Purpose <p>Breast cancer remains a leading cause of cancer-related death among women worldwide. The advancement of targeted therapies to enhance efficacy and reduce systemic toxicity is essential. The aim of this study was to develop hyaluronic-acid coated nanoparticles for the targeted delivery of palbociclib, utilizing poly(lactic-co-glycolic acid), by applying QbD approach.</p> Methods <p>The nanoparticles were developed using single-emulsion solvent evaporation technique. Utilizing the QbD approach, a QTPP was defined, and a comprehensive risk assessment was conducted. A 2⁷⁻³ fractional-factorial design was used to identify the factors affecting the particle size and entrapment efficiency. A Central-composite design was employed to obtain the optimized formulation, yielding a particle size of &lt; 200&#xa0;nm and high encapsulation efficiency. The optimized NPs were then surface modified with hyaluronic-acid and tested on MCF-7 cell lines.</p> Results <p>The particle size, zeta potential and entrapment efficiency of optimized and coated nanoparticles were 188.38 <i>±</i> 1.35&#xa0;nm, -27.23 <i>±</i> 1.67mV and 85 <i>±</i> 2.14%; 195.7 <i>±</i> 1.45, -28.52 <i>±</i> 2.32mV and 84.78 + 2.67% respectively. The nanoparticles were spherical in shape with smooth surface. The nanoparticles were &lt; 200&#xa0;nm and preferentially accumulated in tumour sites attributable to the enhanced permeation and retention.</p> Conclusion <p>The hyaluronic-acid coated nanoparticles exhibited enhanced cytotoxicity, apoptosis, and nuclear damage compared to the optimized formulation and the free drug. This is likely attributed to the increased affinity of hyaluronic-acid to CD44 receptors, which are overexpressed in cancer cells, thus facilitating a targeted approach.</p> Graphical Abstract <p></p>