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

Abstract

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 (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.

Graphical abstract

Drug-loaded NP ³ _ST anchored with β-CD is crosslinked by hyaluronic acid-ferrocene (HA-Fc) conjugates to large-sized HA-Fc/NP ³ _ST nanoassemblies through multivalent host-guest interactions between β-CD/Fc. After accumulating in atherosclerotic plaque mediated by the HA-CD44 recognition, HA-Fc/NP ³ _ST rapidly disassembles caused by excess ROS in the intima and release smaller NP ³ _ST, allowing for further plaque penetration, macrophage-targeted cholesterol efflux and drug delivery to alleviate atherosclerosis.

Highlights

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  HA-Fc/NP ³ _ST is designed for long blood circulation and deep plaque penetration.

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  Nanoassemblies are formed by multivalent host-guest interactions of β-CD/ferrocene.

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  Release of NP ³ _ST triggered by excess ROS aims for macrophage-targeted drug delivery.

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  FRET method is utilized to characterize the ROS-responsiveness of nanoassemblies.

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  Biomimic cell coculture model is constructed to simulate the atherosclerotic plaque.