Poly (β-amino esters)/Mobil Composition of Matter 41-mediated delivery of siIL-1β alleviates deep vein thrombosis in rat hind limbs.

Abstract

Introduction: Deep vein thrombosis (DVT) is a major cause of cardiovascular disease-related deaths worldwide and is considered a thrombotic inflammatory disorder. IL-1β, as a key promoter of venous thrombus inflammation, is a potential target for DVT treatment. Constructing a nanocarrier system for intracellular delivery of siIL-1β to silence IL-1β may be an effective strategy for alleviating DVT. Methods: ELISA was used to detect the expression levels of IL-1β and t-PA in the serum of DVT patients and healthy individuals. In vitro, HUVEC cells were treated with IL-1β, and changes in VWF and t-PA expression levels were assessed. PBAE/MCM-41@siIL-1β (PM@siIL-1β) nano-complexes were synthesized, the characterization and biocompatibility of PM@siIL-1β were evaluated. A rat hind limb DVT model was established, and PM@siIL-1β was used to treat DVT rats. Morphology of the inferior vena cava, endothelial cell count, IL-1β, vWF, and t-PA levels, as well as changes in the p38 MAPK and NF-κB pathways, were examined in the different groups. Results: IL-1β and t-PA were highly expressed in DVT patients, and IL-1β treatment induced a decrease in VWF levels and an increase in t-PA levels in HUVEC cells. The synthesized PM@siIL-1β exhibited spherical shape, good stability, high encapsulation efficiency, and high drug loading capacity, with excellent biocompatibility. In the DVT model rats, the inferior vena cava was filled with blood clots, endothelial cells increased, IL-1β and VWF levels significantly increased, while t-PA levels were significantly downregulated. Treatment with PM@siIL-1β resulted in reduced thrombus formation, decreased endothelial cell count, and reversal of IL-1β, VWF, and t-PA levels. Furthermore, PM@siIL-1β treatment significantly inhibited p38 phosphorylation and upregulation of NF-κB expression in the DVT model group. Conclusion: IL-1β can be considered a therapeutic target for suppressing DVT inflammation. The synthesized PM@siIL-1β achieved efficient delivery and gene silencing of siIL-1β, demonstrating good therapeutic effects on rat hind limb DVT, including anti-thrombotic and anti-inflammatory effects, potentially mediated through the p38 MAPK and NF-κB pathways.