5-Fluorouracil (5FU) and FeO nanoparticles were encapsulated in core-shell polycaprolactone (PCL)/chitosan (CS) nanofibers as a multi-mode anticancer system to study drug release sustainability. The structure of the core-shell drug delivery system was also optimized according to drug release behavior by artificial intelligence. The core-shell nanofibers were electrospun by a coaxial syringe. Artificial neural network (ANN) was used for function approximation to estimate release parameters. A genetic algorithm was then used for optimizing the structure. Chemical assay of the optimized sample was performed by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and energy-dispersive X-ray spectroscopy (EDX). vibration sample magnetometer (VSM) test was conducted to measure the real amount of loaded magnetic nanoparticles. HepG2 cell cytotoxicity was studied and the results for the optimized samples with and without FeO after 72 hours were reported. Feeding ratio of sheath to core and the amount of CS, FeO, and 5FU had a statistical effect on nanofibers diameters, which were 300-450 nm. The drug loading efficiency of these nanofibers was 65-86%. ANN estimated the release parameters with an error of 10%. The temperature increased about 5.6°C in the alternative magnetic field (AMF) of 216 kA.m300 kHz and 4.8°C in the AMF of 154 kA.m400 kHz after 20 minutes. HepG2 cell cytotoxicity for the optimized samples with and without FeO after 72 hours were 39.7% and 38.8%, respectively. Since this core-shell drug release system was more sustainable compared to the blend structure despite the low half-life of 5FU, it is suggested to utilize it as post-surgical implants for various cancer treatments such as liver or colorectal cancer in the future. This system is capable of providing chemotherapy and hyperthermia simultaneously.