Membrane Budding Inspired Biomimetic Nanocarrier Delivers Brain‐derived Neurotrophic Factor to Improve AD Cognition

Abstract Neurotropic factors, crucial for neural cell maturation and proliferation, hold great therapeutic potential for treating neurodegenerative diseases but face challenges in brain delivery. This study introduces a novel membrane budding‐inspired lipoprotein biomimetic nanocarrier for efficient packaging and precise brain delivery of brain‐derived neurotrophic factor (BDNF). The nanocarrier is created by mixing protein‐loaded biomimetic gel with liposomes composed of lipids prone to forming liquid‐disordered and liquid‐ordered phases. This interaction triggers phase separation and lipid membrane rearrangement, enabling effective protein encapsulation. To enhance blood‐brain barrier permeability and target damaged cerebral vasculature in Alzheimer's Disease, the nanocarrier (RAP‐BHP‐rHDL) is functionalized with Apolipoprotein E3 and αRAP peptides. The obtained RAP‐BHP‐rHDL alleviates neuronal damage, promotes neurogenesis, normalizes the cerebral microvasculature, improves the function of neurovascular units, and restores memory function in 5 × FAD mice. This innovative packaging approach and biomimetic nanocarrier design offer a promising strategy for delivering neurotropic factors to the central nervous system, potentially advancing the management of neurodegenerative diseases.