A research team co-led by the Institute for Bioengineering of Catalonia (IBEC) and West China Hospital Sichuan University (WCHSU), working with partners in the UK, has demonstrated a nanotechnology strategy that reverses Alzheimer's disease in mice. Unlike traditional nanomedicine, which relies on nanoparticles as carriers for therapeutic molecules, this approach employs nanoparticles that are bioactive in their own right: "supramolecular drugs." Instead of targeting neurons directly, the therapy restores the proper function of the blood-brain barrier (BBB), the vascular gatekeeper that regulates the brain's environment. By repairing this critical interface, the researchers achieved a reversal of Alzheimer's pathology in animal models.
The brain is the most expensive organ of the body, consuming 20% of the energy in adults and up to 60% in children. This energy arrives through a vast blood supply, assured by a unique and dense vascular system where each neuron is nourished by one capillary. Our brain contains approximately one billion capillaries, highlighting the vital role of brain vasculature in maintaining health and combating disease. These findings highlight the crucial role of vascular health, especially in diseases like dementia and Alzheimer's, where a compromised vascular system is closely linked.
The BBB is a cellular and physiological barrier that separates the brain from the blood flow to protect it from external dangers such as pathogens or toxins. The team demonstrated that targeting a specific mechanism enables undesirable "waste proteins" produced in the brain to pass through this barrier and be eliminated in the blood flow. In Alzheimer's disease, the main "waste" protein is amyloid-β (Aβ), whose accumulation impairs the normal functioning of the neurons.
Researchers used mouse models that are genetically programmed to produce larger amounts of Aβ protein and develop a significant cognitive decline mimicking Alzheimer's pathology. They administered only 3 doses of the supramolecular drugs and afterwards regularly monitored the evolution of the disease. "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).
The most striking data were the therapeutic effects. Researchers conducted various experiments to analyze the behavior of the animals and measure their memory decline over several months, covering all stages of the disease. In one of the experiments, they treated a 12-month-old mouse (equivalent to a 60-year-old human) with the nanoparticles and analysed its behaviour after 6 months. The result was impressive: the animal, aged 18 months (comparable to a 90-year-old human), had recovered the behaviour of a healthy mouse.
"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."
Giuseppe Battaglia, ICREA Research Professor at IBEC, Principal Investigator of the Molecular Bionics Group and leader of the study.
Amyloid-β clearance from the brain
In Alzheimer's disease, one of the key problems is that the brain's natural clearance system for toxic species like amyloid-β stops working properly. Normally, the protein LRP1 acts as a molecular gatekeeper: it recognizes Aβ, binds to it through ligands, and ferries it across the blood-brain barrier into the bloodstream, where it can be removed. But this system is fragile. If LRP1 binds too much Aβ too tightly, the transport clogs and the protein itself gets degraded inside the brain barrier cells, leaving fewer LRP1 "carriers" available. On the other hand, if it binds too little, the signal is too weak to trigger transport. In both cases, the result is the same: Aβ builds up inside the brain.
The supramolecular drugs developed in this work act like a switch that resets the system. By mimicking the ligands of LRP1, they can bind to Aβ, cross the blood–brain barrier, and initiate the process of removing toxic species from the brain. In doing so, they help restore the vasculature's natural role as a waste-clearing pathway and bring it back to proper function.
Nanoparticles to treat Alzheimer's
In this study, the researchers introduce nanoparticles that act as supramolecular drugs, therapeutic agents in their own right rather than carriers of medication. Designed with a bottom-up molecular engineering approach, these nanoparticles combine precise size control with a defined number of surface ligands, creating a multivalent platform able to interact with cellular receptors in a highly specific way. By engaging receptor trafficking at the cell membrane, they open up a unique and novel way to modulate receptor function. This precision not only enables the effective clearance of amyloid-β from the brain but also restores balance to the vascular system that maintains healthy brain function.
This innovative therapeutic paradigm offers a promising pathway for developing effective clinical interventions, addressing vascular contributions to Alzheimer's disease, and ultimately enhancing 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 study was a collaboration among 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).
About IBEC
The Institute for Bioengineering of Catalonia (IBEC) is a CERCA center, three times recognized as a Severo Ochoa Center of Excellence, and holds the TECNIO label as a technology developer and business facilitator. IBEC is a member of the Barcelona Institute of Science and Technology (BIST) and conducts multidisciplinary research at the forefront of engineering and life sciences to generate knowledge. The institute integrates fields such as nanomedicine, biophysics, biotechnology, tissue engineering, and applications of information technologies in the health sector. IBEC, established in 2005, is a collaborative effort of the Generalitat de Catalunya, the University of Barcelona (UB), and the Polytechnic University of Catalonia (UPC).
