Neutrophil-mediated BDNF delivery for the treatment of moderate to severe Alzheimer's disease.

Alzheimer's disease (AD), especially its moderate-to-severe stage (MSAD), remains a global health challenge with no disease-modifying therapies. Here, we identified a dual pathological signature in MSAD patients and murine models: a systemic pro-inflammatory milieu and critically reduced brain-derived neurotrophic factor (BDNF) levels in both the hippocampus and serum. To mitigate the decrease in BDNF, we developed an engineered neutrophil capsule, in which neutrophils carrying lipid nanoparticles encapsulating BDNF penetrated the brain and ameliorated cognitive capacity deficits in MSAD mice. The pro-inflammatory state in the MSAD brain facilitated neutrophil passage through the blood-brain barrier, and inflammatory mediators triggered the release of BDNF from the engineered neutrophils. Collectively, our findings show that engineered neutrophil-mediated brain delivery of BDNF efficiently reduces the amyloid-β plaque deposition in the hippocampus, leading to significantly improved learning and memory in MSAD mice. This study establishes neutrophil-mediated delivery as a paradigm strategy for MSAD, merging cell biology with nanotechnology to reverse neurodegeneration.