A team co-led by the Institute of Bioengineering of Catalonia (IBEC) and West China Hospital Sichuan University (WCHSU), in collaboration with partners from the UK, reports on a nanotechnology approach that reverses Alzheimer’s disease in mouse models. Instead of using nanoparticles as passive carriers, the researchers developed bioactive nanoparticles that act as “supramolecular drugs”. The treatment focuses on restoring the blood-brain barrier (BBB), the vascular checkpoint that maintains the brain’s internal environment. By repairing this interface, the animals showed a reversal of Alzheimer’s pathology.
Blood-Brain Barrier and Removal of Waste Proteins
The brain consumes about 20 % of the body’s energy in adults and up to 60 % in children. This energy is supplied via an extraordinarily dense vascular network in which each nerve cell is supplied by its own capillary. With around one billion capillaries, the brain relies on a healthy vascular system to maintain its function and resist disease. These observations underscore how vascular health is linked to diseases such as dementia and Alzheimer’s, in which damage to the vascular system plays an important role.
The blood-brain barrier is a cellular and physiological shield that separates brain tissue from circulating blood and helps to ward off pathogens and toxins. The researchers showed that by acting on a specific mechanism, harmful “waste proteins” produced in the brain can overcome this barrier and enter the bloodstream. In Alzheimer’s disease, amyloid-β (Aβ) is the main waste protein whose accumulation disrupts nerve cell function.
The team worked with mouse models that were engineered to overproduce Aβ and develop marked cognitive decline, mirroring the hallmarks of Alzheimer’s disease. The animals received three doses of the supramolecular drugs, followed by regular controls. “Just one hour after the injection, we observed a 50-60% reduction in the amount of Aβ in the brain,” explains Junyang Chen, first author of the study, researcher at West China Hospital, Sichuan University and PhD student at University College London (UCL).
The therapeutic results were the most remarkable. In several behavioral and memory tests conducted over a period of months, the animals were examined at different stages of the disease. In one example, a 12-month-old mouse (equivalent to a 60-year-old human) was treated with the nanoparticles and examined 6 months later. At the age of 18 months (comparable to a 90-year-old human), its behavior corresponded to that of a healthy mouse.
Restoration of the Vascular System to Resume Self-Cleaning of the Brain
“The long-term effect is based on restoring the brain’s vascular system. We believe that this works like a cascade: When toxic substances such as amyloid-beta (Aβ) accumulate, the disease progresses. However, once the vascular system is functional again, it begins to eliminate Aβ and other harmful molecules, allowing the entire system to regain its balance. Remarkably, our nanoparticles act like a drug, apparently activating a feedback mechanism that brings this cleansing pathway back to normal levels,” said Giuseppe Battaglia, ICREA research professor at IBEC, principal investigator of the Molecular Bionics Group and leader of the study.
In Alzheimer’s disease, there is a critical disruption of the natural degradation process of toxic substances such as Aβ in the brain. Under normal conditions, the protein LRP1 acts as a molecular gatekeeper. It recognizes Aβ, binds it via ligands and helps to transport it across the blood-brain barrier into the bloodstream where it is degraded. The system is sensitive. If LRP1 binds too much Aβ too tightly, transport overload occurs and LRP1 itself is degraded within the BBB cells, reducing the number of available carriers. If the binding is too weak, the transport signal is insufficient. Both scenarios lead to an accumulation of Aβ in the brain.
The supramolecular drugs act like a reset switch. By mimicking LRP1 ligands, they bind Aβ, cross the BBB and trigger the removal of toxic substances. When this process is resumed, the vascular system regains its natural function as a waste eliminator and returns to its normal function.
Improving Treatment Outcomes for Alzheimer’s Patients
In this work, nanoparticles act as therapeutic agents in their own right. Developed using a bottom-up molecular technique, they combine a tightly controlled size with a defined number of surface ligands to create a multivalent platform with highly specific interactions at cellular receptors. By activating receptor transport at the cell membrane, they offer a new way to modulate receptor activity. This precision supports efficient Aβ clearance and helps to rebalance the vasculature that protects brain health. This therapeutic concept points to future clinical strategies that address the vascular contribution to Alzheimer’s disease and aim to improve treatment outcomes for patients.