Barcelona Nanoparticles Clear 60% of Toxic Amyloid From Aging Mouse Brains in an Hour, Restoring Memory in 'Reprogrammed' Blood-Brain Barrier

Scientists at the Institute for Bioengineering of Catalonia and West China Hospital of Sichuan University have used engineered "supramolecular" nanoparticles to clear 50% to 60% of toxic amyloid-beta proteins from the brains of aging mice within an hour of a single injection, and have shown that treated 12-month-old animals — the rough biological equivalent of a 60-year-old human — behave like much younger, healthy mice six months after the therapy. The findings, published this month in Signal Transduction and Targeted Therapy, are the most striking demonstration yet that the blood-brain barrier can be turned into an active drug rather than an obstacle to one.

Amyloid-beta plaques are one of the two pathological hallmarks of Alzheimer's disease, and removing them from the brains of patients has been the dominant strategy of pharmaceutical development for two decades. The two recently approved monoclonal antibodies — Leqembi from Eisai and Biogen and Kisunla from Eli Lilly — slow cognitive decline only modestly and have been linked to brain swelling and microbleeds. The new Barcelona-led approach attacks the problem from a fundamentally different angle: rather than crossing the blood-brain barrier with a drug payload, the team designed nanoparticles that mimic natural molecules that bind to LRP1, a receptor protein that normally shuttles amyloid out of the brain and into the bloodstream.

"The blood-brain barrier becomes part of the treatment, not just an obstacle," said senior author Giuseppe Battaglia, an ICREA research professor at IBEC, in a statement accompanying the paper. The nanoparticles, each only a few tens of nanometers across, do not enter the brain. Instead, they re-engage and reprogram the LRP1-driven export pathway, which becomes progressively dysfunctional with age and in Alzheimer's patients. First co-author Junyang Chen, a PhD student at West China Hospital and University College London, said the team verified the mechanism with electron microscopy, fluorescent tracers and gene-expression assays. Imaging at the one-hour mark after injection showed amyloid-beta concentrations in the cortex and hippocampus had fallen by 50% to 60% across treated animals.

The behavioral effect was equally dramatic. Twelve-month-old mice carrying mutations linked to inherited early-onset Alzheimer's, which would normally show severe cognitive and motor deficits, performed indistinguishably from healthy younger animals in standard Morris water-maze and novel-object-recognition tests six months after a single course of nanoparticles. A treated 18-month-old mouse — comparable to a person in their late seventies — exhibited motor and memory recovery the team described as "comparable to healthy younger animals." The researchers reported no significant inflammation in the liver, kidneys or other clearance organs across a four-month follow-up.

Independent experts urged caution. The mouse colony was small, the animals carried genes for a rare inherited form of Alzheimer's that affects fewer than 1% of patients, and the statistical analyses did not fully account for repeated measurements from the same animals over time, said Tara Spires-Jones, director of the Centre for Discovery Brain Sciences at the University of Edinburgh, in comments to the U.K. Science Media Centre. The IBEC team said it has already begun safety toxicology studies in non-human primates and aims to file an investigational new drug application with the European Medicines Agency by the end of 2027. Battaglia said early human trials, if approved, would likely focus first on patients with mild cognitive impairment rather than late-stage Alzheimer's, where the underlying neuronal damage may already be irreversible.