Multiphasic blood transcriptomic signatures of radioprotection by BIO 300, a synthetic genistein nanosuspension, in a nonhuman primate model of acute radiation syndrome

Background: Prophylactic radioprotectors for pre-exposure administration are notably absent, creating a critical gap in radiation emergency preparedness and ARS management. BIO 300, a wet-nanomilled formulation of synthetic genistein, is in advanced development as a prophylactic radioprotector with demonstrated survival benefits in murine and nonhuman primate (NHP) models when administered prior to lethal radiation exposure. Longitudinal transcriptomic analysis enables characterization of the molecular mechanisms underlying radioprotective drug action and supports development of potential blood-based monitoring tools for clinical translation. We performed longitudinal blood transcriptome profiling in NHPs receiving 5.8 Gy total-body irradiation to characterize BIO 300‘s radioprotective mechanisms and identify candidate transcriptional biomarkers of drug activity. Results: BIO 300 demonstrated multiphasic changes in the transcriptome spanning acute cellular preservation (Days 7–10), immune reconstitution (Day 21), and sustained recovery (Day 60), with peak protection spanning 745–865 genes at Days 7–10 and sustained late-phase protection of 558 genes at Day 60. Differential expression analysis revealed four distinct drug-related molecular mechanisms: direct cellular protection, active damage reversal, drug-specific therapeutic responses, and stress attenuation. A core set of 39 genes showing sustained or consistent differential expression was identified, of which 20 carry conventional gene symbols and are functionally interpretable; LOC-designated genes are excluded from functional annotation. Notable annotated genes include SOX2, AKAP11, TIMD4, BTNL10, VNN2, and CLEC1A, representing candidate exploratory transcriptional markers consistent with hematopoietic recovery and immune surveillance. Temporally orchestrated pathway signatures include neuroimmune modulation (Day 7), hemostatic recovery (Day 14), and immunometabolic reconstitution (Day 21). Conclusions: Our results show that BIO 300 provides multiphasic radioprotection across acute, immune reconstitution, and sustained recovery phases through four distinct mechanisms. Longitudinal transcriptomic signatures identified in this study represent potential blood-based monitoring tools for therapeutic efficacy assessment toward the continued development of BIO 300.