Rewriting Atherosclerosis Therapy: Bioengineering-Inspired Liposomes and Polymeric Nanoparticles as Innovative Nanotools for Targeted Drug Delivery

Atherosclerosis-driven arterial occlusions remain a major cause of ischemic complications, including stroke, myocardial infarction, and limb loss. Although surgical interventions have advanced, the absence of targeted pharmacological strategies continues to limit therapeutic success, particularly due to the systemic toxicity of many promising drugs. Localized vascular drug delivery offers a new frontier, allowing for the modulation of inflammation at early stages of atherosclerotic plaque formation. In this study, we developed a nanocarrier-based delivery platform consisting of liposomes (LPs) and polymeric nanoparticles (PNPs) designed to encapsulate therapeutic monoclonal antibodies (mAbs) and polyphenols. To enable site-specific delivery, the nanocarriers were functionalized with immunouteroglobin-1 (IUG-1), a recombinant protein that selectively binds to the extra-domain B of fibronectin, which is overexpressed in atherosclerotic lesions. LPs were produced via a thin-film hydration technique, while PNPs were obtained using a water/oil/water double-emulsion solvent evaporation method. IUG-1 conjugation was achieved through carbodiimide/N-hydroxysuccinimide chemistry. Nanocarrier characterization included scanning electron microscopy, nanoparticle tracking analysis, and dynamic light scattering to determine morphology, size distribution, and ζ-potential. Both LPs and PNPs showed average diameters of approximately 200 nm and a stable negative surface charge. IUG-1 functionalization led to an increased particle size and an altered ζ-potential, confirming successful surface modification. LP and PNP exposure to human serum for 24 or 48 hours revealed good stability. Drug release profiles were evaluated to confirm controlled delivery over time. A sustained release of mAbs was observed in human serum over time, and biocompatibility tests on endothelial cells, macrophages, and red blood cells demonstrated high tolerance across all concentrations without cytotoxicity or hemolytic effects. These results suggest that the developed IUG-1-functionalized nanocarriers represent a promising and versatile platform for the targeted therapy of atherosclerosis, offering enhanced site-specific efficacy and reduced systemic toxicity. These achievements lay the groundwork for preclinical evaluation in vascular medicine.