Cortical Organoid-on-a-Chip with Physiological Hypoxia for Investigating Tanshinone IIA-Induced Neural Differentiation.

Cytoxan (CTX), an alkylating chemotherapeutic agent, produces severe testicular toxicity in male patients by generating mitochondrial dysfunction and redox imbalance, resulting in an excess buildup of reactive oxygen species (ROS) that compromises sperm function and fertility. Schisandrin A (SchA), a bioactive compound derived from traditional Chinese medicine Schisandra chinensis, can alleviate this injury by mimicking superoxide dismutase activity to scavenge ROS, but its poor water solubility, inability to penetrate the blood-testis barrier (BTB), and high dosage requirement that cause hepatic and gastrointestinal side effects limit clinical application. This study describes a biomimetic SchA delivery system that leverages TM4 (Sertoli-like) cell membrane-coated protein carriers to enable some degree of targeted delivery to testicular tissue. We named it CAT-SchA@SCM. Briefly, SchA was loaded onto catalase (CAT), and protein nanoparticles were disguised with TM4 cell membranes. Transmission electron microscopy and dynamic light scattering results showed that CAT-SchA@SCM had an average particle size of around 170 nm and was well-dispersed and stable. In vitro and in vivo experiments demonstrated that CAT-SchA@SCM could target Sertoli cells to a limited extent, cross the BTB, considerably scavenge intracellular ROS, inhibit apoptosis, and effectively protect Sertoli cells. In a mouse model of CTX-induced testicular damage, CAT-SchA@SCM dramatically increased sperm motility, testicular weight, and serum testosterone levels. Hematoxylin and eosin staining of major organs demonstrated that CAT-SchA@SCM exhibited favorable biosafety. Additionally, activation of the Nrf2-HO-1 signaling pathway was observed, indicating a potential mechanism underlying the therapeutic effect of CAT-SchA@SCM. Therefore, the findings of this study suggest that this nanocomplex-based treatment may offer a viable approach for addressing CTX-induced testicular injury, with potential clinical applications in the future.