Targeted Sustained-Release Therapy for Vulnerable Atherosclerotic Plaques Using Luteolin-Loaded Nanoparticles

Purpose: The early, precise, and safe management of vulnerable atherosclerotic plaques (VAPs) remains a formidable clinical challenge. Here, we present a targeted nanotherapeutic approach in which osteopontin-targeted nanoparticles encapsulate luteolin (NPs-Lut) for the precise delivery and treatment of VAPs. This engineered system enables site-specific accumulation and sustained release of luteolin at plaque sites.

Methods: We innovatively constructed an osteopontin-targeted drug delivery system designed for vulnerable atherosclerotic plaques, in which luteolin and atorvastatin were successfully encapsulated. The system demonstrated sustained-release capability in vitro, and its biosafety and histocompatibility were comprehensively evaluated both in vitro and in vivo. Moreover, therapeutic efficacy was further assessed in apoE^-/- mice, confirming its potential for treating atherosclerotic lesions.

Results: In vivo evaluation in apoE^-/- mice demonstrated that NPs-Lut markedly outperformed atorvastatin-loaded nanoparticles (NPs-AST) in attenuating plaque-associated inflammation, alleviating endoplasmic reticulum stress and foam cell Apoptosis, and enhancing plaque stability. Histological analysis revealed a significant reduction in plaque and necrotic core area, accompanied by increased fibrous cap thickness and Collagen deposition. By improving the aqueous solubility and bioavailability of luteolin, NPs-Lut achieved potent therapeutic efficacy at low doses while minimizing systemic toxicity.

Conclusion: This work provides a robust and translationally promising nanoplatform for the precision treatment of VAPs, offering a novel strategy for safe and effective intervention in atherosclerotic Cardiovascular Disease.