Abstract: Background: Chronic inflammation and immune dysregulation are key drivers of
diabetes complications. Rivaroxaban (RX) and sitagliptin (SITA) are established therapies
for thromboembolism and glycemic control, respectively. This study evaluated the novel
therapeutic potential of nano-rivaroxaban (NRX) alone and in combination with sitagliptin
(SITA) in mitigating inflammation and restoring immune balance in streptozotocin (STZ)-
induced diabetic rats. Methods: Type 2 diabetes was induced in rats using a single injection
of STZ (60 mg/kg). Animals were divided into five groups: control, STZ-diabetic, RXtreated
(5 mg/kg), NRX-treated (5 mg/kg), and NRX+SITA-treated (5 mg/kg + 10 mg/kg).
After 4 weeks of treatment, blood glucose, coagulation markers, pro-inflammatory cytokines
(TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-35, TGF-β1, IL-10) were
analyzed. Histopathological examination of the liver, kidney, pancreas, and spleen was
conducted. Immunohistochemistry was used to assess hepatic NF-κB expression. Results:
STZ significantly elevated pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) and
anti-inflammatory cytokines (IL-35, TGF-β1, IL-10), along with increased hepatic NF-κB expression
and histopathological abnormalities in immune organs. NRX significantly reduced
inflammatory cytokines, improved histopathological changes in organs, and decreased
hepatic NF-κB expression. The combination therapy (NRX + SITA) achieved superior
immune modulation, with enhanced cytokine profile restoration, reduced hepatic NF-κB
expression, and near-complete histopathological normalization. Conclusions: This study
underscores the promise of combining nanoparticle-based drug delivery with established
therapies like sitagliptin to achieve superior immune modulation and inflammation control,
presenting a potential therapeutic strategy for managing diabetes complications.