In this work, biodegradable nanoparticles (NPs) were assembled with sodium carboxymethyl cellulose (CMC) and zein to produce zein-CMC NPs. Paclitaxel (PTX) was 95.5% encapsulated at a zein-CMC weight ratio of 1 : 3 and the NPs were spherical with an average particle size of approximately 159.4 nm, with the PTX concentration maintained at 80 μg mL-1. The NPs demonstrated good stability over a broad range of pH ranging from 3.7 to 11.0. The zein-CMC NPs were seen to provide a sustained release of PTX for up to 72 h, which led to an 80% release of the total loaded PTX in vitro. Confocal laser scanning microscopy (CLSM) and flow cytometry studies showed that the zein-CMC NPs could effectively transport encapsulated molecules into both drug-sensitive (HepG2 cells) and drug-resistant cancer cells (MCF-7 cells). Moreover, in vitro viability studies revealed that the PTX-loaded zein-CMC NPs had greater potency than free PTX in the PTX resistant MCF-7 cells at higher concentration. Furthermore, PTX-loaded NPs displayed obvious efficiency in the apoptosis of HepG2 cells. Zein-CMC NPs have shown significant potential as a highly versatile and potent platform for cancer therapy.