine with enhanced kidney accumulation, boosting its use to treat renal diseases.