Co-delivery of paclitaxel and morin via solid lipid nanoparticles overcomes multidrug resistance in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with paclitaxel (PTX) resistance posing a significant therapeutic hurdle. This study aimed to overcome multidrug resistance (MDR) by co-delivering PTX and the flavonoid morin (MRN) via solid lipid nanoparticles (PM-SLNs). PM-SLNs were optimized using an orthogonal design (L9 array) and characterized for physicochemical properties. In vitro studies evaluated cytotoxicity (MTT assay), apoptosis (Annexin V/PI), caspase activity, and cell cycle effects in PTX-resistant A549/PTX and parental A549 cells. In vivo efficacy was assessed in mice bearing A549/PTX xenografts (n=6 per group) treated with free drugs, combinations, or PM-SLNs. Tumor inhibition, systemic toxicity, and molecular markers were analyzed. Optimized PM-SLNs exhibited high encapsulation efficiency (95.2% MRN, 94.6% PTX) and uniform size (125.6 nm). In vitro , PM-SLNs showed a 6.2-fold lower IC50 than free PTX in resistant cells, induced 76.5% apoptosis (vs. 18.6% for PTX), suppressed cyclins D1/E1, and activated caspases-3/9. In vivo , PM-SLNs achieved a 77.8% tumor inhibition rate relative to the control, significantly outperforming free PTX (40% inhibition), with negligible toxicity. Moreover, PM-SLNs downregulated NF-κB (55%) and P-gp (63%) and modulated oxidative stress markers (elevated SOD/CAT, reduced MDA). PM-SLNs synergistically enhanced PTX efficacy, reversed MDR via NF-κB/P-gp suppression, and reduced systemic toxicity. This nanoplatform represents a promising strategy for refractory NSCLC.