Polymer based nanoformulations offer substantial prospects for efficacious chemotherapy delivery. Here, we developed a pH-responsive polymeric nanoparticle based on acidosis-triggered breakdown of boronic ester linkers. A biocompatible hyaluronic acid (HA) matrix served as a substrate for carrying a doxorubicin (DOX) prodrug which also possesses natural affinity for CD44 cells. DOX was functionalized with a boronic acid group, which was covalently linked with the HA polymer, resulting in a stable chemical linker at neutral pH. Under acidic conditions, the boronic ester linker is degraded, dissociating DOX. Compared to free DOX, the DOX HA NPs exhibited preferential accumulation in 4T1 cells. In a BALB/c mouse model, DOX HA NPs improved antitumor activity, dramatically improved control of lung metastases, and ultimately led to enhanced survival. The pH-sensitive HA nanocarriers provide a promising approach to enhance therapeutic outcomes and reduce toxicity in chemotherapy.