Engineering ROS-responsive size-transformable nanoassemblies to reprogram plaque microenvironment and activate...

Area of Science:

• Biomedical Engineering
• Cardiovascular Research
• Nanomedicine

Background:

• Oxidative stress and impaired macrophage autophagy contribute to vulnerable atherosclerotic plaques and cardiovascular events.
• Current single-target therapies for atherosclerosis are insufficient.
• A dual-action therapeutic strategy is needed to address both oxidative stress and autophagy dysfunction.

Purpose of the Study:

• To develop and evaluate a novel nanotherapeutic system for synergistic atherosclerosis treatment.
• To combine reactive oxygen species (ROS) scavenging with autophagy induction for enhanced plaque stabilization.
• To investigate the efficacy of the nanotherapy in preclinical models of atherosclerosis.

Main Methods:

• Development of a cationic antioxidant dextran derivative (DKT) for co-delivery of rapamycin-loaded reconstituted high-density lipoprotein (RC-rHDL).
• Formation of ROS-triggered disassembling nanoassemblies (RT-rHDL) via electrostatic interactions.
• In vitro assessment of foam cell formation, inflammation, and apoptosis.
• In vivo evaluation of plaque burden, stability, and inflammation in apoE-/- mice.

Main Results:

• RT-rHDL nanoassemblies demonstrated efficient plaque targeting and ROS-triggered disassembly.
• In vitro studies showed inhibition of foam cell formation, inflammation, and apoptosis.
• In vivo treatment significantly reduced plaque size, necrotic core area, and inflammation, enhancing plaque stability.
• Therapeutic benefits were attributed to reduced oxidative stress and restored macrophage autophagy.

Conclusions:

• Simultaneous modulation of cellular functions and the plaque microenvironment is crucial for effective atherosclerosis treatment.
• The developed RT-rHDL nanoassemblies represent a promising synergistic nanotherapeutic strategy for atherosclerosis.
• This approach offers a novel pathway for managing vulnerable atherosclerotic plaques and preventing cardiovascular events.