Reactive oxygen species(ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery  

作　　者：Jianhua He Wenli Zhang Xiaoju Zhou Fengfei Xu Jiahui Zou Qiqi Zhang Yi Zhao Hongliang He Hu Yang Jianping Liu 

机构地区：[1]Department of Pharmaceutics,China Pharmaceutical University,Nanjing,Jiangsu,210009,PR China [2]School of Biomedical Engineering,Sun Yat-sen University,Shenzhen,518107,PR China [3]State Key Laboratory of Bioelectronics,Jiangsu Key Laboratory for Biomaterials and Devices,School of Biological Science and Medical Engineering,Southeast University,Nanjing,210096,PR China [4]Linda and Bipin Doshi Department of Chemical and Biochemical Engineering,Missouri University of Science and Technology,Rolla,MO,65401,United States

出　　处：《Bioactive Materials》2023年第1期115-126,共12页生物活性材料（英文）

基　　金：supported by grants from the National Natural Science Foundation of China(grant no.81773669,82073788);National Major Science and Technology Projects of China(grant no.2017YFA0205400).

摘　　要：Nanoparticle-based therapeutics represent potential strategies for treating atherosclerosis;however,the complex plaque microenvironment poses a barrier for nanoparticles to target the dysfunctional cells.Here,we report reactive oxygen species(ROS)-responsive and size-reducible nanoassemblies,formed by multivalent host-guest interactions betweenβ-cyclodextrins(β-CD)-anchored discoidal recombinant high-density lipoprotein(NP^(3)_(ST))and hyaluronic acid-ferrocene(HA-Fc)conjugates.The HA-Fc/NP^(3)_(ST)nanoassemblies have extended blood circulation time,specifically accumulate in atherosclerotic plaque mediated by the HA receptors CD44 highly expressed in injured endothelium,rapidly disassemble in response to excess ROS in the intimal and release smaller NP^(3)_(ST),allowing for further plaque penetration,macrophage-targeted cholesterol efflux and drug delivery.In vivo pharmacodynamicses in atherosclerotic mice shows that HA-Fc/NP^(3)_(ST)reduces plaque size by 53%,plaque lipid deposition by 63%,plaque macrophage content by 62%and local inflammatory factor level by 64%compared to the saline group.Meanwhile,HA-Fc/NP^(3)_(ST)alleviates systemic inflammation characterized by reduced serum inflammatory factor levels.Collectively,HA-Fc/NP^(3)_(ST)nanoassemblies with ROS-responsive and size-reducible properties exhibit a deeper penetration in atherosclerotic plaque and enhanced macrophage targeting ability,thus exerting effective cholesterol efflux and drug delivery for atherosclerosis therapy.

关 键 词：ATHEROSCLEROSIS MACROPHAGE Reactive oxygen species Size-reducible nanoassemblies Recombinant high-density lipoprotein 

分 类 号：R543.5[医药卫生—心血管疾病]