pH-Responsive Folate-PEG modified ZIF-8 Nanoparticles Deliver Fisetin to Aquaporin-3 for Cervical Cancer Therapy

Conventional cervical cancer therapies often cause severe side effects and face recurrence challenges. Although the natural flavonoid fisetin (FIS) exhibits strong anticancer properties, its clinical utility is restricted by poor aqueous solubility. To overcome this, we engineered a tumor-targeting nanotherapeutic, PEG-FA@ZIF-8@FIS, by encapsulating FIS within a zeolitic imidazolate framework-8 (ZIF-8) core surface-functionalized with polyethylene glycol-folic acid(PEG-FA). Both in vitro and in vivo models demonstrate that this system effectively suppresses cancer cell proliferation, migration, and tumor growth with excellent biocompatibility. Mechanistically, transcriptomic and lipidomic analyses reveal that PEG-FA@ZIF-8@FIS exerts its anticancer effects by downregulating aquaporin-3 (AQP3) expression, which subsequently disrupts tumor lipid metabolism. By linking AQP3 inhibition to metabolic impairment via a targeted delivery platform, this work establishes a highly biocompatible and effective translational strategy for cervical cancer intervention.