ROS-responsive carrier-free nanodrugs for three-pronged acute ischemic stroke therapy

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Neuroscience

Background:

• Acute ischemic stroke (AIS) presents limited therapeutic options due to complex pathophysiology including oxidative stress and neuronal injury.
• Current treatments for AIS face challenges in effectively delivering therapeutic agents to the brain and addressing multiple pathological factors simultaneously.

Purpose of the Study:

• To develop a reactive oxygen species (ROS)-responsive, carrier-free nanodrug (RAC) for enhanced acute ischemic stroke (AIS) therapy.
• To investigate the integrated therapeutic functions of RAC, including ROS scavenging, oxygen generation, and neuroprotection, for improved treatment outcomes.

Main Methods:

• Fabrication of RAC via microwave-assisted coordination assembly of ruthenium (Ru), L-arginine (L-Arg), and curcumin (Cur).
• Evaluation of RAC's stability, ROS/acidosis-responsive disassembly, and drug release characteristics.
• In vitro assessment of RAC's efficacy in N2a neuronal cells under oxygen-glucose deprivation/reperfusion (OGD/R) conditions.
• In vivo studies using a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mouse model, including fluorescence imaging and analysis of therapeutic effects.

Main Results:

• RAC demonstrated a distinct supramolecular nanostructure, stable under physiological conditions but responsive to ROS/acidosis.
• In vitro studies showed RAC effectively reduced intracellular ROS, preserved mitochondrial function, and attenuated apoptosis in neuronal cells.
• In vivo studies revealed enhanced brain accumulation of RAC, improved cerebral blood flow recovery, reduced infarct volume, and better neurological outcomes in a mouse model of AIS.

Conclusions:

• The coordination-driven nanoassembly of RAC provides synergistic therapeutic effects for AIS, surpassing simple physical mixtures.
• RAC represents a promising carrier-free nanodrug strategy for AIS, integrating multiple therapeutic functions for enhanced efficacy and neuroprotection.