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