A natural neuronal receptor-derived MRI probe targets β-amyloid oligomers for the diagnosis of Alzheimer's disease

Early-to-mid detection of Alzheimer's disease (AD) remains challenging because clinically used amyloid positron emission tomography (PET) probes primarily visualize fibrillar β-amyloid (Aβ) deposits and require radioactive isotopes. Magnetic resonance imaging (MRI) offers a radiation-free alternative, but its application in molecular AD diagnosis is limited by insufficient blood-brain barrier (BBB) penetration and poor specificity toward early-to-mid Aβ species. Here, we developed a BBB-crossing liposomal MRI probe, Lipo@D1D2-Gd, by integrating a natural Aβ oligomer-binding receptor domain with a gadolinium chelator. The extracellular D1D2 domains of human leukocyte immunoglobulin-like receptor B2 (LilrB2), a neuronal receptor that recognizes neurotoxic Aβ oligomers, were recombinantly produced and bioorthogonally conjugated with a gadolinium chelator. The resulting D1D2-Gd retained its Aβ-binding capability and MRI contrast activity. To enable brain delivery, D1D2-Gd was encapsulated within maltose-functionalized PEGylated liposomes designed to facilitate BBB transport. After intravenous administration to 4-month-old 5xFAD mice, Lipo@D1D2-Gd crossed the BBB, accumulated in Aβ-rich brain regions, and generated MRI contrast enhancement that differentiated 5xFAD mice from wild-type controls. Systemic safety evaluation showed no obvious hematological, biochemical, or histological toxicity. This study establishes a receptor-derived, BBB-crossing biomaterial platform for radiation-free molecular imaging of early-to-mid AD-associated Aβ pathology. STATEMENT OF SIGNIFICANCE: 1) Promising Targeting Strategy: We repurposed a human-derived natural receptor domain (LilrB2 D1D2) as a targeting module for β-amyloid (Aβ) oligomers, a key pathogenic species in Alzheimer's disease (AD). 2) Non-invasive MRI Approach: We constructed a liposomal probe designed to deliver the Gd-labeled targeting agent to the brain, enabling the detection of Aβ-associated pathology in 4-month-old 5xFAD mice via non-radioactive MRI, well before overt cognitive decline. 3) Experimental Validation: We demonstrate the probe's association with Aβ oligomers/plaques, effective BBB crossing, differences in MRI signals between AD model and wild-type mice, and an initially favorable biosafety profile, with no observed toxicity under the tested conditions. 4) Clinical Translation Potential: Our work presents a promising pathway toward a safe, accessible, and early-to-mid-stage AD screening tool, with the potential to facilitate population-wide screening and earlier therapeutic intervention.