This study presents a novel approach to synergistically treat colon cancer using hybrid films loaded with 5-fluorouracil (5-FU) and Reglan (ondansetron). The hybrid films are designed to achieve asynchronous dual-drug delivery, where Reglan is rapidly released first to prevent vomiting, followed by sustained release of 5-FU. The drugs are loaded into core-shell nanoparticles via coaxial electrospraying, which are then incorporated into polyvinylpyrrolidone K30 (PVP K30) films through casting. The core-shell nanoparticles consist of 5-FU and cellulose acetate (CA), with the CA shell preventing initial drug release. The hybrid films exhibit a semitransparent appearance and a thickness of approximately 2.0 mm. In vitro dissolution tests show that Reglan is rapidly released, while 5-FU is released in a sustained manner over 30 hours. The study demonstrates the potential of this hybrid film for synergistic cancer therapy, combining the advantages of advanced nanotechniques and traditional pharmaceutical techniques.This study presents a novel approach to synergistically treat colon cancer using hybrid films loaded with 5-fluorouracil (5-FU) and Reglan (ondansetron). The hybrid films are designed to achieve asynchronous dual-drug delivery, where Reglan is rapidly released first to prevent vomiting, followed by sustained release of 5-FU. The drugs are loaded into core-shell nanoparticles via coaxial electrospraying, which are then incorporated into polyvinylpyrrolidone K30 (PVP K30) films through casting. The core-shell nanoparticles consist of 5-FU and cellulose acetate (CA), with the CA shell preventing initial drug release. The hybrid films exhibit a semitransparent appearance and a thickness of approximately 2.0 mm. In vitro dissolution tests show that Reglan is rapidly released, while 5-FU is released in a sustained manner over 30 hours. The study demonstrates the potential of this hybrid film for synergistic cancer therapy, combining the advantages of advanced nanotechniques and traditional pharmaceutical techniques.