QbD Optimized HA–BSA Coated Nanostructured Lipid Carriers for CD44-Targeted Combinational Delivery of Fisetin and Flavokawain A in Non–Small Cell Lung Cancer

Non–small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with current chemotherapeutic strategies limited by systemic toxicity, poor tumor selectivity, and the development of drug resistance. Flavonoids have emerged as promising anticancer agents; however, their clinical translation is hindered by their poor aqueous solubility, low bioavailability, and physicochemical instability. In the present study, a Quality-by-Design (QbD) driven approach was employed to develop and optimize hyaluronic acid–bovine serum albumin (HA–BSA) coated nanostructured lipid carriers (NLCs) for the targeted delivery of flavonoids in lung cancer. A systematic QbD framework was applied to define the Quality Target Product Profile and identify critical quality attributes, material attributes, and process parameters influencing formulation performance. Nanostructured lipid carriers were prepared using high-pressure homogenization, followed by sequential surface functionalization with BSA and hyaluronic acid to enhance stability and CD44-mediated targeting. Design of experiments enabled optimization of particle size, drug entrapment efficiency, and sustained drug release behavior. The optimized HA–BSA coated NLCs exhibited nanoscale particle size with narrow size distribution, favorable zeta potential, high drug entrapment efficiency, and reduced drug crystallinity, as confirmed by FTIR, DSC, and PXRD analyses. In-vitro drug release studies demonstrated a controlled and sustained release profile compared with free drug. Stability studies revealed superior physicochemical stability under refrigerated conditions, with the optimized formulation showing minimal changes in particle size, surface charge, and drug retention. Comparative analysis identified the optimized formulation as robust and suitable for further evaluation. Overall, this study establishes a stable, reproducible, and scalable nano-engineering platform for flavonoid delivery in lung cancer. The integration of QbD principles with HA–BSA functionalized NLCs offers a rational strategy to enhance the therapeutic potential of phytochemicals and provides a promising foundation for future preclinical and clinical development in NSCLC treatment.