We started our studies with the development of brain-targeted liposomes (BTL) decorated with transferrin ligands and loaded with the monoclonal antibody SynO4. These nanoparticles were able to cross the blood–brain barrier (BBB), enter neurons, and inhibit toxic alpha-synuclein aggregation. Confocal and super-resolution microscopy confirmed their intracellular localization and binding to alpha-synuclein oligomers, both inside neurons and in the extracellular space. In in vivo Parkinson’s disease model, treatment with BTL reduced protein aggregation and neuroinflammation, preserved dopaminergic neurons in the substantia nigra as well as a significant recovery of motor function. Importantly, systemic administration of BTL was well tolerated, with no evidence of toxicity in liver, kidney, or spleen, and longitudinal monitoring demonstrated a favorable safety profile. These results demonstrate that antibody-loaded brain-targeted liposomes can cross the BBB, act directly on pathological protein aggregates, and provide functional neuroprotection in vivo. (Sela et al., Adv. Mater, 2023 – doi:10.1002/adma.202304654)
Next, we expanded the platform to brain-targeted lipid nanoparticles carrying mRNA, decorated with small molecules that interact with the BBB. These LNPs achieved substantially higher brain uptake compared to untargeted controls and showed cell-type selectivity, with certain formulations preferentially transfecting neurons and astrocytes, while others targeted microglia. Human iPSC-derived BBB models and cortical organoids confirmed their ability to cross human-relevant barriers and transfect deep neural tissue. Mechanistic studies revealed that designed LNPs engage receptor-mediated pathways and exploit membrane microdomains to enhance uptake and transgene expression. An AI-based predictive model supported these findings by highlighting the most effective ligands, underscoring the potential of computational approaches to accelerate nanoparticle design and improve targeting specificity. (Sela et al., ACS Nano, 2025 - doi: 10.1021/acsnano.4c15013)
