A groundbreaking study published in Signal Transduction and Targeted Therapy by Junyang Chen et al. describes a novel therapeutic amyloid-beta clearance and cognitive recovery by repairing the blood-brain barrier rather than merely bypassing it. The researchers focused on the low-density lipoprotein receptor-related protein 1, which is called LRP1 and is crucial for removing amyloid beta from the brain. Dysfunction of this receptor is one of the major contributors to Alzheimer’s pathology.
Under normal conditions, LRP1 facilitates the amyloid beta transport out of the brain via PACSIN2-mediated tubular transcytosis. In Alzheimer’s disease, however, aggregated amyloid beta binds strongly to LRP1, diverting it to a degradative pathway, resulting in the loss of receptors and dysfunction of the blood-brain barrier. This impairs amyloid-beta clearance and accelerates disease progression.
To address this, the researchers engineered multivalent nanoparticles called A40-POs, which target LRP1 with an intermediate degree of binding strength. This strategy redirects trafficking of receptors to favor healthy transport rather than degradation.
These nanoscale carriers were constructed from angiopep-2 molecules organized in a precise spatial configuration that mimics natural LRP1 interactions. This design suppresses aberrant receptor signaling on endothelial cells and restores normal amyloid-beta transport. Instead of simply delivering drugs across the BBB, A40-POs correct the underlying transport dysfunction, effectively restoring the barrier’s clearing capacity.
In preclinical mouse models of Alzheimer’s disease, intravenous administration of A40-POs produced rapid and significant effects. The enzyme-linked immunosorbent assays indicated almost a 50% decrease in the levels of amyloid beta in the brain and an eight times greater increase in the levels of the protein in blood plasma, indicating effective clearance. These were confirmed by imaging studies such as PET-CT and confocal microscopy that revealed a 41% reduction in amyloid-beta deposits across multiple brain regions. Notably, endothelial LRP1 was also restored by the treatment, with a 78% recovery of LRP1–CD31 colocalization, a marker of blood-brain barrier integrity.
Behavioral assessments demonstrated substantial improvements in spatial learning and memory, with treated mice performing comparably to healthy wild-type controls. These cognitive advantages were maintained at least six months post-treatment. Also, the animals during treatment exhibited improved daily behaviors and emotional welfare, reflected in improved nest-building and sucrose preference—A40-POs produced quicker and longer-lasting effects compared to the traditional antibody therapies that usually operate slowly and transiently.
The underlying mechanism of this therapy, termed avidity-optimized trafficking reprogramming, balances the strength of receptor binding to achieve the desired receptor recycling and prevent receptor degradation. A40-POs restore normal amyloid-beta clearance by increasing LRP1 levels through reactivation of PACSIN2-mediated transport while inhibiting Rab5-mediated degradation.
This study changes the way of treating Alzheimer’s through drug delivery to repair its system. It demonstrates that the blood-brain barrier is not a barrier but a versatile, repairable interface, which can be rebuilt in response to intelligent nanotechnology. A40-POs act as molecular regulators that correct abnormal receptor behavior and restore normal cellular function.
The research establishes a therapeutic trilogy: amyloid clearance, barrier restoration, and sustained cognitive recovery. It provides the basis of precision neurovascular medicine and may be applicable to other neurodegenerative disorders like Alzheimer’s and Parkinson’s, amyotrophic lateral sclerosis, where vascular transport defects are also evident. Overall, Chen and colleagues demonstrate that rationally designed nanomedicines can repair biological barriers, restore brain homeostasis, and reverse cognitive decline through advanced supramolecular engineering and receptor-targeted strategies.
Reference: Chen J, Xiang P, Duro-Castano A, et al. Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport. Signal Transduct Target Ther. 2025;10(1):331. doi:10.1038/s41392-025-02426-1
