Enhanced Bone Targeting of Poly(<scp>l</scp>-glutamic acid)s through Cationic or Aromatic Substitution

Poly(l-glutamic acid)s (PLGs) are promising bone-targeting ligands due to their high molecular weight and facile preparation. Nevertheless, the bone-targeting efficiency of PLGs is still relatively low, validating the necessity to further enhance targeting through structural optimization. Herein, we report the use of a heteropolypeptide strategy to improve the bone targeting of PLGs through the incorporation of another side-chain functionality for enhanced affinity with bone tissues. Specifically, the introduction of cationic amino or aromatic phenolic side-chain residues resulted in a ∼2.3-fold or ∼1.6-fold increase in the <i>in vivo</i> bone targeting, respectively. Cationic modification not only improved the affinity with bone minerals but also exhibited prolonged retention in the bone tissues for more than 60 days. This work highlights the use of a heteropolypeptide library to screen and optimize the performance of polypeptide materials, offering promising bone-targeting polymeric materials for the design of bone-related nanomedicine.