• Isorhamnetin preconditioning enhances MSC-derived exosomes' therapeutic efficacy against chemotherapy-induced premature ovarian failure.
• ISO-MSC-Exos suppress ferroptosis by downregulating Alox15 and Tf, reducing lipid peroxidation and iron uptake.
• ISO-MSC-Exos restore ovarian function, hormone levels, and fertility more effectively than unmodified MSC-Exos.
• This study provides a novel cell-free therapeutic strategy for POF, potentially applicable to other ferroptosis-related diseases.