Design of Low-Dose, Non-Hormonal Female Contraceptives Targeting Trophoblast Cells Using Vitamin B13 Copper Metal-Organic Frameworks

Unintended pregnancy remains a significant concern in women's healthcare. Although current short-term contraceptive methods, particularly hormonal approaches, are effective in preventing unintended pregnancy, their potential long-term adverse effects necessitate the development of safer alternatives. A nanostrategy that interrupts early pregnancy by inhibiting embryonic trophoblast cell proliferation presents a promising non-hormonal approach with minimal adverse effects on female reproductive system. In this study, we further advanced this strategy by designing a highly effective, low-dose contraceptive using vitamin B13 copper metal-organic framework (VB13 Cu-MOF) as the active agent. VB13 Cu-MOF exhibited rapid dissolution in aqueous environments with a sustained and low Cu²⁺ release rate, facilitating preferential uptake by embryonic trophoblast cells due to their tumor-like characteristics. Upon contact with cells in the in vitro cellular model, the released Cu²⁺ was transported into cells via proteins on cell membrane in two pathways, direct Cu²⁺ intracellular transport, and Cu²⁺ reduction to Cu⁺ and Cu+ intracellular transport. Both Cu²⁺ and Cu⁺ in cells triggered parallel Fenton-like reactions, resulting in excessive reactive oxygen species generation, mitochondrial damage, apoptosis, and ferroptosis. RNA-seq analysis identified the key biological processes and the associated genes involved in these interactions. In vivo experiments in rat models demonstrated contraceptive efficacy using VB13 Cu-MOF at an ultra-low dose (65 μg/mL) and its hydrogel formulation, without inducing adverse effects on serum copper levels, estrogen concentrations, inflammatory markers, or organ morphology. These findings establish VB13 Cu-MOF as a promising non-hormonal contraceptive with strong potential to prevent unintended pregnancies while minimizing risks to women's health. STATEMENT OF SIGNIFICANCE: Vitamin 13 copper metal-organic Framework (VB13 Cu-MOF) was designed and developed as a bioactive material for female non-hormonal contraceptives. As a new source of copper ions, VB13 Cu-MOF demonstrated a controlled release of copper ions, effectively targeting and inducing trophoblast cell death to achieve high contraceptive efficacy in a rat model at low dosage, without causing adverse effects in vitro or in vivo. Moreover, VB13 can increase the histocompatibility of Cu-MOF to normal cells. VB13 Cu-MOF was employed to validate a novel contraceptive mechanism targeting trophoblast cells to interrupt the pregnancy process 5-8 days after mating. Significantly, this demonstrates its potential as a promising non-hormonal contraceptive for clinical use, contributing to enhanced women's healthcare.