Ovarian radiation injury and protection: Mechanisms, delivery-enabled interventions, and future directions

Incidental ovarian irradiation during pelvic radiotherapy or total-body irradiation leads to irreversible endocrine dysfunction, premature ovarian insufficiency, and infertility in young women with cancer. Current clinical strategies-ovarian transposition, shielding, and organ-at-risk dose constraints-provide only partial protection and offer limited control over temporal exposure or spatial confinement. These limitations underscore the need for delivery-enabled radioprotective systems capable of targeting the ovary with precision, synchronizing protection with radiation fractions, and minimizing tumor co-protection.This review integrates the mechanistic foundations of ovarian radiosensitivity with emerging opportunities in drug delivery and biomaterials engineering. We first summarize key biological pathways-including DSB-CHK2/TAp63-mediated oocyte apoptosis, ferroptosis-associated lipid peroxidation (GPX4 loss, 4-HNE accumulation), mitochondrial injury, and microvascular-stromal remodeling-that collectively define the ovarian vulnerability to ionizing radiation and reveal discrete physicochemical intervention windows. Building on this foundation, we evaluate a spectrum of next-generation delivery platforms with direct relevance to ovarian radioprotection: antibody-drug conjugates for ovary-targeted intracellular deposition; lipid nanoparticle-mediated siRNA for transient pathway modulation; ultrasound- or magnetically actuated micro/nanomotors for active tissue penetration and precision positioning; and injectable biodegradable hydrogels for localized, fraction-matched release.We also highlight the emerging "estrogen-anti-ferroptosis axis" as a hypothesis-generating pathway that may synergize with material-enabled strategies to reduce early oxidative and lipid-peroxidative injury. Together, these insights outline a translational roadmap for integrating targeting, controlled release, and bioresponsive materials into radiotherapy workflows, offering new directions for precise, organ-specific protection without compromising oncologic control.