Carrier-free nano-prodrugs (NPDs) were developed for selective drug release in cancer cells using stimulus-responsive systems: esterases, reactive oxygen species (ROS), and glutathione (GSH). Esterase-activated NPDs showed hydrophobicity-dependent drug release through SN-38 modification. ROS-responsive NPDs with trimethyl lock groups demonstrated selective activation by intracellular H2O2. GSH-responsive dimeric SN-38 prodrugs exhibited enhanced antitumor effects with reduced side effects. These NPDs achieved high drug loading and excellent stimulus responsiveness without using carriers, providing a promising platform for safer and more effective cancer therapy.
