Recent Advances in Nanodelivery Systems Based on Extracellular and Intracellular Reprogramming Strategies for Enhanced Therapy of Atherosclerosis

Yilin Liu,1,* Yao Li,1,2,* Qian Wang,3,* Mengxi Wu,1,4 Zongquan Zhang,1 Xiaoya Liang,1 Xi Yang,1 Xinghui He,1 Jun Tang,5 Chunhong Li,1 Ping Yuan,6 Tao Li7 1Department of Pharmacy Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 2Science and Technology Department, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 3Classical Teaching and Research Department, College of Integrated Chinese and Western Medicine, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 4Chinese Pharmacy Laboratory, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 5Analysis and Testing Center, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 6Department of Neurology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People’s Republic of China; 7Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ping Yuan, Email 382400407@qq.com Tao Li, Email leta49@swmu.edu.cnAbstract: Atherosclerosis (AS) represents a chronic immunoinflammatory disorder characterized by lipid metabolism dysregulation, predominantly affecting medium and large arteries. During the initial phase of the disease, endothelial cells (ECs) undergo mesenchymal transformation, subsequently releasing various adhesion molecules and chemokines that facilitate the recruitment of monocytes and neutrophils (NEs) to developing plaque sites. Under sustained inflammatory stimulation, NEs transform into neutrophil extracellular traps (NETs), monocytes differentiate into pro-inflammatory macrophages, and vascular smooth muscle cells (VSMCs) exhibit phenotypic switching, and adopt macrophage-like characteristics. These inflammatory cells release excessive inflammatory factors and reactive oxygen species (ROS), thereby amplifying the inflammatory cascade. Concurrently, these activated macrophages and VSMCs internalize oxidized low-density lipoprotein (ox-LDL) particles, promoting foam cell’s generation and plaque’s formation. Given the critical role of the activation of various inflammatory cells and the accumulation of inflammatory mediators in progression of the disease, nanodelivery systems (NDSs) have shown remarkable promise in treating AS, attributed to their excellent cell-specific targeting capabilities and regulation capabilities for inflammatory mediator. This paper comprehensively reviews the progress of NDSs based on intracellular and extracellular reprogramming strategies for the therapy of AS, emphasizing their role in reversing EC’s phenotypes, monocytes’ reprogramming, macrophages’ repolarization, inhibition of Nes’ recruitment, suppression of VSMCs’ proliferation, modulation of inflammatory mediators, reprogramming of lipid’s metabolism, and scavenging of ROS to enhance therapeutic efficacy. We further elaborate on the advantages, challenges, and opportunities of NDSs in enhancing intracellular and extracellular reprogramming strategies, aiming to deepen these strategies and their potential applications in the therapy of AS. Keywords: atherosclerosis, nanodelivery systems, microenvironment, reprogramming strategies