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 tumour 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 optimised FC-coated TQ nanoparticles (∼105 nm) exhibited high encapsulation efficiency (82.3 ± 0.77%) and low polydispersity (<0.2), enabling passive tumour 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. <i>In vivo</i>, FC-coated TQ-NPs induced significant tumour regression (75.26 ± 2.24%) and prolonged median survival (49 days) in C26 tumour-bearing mice versus free TQ (22 days). Biochemical analysis showed normal hepatic (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and renal (blood urea nitrogen (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.