Berberine (BBR) has many pharmacological activities including anti-inflammatory, antibacterial, and against many diseases, especially cancer. However, berberine is a large molecular compound with rapid metabolism by enzymes in the human body and limited bioavailability. To improve, berberine needs to be coated and combined with other active ingredients. In this study, berberine is successfully encapsulated by coaxial electrosprayed chitosan (CS) without cross-linked agents, and piperine (PPR) is also added via two different approaches to improve absorption and bioavailability. The obtained nanoparticles have a spherical shape with smooth surface and relatively wide particle size distribution observed by SEM. The uniform core/ shell structure with clear boundary, non-agglomerated encapsulated spheres, and average diameter of 143.67±56.16 nm (for BBR-PPR@CS) and 152.91 ± 48.50 nm (for BBR@PPR-CS) were analyzed by TEM images. The appearance of some weak peaks and slight shifting of major peaks in FTIR spectra of BBR-PPR@CS and BBR@PPR-CS samples and their high encapsulation efficiencies reflected their successful encapsulation. In drug release experiments, as expected, with the combination of PPR and CS in the outer shell (BBR@PPR-CS), the release of PPR was faster than that of BBR. The amount of drug in all samples was released more strongly at pH 5.0 than at pH 7.4, and the release time extended up to 36 h. Therefore, coaxial electrosprayed chitosan nanoparticle is a promising functional material for the simultaneous encapsulation of BBR and PPR, as well as increasing bioavailability of BBR, contributing to the development of controlled drugs toward effective anticancer.