Nano Delivery of Flavonoids in NSCLC: Mechanistic Insights and Translational Perspectives

Non-small cell lung cancer (NSCLC) has high mortality rates owing to multidrug resistance, inadequate tumor selectivity, and systemic toxicity associated with conventional chemotherapy. In contrast, flavonoids, including fisetin, quercetin, and flavokavain A, show promising anticancer activity. However, their clinical application is limited by poor solubility, instability, and insufficient intracellular accumulation. Recent studies, mainly on nanostructured lipid carriers (NLCs), have provided a strategic approach to address these challenges. This critical review examines nanocarrier-enabled flavonoid delivery systems for NSCLC, focusing on the role of lipid-based nanocarriers in enhancing pharmacokinetics, improving tumor targeting, and reversing drug resistance mechanisms. Surface-functionalized NLCs, including hyaluronic acid (HA) and protein-based ligands, facilitate receptor-mediated uptake, enhance therapeutic efficacy, and inspire current preclinical evidence. This review discusses the mechanistic advantages and translational potential of NLC-based flavonoid delivery and identifies the important challenges that must be addressed for clinical advancement.