Targeting granulosa cells with engineered DFO nanoparticles for the treatment of chemotherapy-induced premature ovarian failure

Premature ovarian failure (POF) is a prevalent and lethal adverse event that severely affects female cancer patients receiving chemotherapy. It is highly correlated with the collateral damage to ovarian granulosa cells caused by ferroptosis. The excessive iron accumulation in the intracellular labile iron pool (LIP) and the aberrant generation of reactive oxygen species (ROS) is the major cause of ferroptosis. No compounds with both ferroptosis inhibition functions and ovarian-targeting specificity that do not reduce systemic chemotherapeutic efficacy have been successful in treating the POF in the clinic trials. We herein in report a multifunctional FSH-mPDA@DFO nanoparticle that can prevent chemotherapy-induced DFO by targeting LIP and ROS to restrict ferroptosis. The FSH-mPDA@DFO are constructed by encapsulating deferoxamine (DFO) within mesoporous polydopamine nanoparticles conjugated with an ovarian granulosa cell-targeting peptide (FSHβ). They downregulate transferrin receptor (TFRC) expression, reduce cellular iron ion uptake, and inhibit ferritinophagy-mediated iron mobilization, thereby ameliorating LIP overload and regulating iron metabolism. More importantly, FSH-mPDA@DFO nanoparticles can specifically accumulate in the mitochondria and suppress excessive mitophagy to preserve mitochondrial integrity and attenuate iron release and ROS generation. <i>In vivo</i> experiments demonstrate that FSH-mPDA@DFO nanoparticles improve oocyte quantity and quality while restoring fertility and endocrine homeostasis in chemotherapy-induced POF mice. Collectively, FSH-mPDA@DFO nanoparticles hold a great potential for clinical prevention and treatment of POF patients.