Redox-Responsive Delivery System for Alzheimer's Disease

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, poses significant therapeutic challenges due to the complexity of its pathology combined with the inadequacy of the conventional route of drug delivery, which is based on pharmacology, in crossing the blood-brain barrier (BBB). Advances in redox-responsive drug delivery systems (RRDDS) enable a valuable approach for this pathology because they take advantage of the elevated oxidative stress and altered redox homeostasis observed in the pathology of AD. These smart nanocarriers can remain stable when administered in physiologic conditions but release their payload through a triggered mechanism once in the disease neuron-specific environment, experiencing increased reactive oxygen species (ROS) or altered glutathione (GSH) levels. RRDDS can allow the site-specific and controlled release of therapeutic agents, e.g., antioxidant, neuroprotective, or gene delivery drugs, instead of systemic delivery, improving bioavailability and reducing systemic toxicity to increase therapeutic efficacy. These systems will have additional developments to include targeting ligands that can cross the BBB. Recent advances highlighting the successful use of these redox-responsive polymers, liposomes, and dendrimers to repurpose naturally or newly developed agents with proven activity, including curcumin, donepezil, and siRNA, point to their potential in medical therapies to slow dementia or cognitive impairment. While recent efforts show preclinical efficacy, the challenges remain in the development of specific engineered RRDDS based on biocompatibility, scalability, and the regulatory process.