A team co-led by the Institute for Bioengineering of Catalonia (IBEC) and West China Hospital Sichuan University (WCHSU), in collaboration with partners in the UK, reports a nanotechnology approach that reverses Alzheimer’s disease in mouse models. Rather than using nanoparticles as passive carriers, the researchers designed bioactive nanoparticles that function 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.
The brain consumes about 20% of the body’s energy in adults and as much as 60% in children. That energy arrives through an exceptionally dense vascular network in which each neuron is supplied by its own capillary. With roughly one billion capillaries, the brain relies on healthy vasculature to sustain function and resist disease. These observations reinforce how vascular health connects to conditions such as dementia and Alzheimer’s, where damage to the vascular system is closely associated.
Blood-brain barrier function and removal of waste proteins
The BBB is a cellular and physiological shield that separates brain tissue from circulating blood, helping block pathogens and toxins. The researchers showed that by acting on a specific mechanism, harmful “waste proteins” produced in the brain can cross this barrier and be cleared into the bloodstream. In Alzheimer’s disease, amyloid-β (Aβ) is the primary waste protein, and its buildup disrupts neuronal function.
The team worked with mouse models engineered to overproduce Aβ and to develop marked cognitive decline that mirrors Alzheimer’s features. The animals received three doses of the supramolecular drugs, followed by regular monitoring. “Only 1h after the injection we observed a reduction of 50-60% in Aβ amount inside the brain” explains Junyang Chen, first co-author of the study, researcher at the West China Hospital of Sichuan University and PhD student at the University College London (UCL).
Therapeutic outcomes were the most notable. Across several behavioral and memory tests conducted over months, animals were assessed at different disease stages. In one example, a 12-month-old mouse (equivalent to a 60-year-old human) was treated with the nanoparticles and evaluated 6 months later. By 18 months of age (comparable to a 90-year-old human), its behavior matched that of a healthy mouse.
Restoring vasculature to restart brain self-clearing
“The long-term effect comes from restoring the brain’s vasculature. We think it works like a cascade: when toxic species such as amyloid-beta (Aβ) accumulate, disease progresses. But once the vasculature is able to function again, it starts clearing Aβ and other harmful molecules, allowing the whole system to recover its balance. What’s remarkable is that our nanoparticles act as a drug and seem to activate a feedback mechanism that brings this clearance 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, a key breakdown occurs in the brain’s natural clearance process for toxic species such as Aβ. Under normal conditions, the protein LRP1 serves as a molecular gatekeeper. It recognizes Aβ, binds it via ligands, and helps shuttle it across the BBB into the bloodstream for removal. The system is delicate. If LRP1 binds too much Aβ too tightly, transport becomes congested and LRP1 itself is degraded within BBB cells, reducing the number of available carriers. If binding is too weak, the transport signal is insufficient. Either scenario leads to Aβ accumulation in the brain.
The supramolecular drugs act as a reset switch. By imitating LRP1 ligands, they bind Aβ, traverse the BBB, and trigger the removal of toxic species. As this process resumes, the vasculature regains its natural waste-clearing role and returns toward normal function.
Precision-engineered nanoparticles and receptor control
In this work, nanoparticles operate as therapeutic agents in their own right. Built through a bottom-up molecular engineering strategy, they combine tightly controlled size with a defined number of surface ligands to create a multivalent platform with highly specific interactions at cellular receptors. By engaging receptor trafficking at the cell membrane, they provide a new way to modulate receptor activity. This precision supports efficient Aβ clearance and helps rebalance the vascular system that safeguards brain health.
This therapeutic concept points toward future clinical strategies that address the vascular contribution to Alzheimer’s disease and aim to improve patient outcomes. “Our study demonstrated remarkable efficacy in achieving rapid Aβ clearance, restoring healthy function in the blood-brain barrier and leading to a striking reversal of Alzheimer’s pathology,” concludes Lorena Ruiz Perez, researcher at the Molecular Bionics group from the Institute for Bioengineering of Catalonia (IBEC) and Serra Hunter Assistant Professor at the University of Barcelona (UB).
The project brought together the Institute for Bioengineering of Catalunya (IBEC), West China Hospital of Sichuan University, West China Xiamen Hospital of Sichuan University, University College London, the Xiamen Key Laboratory of Psychoradiology and Neuromodulation, University of Barcelona,Chinese Academy of Medical Sciences and the Catalan Institution for Research and Advanced Studies (ICREA).
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