Aberrant sialylation of cancer cells is emerging as an attractive method for generating effective antitumor strategies. However, as sialic acid (SA) is also present in healthy tissues, systems targeting SA in tumors must be strategically designed to be specifically activated in an intratumoral environment while avoiding systemic interaction. Phenylboronic acid (PBA) and its derivatives have shown potential for developing such smart ligands based on its triggered binding to SA at intratumoral pH. Because the affinity of PBAs against SA can be structurally controlled, the approach may further offer the possibility to enhance tumor targeting by molecularly engineering PBAs. Thus, to demonstrate that the modification of the chemical structure of PBAs can promote tumor targeting, we compared nanomedicines installed with the standard PBA or 5-boronopicolinic acid (5-BPA), which shows an exceptionally high binding affinity to SA in acidic pH. Platinum anticancer drugs were loaded into these nanomedicines and evaluated against orthotopic head and neck tumors, featuring a large fraction of SA-rich cancer stem-like cells (CSCs) that are resistant to platinum drugs. The 5-BPA ligands increased intracellular drug delivery of nanomedicines at intratumoral pH (pH 6.5) and enhanced the accumulation of nanomedicines in tumors to efficaciously eliminate the malignant CSCs, suppress tumor growth, and prolong mice survival. These findings indicate the potential of engineered PBA ligands for developing effective strategies targeting SA in tumors.