摘要
Remodeling of the lesional macrophages in atherosclerotic plaques from pro-inflammatory M1 to pro-resolving M2 phenotype is emerging as a promising approach to atherosclerosis treatment.Tilianin(Til),as a natural plant-derivedingredient,hasthepotential tosuppress atherosclerosis progression.However,the poorly aqueous solubility and capacity of targeted plaques limit to clinic transformation of Til.Furthermore,whether Til can remodel the lesional macrophage phenotype remains uninvestigated.Herein,we developed a lesional macrophage-targeted Til lipid nanoparticles(FA@Til-LNPs)via folate modification and investigated their therapeutic efficiency and potential mechanisms for atherosclerosis treatment.We observed that the FA@Til-LNPs not only improved solubility and bioavailability,but also actively targeted M1 macrophages in atherosclerotic plaques,and the internalized FA@Til-LNPs could effectively regulate macrophage polarization toward the M2 phenotype.The nanotherapeutics reduced plaque areas and substantially improved plaque stability by effectively reducing necrotic core area and augmenting the collagen cap area in high-fat diet-fed ApoE--mice.Mechanistically,RNA-sequencing analysis revealed that the FA@Til-LNPs inhibited the pro-inflammatory signaling pathway by down-regulating the expression of pro-inflammatory genes associated with cytokine and chemokine pathways in lesional macrophages.This study first developed the innovative targeting nanotherapeutics of Til to regulate macrophage phenotype for atherosclerosis treatment.
基金
This research was supported by the Science and Technology Project of Xinjiang Production and Construction Corps(No.2022AB020)
the Youth Fund of National Natural Science Foundation of China(Nos.82104081 and 82400537)
the Sichuan Province Science and Technology Support Program(No.2023NSFSC1682,and No.2024NSFSC0714,Zhongshan He)
the Postdoctoral Fellowship Program of CPSF under Grant(No.GZC20241133,Zhongshan He)
the Sichuan University Postdoctoral Research and Development Fund(No.2024SCU12014)
the West China Hospital Postdoctoral Research and Development Fund(No.2024HXBH058)
the Sichuan University Postdoctoral Interdisciplinary Innovation Fund(No.JCXK2203).
