Polysaccharide-Coated mPEG-PLA Nanoparticles Enhance Thymoquinone Delivery and Therapeutic Efficacy against Colorectal Cancer

Colorectal cancer (CRC) remains a major therapeutic challenge due to systemic toxicity and poor tumor selectivity of conventional treatments. Thymoquinone (TQ), a natural anticancer compound, faces limited clinical utility because of poor solubility and bioavailability. To overcome these challenges, a fucoidan (FC)-coated methoxy poly(ethylene glycol)-poly(lactic acid) (mPEG-PLA) nanoparticle system was developed for targeted TQ delivery. The optimized FC-coated TQ nanoparticles (∼105 nm) exhibited high encapsulation efficiency (82.3 ± 0.77%) and low polydispersity (<0.2), enabling passive tumor targeting via the enhanced permeability and retention (EPR) effect. The formulation showed sustained, pH-responsive release and enhanced cytotoxicity in HCT-116 cells (IC₅₀ = 68.97 ± 1.10 µM) compared to uncoated NPs and free TQ. Confocal microscopy confirmed efficient uptake, while Western blot analysis demonstrated a concentration-dependent increase in cleaved caspase-3 in HCT-116 and HT-29 cells, indicating apoptosis induction. In vivo, FC-coated TQ-NPs induced significant tumor regression (75.26 ± 2.24%) and prolonged median survival (49 days) in C26 tumor-bearing mice versus free TQ (22 days). Biochemical analysis showed normal hepatic (ALT, AST) and renal (BUN, creatinine) profiles, and cardiac histology remained intact, confirming biosafety. Thus, FC-coated mPEG-PLA-TQ nanoparticles enhance efficacy and safety, offering a promising nanoplatform for targeted CRC therapy.