THE THERAPEUTIC POTENTIAL OF LAV-BPIFB4: IMPROVING VASCULAR FUNCTION, MODULATING THE IMMUNE SYSTEM, AND REPROGRAMMING THE CYTOKINE NETWORK IN APOE-/- MODELS.

ATHEROSCLEROSIS, DRIVEN BY ENDOTHELIAL DYSFUNCTION, CHRONIC INFLAMMATION, AND PLAQUE INSTABILITY, REMAINS THE MAIN CAUSE OF CARDIOVASCULAR MORTALITY. LAV-BPIFB4, A LONGEVITY-ASSOCIATED GENETIC VARIANT ENRICHED IN LONG-LIVING INDIVIDUALS, PRESERVES VASCULAR HOMEOSTASIS THROUGH ENOS ACTIVATION AND IMMUNE MODULATION. THIS DOCTORAL THESIS INVESTIGATES RECOMBINANT HUMAN PROTEIN LAV-BPIFB4 (RHLAV-BPIFB4) THERAPEUTIC POTENTIAL IN HIGH-FAT DIET (HFD) INDUCED ATHEROSCLEROSIS USING APOE-/- MICE. ORAL ADMINISTRATION OF RHLAV-BPIFB4 ACHIEVED COMPLETE ENDOTHELIAL FUNCTION, IMPROVED PLAQUE STABILIZATION AND SYSTEMIC IMMUNE REPROGRAMMING. CYTOKINE PROFILING REVEALED THAT TNF-Α, IFN-Γ, IL-2 AND MCP-1 WERE REDUCED, WHILE IL-10 LEVELS INCREASED, THEREBY MITIGATING PRO-ATHEROGENIC INFLAMMATION. TO OVERCOME LIMITATIONS OF RECOMBINANT PROTEIN THERAPY, LIPID NANOPARTICLES (LNPS) WERE OPTIMIZED FOR MRNA DELIVERY. C-DOTMA LNPS DEMONSTRATED SUPERIOR MRNA ENCAPSULATION AND SELECTIVE MACROPHAGE INTERNALIZATION, ESTABLISHING AN ADVANCED TRANSLATIONAL PLATFORM FOR TARGETED GENE THERAPY IN ATHEROSCLEROSIS.