Objective To develop a hyaluronic acid (HA)-modified crizotinib (Cri) nanoparticle drug delivery system (HDC NPs) to address the poor water solubility and low bioavailability of Cri, while endowing it with properties of pH-responsive controlled release, active targeting and long circulating, so as to provide a novel strategy for precise treatment of non-small cell lung cancer (NSCLC).Methods Using 3,3'-dithiodipropionic acid (DTPA) as a linker, HA and Cri were covalently conjugated via amidation reaction to synthesize the amphiphilic polymer HA-DTPA-Cri (HDC), followed by self-assembly to prepare HDC NPs. The structure of the polymer was verified using Fourier transform infrared spectroscopy (FTIR) and proton nuclear magnetic resonance (1H-NMR). Dynamic light scattering (DLS) was employed to determine the particle size and zeta potential, while transmission electron microscopy (TEM) was used to observe nanoparticle morphology. Ultraviolet spectrophotometry was used to determine drug loading (DL) and encapsulation efficiency (EE). In vitro release behavior (pH 7.4 vs. 5.0) was evaluated via dialysis. Flow cytometry and confocal microscopy were used to analyze the cellular uptake efficiency in A549 cells, while cytotoxicity assay (MTT method) to assess the antitumor activity.Results The HDC polymer was successfully synthesized. By optimizing the ratio of hydrophilic to hydrophobic materials, various HDC NPs with different sizes were prepared. When the mass ratio of HA-DTPA (HD) to Cri is 1∶1, the nanoparticles exhibited a size of (215.97±10.12) nm, a zeta potential of (-17.23±0.98) mV, and a polydispersity index (PDI) of (0.197±0.048). Observation of nanoparticles as uniform spherical shapes through TEM. The nanodrug formulation prepared at this ratio has a drug loading capacity of (3.55±0.48)% and an encapsulation efficiency of (42.61±3.96)%. In vitro release studies showed that HDC NPs exhibited sustained release properties and pH-responsive controlled release under acidic conditions (pH 5.0), with a 72-hour release rate of (73.28±1.88)%. Cellular experiments using A549 cells as an NSCLC model showed that HDC NPs achieved a cellular uptake rate of (28.12±0.66)%, significantly higher than free Cri, and exhibited enhanced inhibition of tumor cell proliferation and viability.Conclusion The newly developed HDC NPs exhibit uniform size, well-defined morphology, excellent dispersibility, and stability. They enable sustained and controlled release and demonstrate superior antitumor efficacy in vitro. This study provides a promising strategy for the improvement of crizotinib formulations and targeted therapy for NSCLC.