Smart ROS-Responsive Nanoparticles for Neurodegenerative Diseases: Advances, Challenges, and Future Perspectives

Abstract

Background: Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) represent global health problems with the common feature of progressive neuronal degeneration. Oxidative stress, mitochondrial dysfunction, and neuronal death associated with overproduction of reactive oxygen species (ROS) have been reported as the major pathology in NDDs. Traditional drugs usually treat the symptoms but are ineffective due to limited access to the brain parenchyma via poor blood-brain barrier (BBB) permeability and specificity. ROS responsive nanoparticles (ROS-NPs) serve as an innovative platform of nanomedicine that can capitalize on increased amounts of ROS as the trigger for drug delivery. Purpose: The present review highlights current achievements in ROS-responsive nanoparticles in the field of neurodegeneration with a particular focus on oxidative mechanisms in disease, ROS-sensitive drug delivery technologies, nanocarriers, BBB targeted nanomedicine, theranostics, preclinical evidence, and perspectives of translation. Methods: Systematic searching in PubMed/MEDLINE, Scopus, and Web of Science was performed for the articles published in the period from 2000-2024 using keywords “ROS responsive nanoparticles”, “drug delivery in neurodegenerative disease”, “nanomedicine against oxidative stress”, “blood-brain barrier nanocarrier” and “neurodegenerative theranostic nanoparticles”. Results: ROS responsive linkages, such as thioethers, diselenides, boronic esters, thioketals, peroxalate esters, and plasmalogen vinyl ethers, were used to achieve selective drug release in oxidized microenvironments. Polymeric nanoparticles, lipid nanoparticles, metal organic frameworks, dendrimers, and exosome mimicking nanoparticles showed superior BBB crossing ability, neuroprotection, and therapeutic effects. The development of theranostic systems incorporating MRI, photoacoustic, and fluorescent imaging was another step forward in this direction. Conclusion: ROS responsive nanoparticles are an excellent neuropharmacotherapy approach since they utilize the pathological oxidative stress to release drugs selectively. Advances in intelligent nanomaterials, AI-assisted design, and personalized iPSC-based treatment will probably help with their transition from the bench to bedside in neurodegenerative diseases.