Wang_2025_Int.J.Biol.Macromol__147707

The therapeutic efficacy of the anticancer drug chlorambucil (Cbl) is severely hampered by its poor water solubility and serious off-target toxicity. To address these issues and to further improve therapeutic outcomes, we developed an innovative nano-agent that combines an activatable prodrug with an active tumor-targeting delivery system for the simultaneous imaging and treatment of cervical cancer. Guided by what we call a "two-birds-with-one-stone" concept, we first synthesized a carboxylesterase-activated near-infrared fluorescent prodrug capable of photo-sonodynamic therapy, that can generate abundant reactive oxygen species so as to enhance antitumor efficacy. This prodrug was subsequently encapsulated into an assembly formed from hyaluronic acid and alpha-tocopherol succinate (TOS), endowing the final nano-agent with improved water-solubility, extended blood retention half-life, CD44-mediated tumor-targeting ability, and TOS-derived cytotoxicity. This compact nano-agent served as both a sensitive near-infrared carboxylesterase indicator (with a detection limit of 0.057 U/mL) and a potent antitumor drug, achieving both 76 % inhibition of HeLa cell growth upon laser/ultrasound irradiation and significant tumor suppression in vivo. Unlike most reported nano-formulations that rely on complex multi-component systems for synergistic therapy, our design was built upon the repeated application of a "two-birds-with-one-stone" philosophy, resulting in a simplified yet effective nano-agent with great clinical potential.