Solid lipid nanoparticles (SLNs) coated with N-trimethyl chitosan (TMC) represent advanced strategy for oral drug delivery due to enhanced mucoadhesion and gastrointestinal stability. This study aimed to develop, characterize, and evaluate TMC-coated SLNs for the oral co-delivery of docetaxel (DTX) and curcumin (CUR). Main objectives of this study are enhancement of gastrointestinal stability, sustained drug release, and improvement of antitumor effects against breast cancer cells. TMC-modified SLNs were synthetized using a microemulsion and ultrasonication technique. Characterization of physicochemical properties (particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE%), morphological appearance (SEM)) and in vitro release behavior was performed. Moreover, the pH-dependent drug release mechanism and kinetic modeling of the release process were studied. Cytotoxicity was determined in MCF-7 breast cancer cells and normal MCF-10 A cells using the MTT assay. The optimized TMC-SLNs represent a spherical morphology with a mean particle size of 136.7 ± 6.4 nm, PDI of 0.315 ± 0.037, and a zeta potential of - 10.9 mV. The formulation achieved high EE% (> 97%) for both drugs. Gastric burst release was effectively decreased to less than 2%, mainly because of the protonation of amine groups of TMC at acidic conditions, thus increasing stability in the gastrointestinal tract. The release kinetics followed the Korsmeyer-Peppas model (97%), indicating a non-Fickian diffusion mechanism governed by polymer relaxation. The system showed sustained and pH-triggered drug release, with a cumulative drug release profile reaching 50.4% of DTX and 58.6% of CUR release over 96 h. In vitro cytotoxicity confirmed the increased cytotoxic effect of TMC-SLNs compared to free drugs and blank SLNs. The effect could be related to their better mucoadhesive properties and intracellular internalization. Moreover, no toxic effects were observed towards normal MCF-10 A cells. The developed TMC-coated SLNs provide a robust platform for the oral co-delivery of DTX and CUR. The formulation offers enhanced stability, controlled release kinetics, and therapeutic potential, that support its further investigation for breast cancer treatment.
