An international team co-led by the Institute for Bioengineering of Catalonia (IBEC), based at the Barcelona Science Park, and the West China Hospital of Sichuan University (WCHSU) has succeeded in reversing the progression of Alzheimer’s disease in mice with just three injections of nanoparticles. The innovative approach to treating this condition focuses on restoring the normal function of the vascular system, rather than targeting neurons or other brain cells, as has commonly been done until now. This achievement, published in the journal Signal Transduction and Targeted Therapy, represents a promising step toward an effective treatment for Alzheimer’s disease.

Unlike traditional nanomedicine, which relies on nanoparticles as carriers of therapeutic molecules, IBEC researchers have designed “supramolecular drugs” — nanoparticles that are bioactive on their own. Instead of directly targeting neurons, 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 were able to reverse 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 analyse the behaviour 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”, explains Giuseppe Battaglia, principal investigator of the Molecular Bionics group and leader of the study.

Light-sheet fluorescence microscopy images of a mouse brain 12 hours after being treated (right) or not (left) with nanoparticles.

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 Pérez, researcher at the Molecular Bionics group from the Institute for Bioengineering of Catalonia (IBEC) and Serra Hunter Assistant Professor in the Faculty of Physics 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).

» Article of reference: Junyang Chen, Pan Xiang, Aroa Duro-Castano, Huawei Cai, Bin Guo, Xiqin Liu, Yifan Yu, Su Lui, Kui Luo, Bowen Ke, Lorena Ruiz Pérez, Xiawei Wei, Qiyong Gong, Xiaohe Tian, Giuseppe Battaglia. Multivalent modulation of endothelial LRP1 induces fast neurovascular amyloid-β clearance and cognitive function improvement in Alzheimer’s disease models. Signal Transduction and Targeted Therapy (2025). doi: 10.1038/s41392-025-02426-1

» Link to the news: IBEC website [+]