Biomimetic Nanotechnology Overcoming the Blood–Testis Barrier for Testicular Protection in Chemotherapy

Cancer patients exposed to chemotherapeutic drugs and whole-body radiation can result in testicular injury and germ cell loss. One of the mechanisms is that these drugs lead to the accumulation of reactive oxygen species (ROS) in the testes, which has been documented to cause testicular damage. Therefore, this highlights the critical need for ROS clearance in testes to preserve male fertility during cancer treatment. The blood-testis barrier (BTB) poses a major challenge, due to the absence of effective pharmaceutical agents that can penetrate this barrier to neutralize ROS effectively. We synthesized nanomaterials based on manganese-superoxide dismutase (PCN-222-Mn), demonstrating the ability to cross BTB and facilitate ROS clearance. Real-time T1-weighted magnetic resonance imaging confirmed the targeted delivery of PCN-222-Mn to the testes in mice. In murine models of testicular injury induced by cyclophosphamide, PCN-222-Mn showed major therapeutic effects by protecting germ cells and associated somatic cells through ROS reduction and autophagy enhancement. Additionally, PCN-222-Mn was demonstrated to penetrate Sertoli cells via clathrin-mediated and caveolae-mediated endocytosis and expelled by exocytosis, facilitating transport across the BTB. This research not only proposes a viable therapeutic approach to preserve male fertility during cancer treatment but also underscores the transformative potential of nanozymes in clinical settings.