AbstractThe development of electro‐stimulated drug release devices is an innovative approach to attain the drug delivery in accurate doses at target sites in a programmed manner. In this work, novel electroactive nanocomposite hydrogels were prepared by encapsulating green‐synthesized polypyrrole (PPy) colloids within chondroitin sulfate (CS) networks during the self‐crosslinking of CS via N‐ethyl‐N′‐(3‐dimethylaminopropyl) carbodiimide chemistry. The structural and morphological properties of CS/PPy hydrogels were studied by Fourier‐transformed infrared spectroscopy, scanning electron microscopy, and swelling kinetic measurements. The chemotherapeutic agent 5‐fluorouracil (5‐FU) was loaded into CS/PPy samples by hydrogel swelling method, or alternatively, by pre‐incubating the drug in polymer mixture before crosslinking. Different electrical stimulations can be used to switch ON and accurately tune the 5‐FU delivery from GG/PPy hydrogels. A single pulse potential of 5 V switched on the drug delivery up to 90% from nanocomposite hydrogel, in contrast to the low 5‐FU amount released in a passive form (< 20%). PPy electroactive behavior played a determining role as the main driving force in 5‐FU release activation. Cytotoxicity of hydrogels with and without 5‐FU was examined in normal and cancer cells. Considering the high cytotoxicity of 5‐FU, the ON/OFF 5‐FU release patterns evidenced the potential of CS/PPy hydrogels for electrically controlled drug delivery in implantable or transdermal drug release devices.