Reactive Oxygen Species (ROS)-Responsive Size-Reducible Nanoassemblies for Deeper Atherosclerotic Plaque Penetration and Enhanced Macrophage-Targeted Drug Delivery
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 between β-cyclodextrins (β-CD)-anchored discoidal recombinant high-density lipoprotein (NP3ST) and hyaluronic acid-ferrocene (HA-Fc) conjugates. The HA-Fc/NP3ST 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 NP3ST, allowing for further plaque penetration, macrophage-targeted cholesterol efflux and drug delivery. In vivo pharmacodynamicses in atherosclerotic mice shows that HA-Fc/NP3ST 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/NP3ST alleviates systemic inflammation characterized by reduced serum inflammatory factor levels. Collectively, HA-Fc/NP3ST 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.
J. He and W. Zhang and X. Zhou and F. Xu and J. Zou and Q. Zhang and Y. Zhao and H. He and H. Yang and J. Liu, "Reactive Oxygen Species (ROS)-Responsive Size-Reducible Nanoassemblies for Deeper Atherosclerotic Plaque Penetration and Enhanced Macrophage-Targeted Drug Delivery," Bioactive Materials, vol. 19, pp. 115 - 126, Elsevier, Apr 2022.
The definitive version is available at https://doi.org/10.1016/j.bioactmat.2022.03.041
Chemical and Biochemical Engineering
Keywords and Phrases
Atherosclerosis; Macrophage; Reactive Oxygen Species; Recombinant High-Density Lipoprotein; Size-Reducible Nanoassemblies
International Standard Serial Number (ISSN)
Article - Journal
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Creative Commons Licensing
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
07 Apr 2022
Article available online 07 April 2022
This work was supported by grants from the National Natural Science Foundation of China (grant no. 81773669 and 82073788), National Major Science and Technology Projects of China (grant no. 2017YFA0205400).