Periodic Reporting for period 1 - Smart Nanoparticles (4D Brain-Targeting Nanomedicines for Treating Neurodegeneration)
Período documentado: 2023-05-01 hasta 2025-10-31
The prevalence of neurodegenerative brain conditions, including Parkinson’s and Alzheimer’s disease, has increased dramatically due to aging, genetic, and environmental factors, while treatment options remain limited. A major prerequisite for effective therapies is the ability to deliver next-generation biologics, such as RNA- and protein-based drugs, directly to specific neurons and brain regions. Nanotechnology platforms provide new opportunities for targeted delivery to organs and cells, but their use in neurodegenerative diseases is still at an early stage.
This ERC-COG research program aims to close this gap by establishing the molecular and structural principles that enable nanomedicines to cross the blood–brain barrier (BBB) intact and reach defined neuronal populations. The overall objective is to develop 4D brain-targeting nanoparticles that can deliver therapeutic biologics to diseased areas of the brain with high precision. To achieve this goal, we are combining computational design, robotic nanoparticle synthesis, advanced screening in BBB models, and in vivo tracking of nanoparticle localization and therapeutic activity.
So far, we have developed two complementary nanotechnology platforms. First, we engineered brain-targeted liposomes loaded with the monoclonal antibody SynO4. These brain-targeted liposomes (BTL) crossed the BBB, entered neurons, and reduced alpha-synuclein aggregation in Parkinson’s disease models, leading to improved neuronal survival and motor function. Second, we designed a library of brain-targeted mRNA lipid nanoparticles decorated with small molecules that interact with the BBB. An AI-based predictive model supported these findings, showing alignment with the experimental results for the most effective formulations and validating computational design as a powerful tool for nanoparticle development.
This ERC-COG research program aims to close this gap by establishing the molecular and structural principles that enable nanomedicines to cross the blood–brain barrier (BBB) intact and reach defined neuronal populations. The overall objective is to develop 4D brain-targeting nanoparticles that can deliver therapeutic biologics to diseased areas of the brain with high precision. To achieve this goal, we are combining computational design, robotic nanoparticle synthesis, advanced screening in BBB models, and in vivo tracking of nanoparticle localization and therapeutic activity.
So far, we have developed two complementary nanotechnology platforms. First, we engineered brain-targeted liposomes loaded with the monoclonal antibody SynO4. These brain-targeted liposomes (BTL) crossed the BBB, entered neurons, and reduced alpha-synuclein aggregation in Parkinson’s disease models, leading to improved neuronal survival and motor function. Second, we designed a library of brain-targeted mRNA lipid nanoparticles decorated with small molecules that interact with the BBB. An AI-based predictive model supported these findings, showing alignment with the experimental results for the most effective formulations and validating computational design as a powerful tool for nanoparticle development.
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)
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)
This project has advanced the state of the art by demonstrating that nanotechnology can be used to deliver biologics into the brain with precision. We showed that antibody-loaded brain-targeted liposomes (BTL) are able to cross the blood–brain barrier, enter neurons, and act directly on intracellular protein aggregates. This expands the therapeutic potential of antibodies, which until now have been largely limited by poor brain penetration and extracellular activity.
In addition, we developed brain-targeted lipid nanoparticles carrying mRNA, introducing a new approach for selective gene delivery to the central nervous system. These nanoparticles demonstrated cell-type specificity, and an AI-based predictive model supported the identification of effective ligands, underscoring the potential of combining computational approaches with experimental screening to guide nanoparticle design.
Taken together, these results provide valuable scientific insights into the design of nanomedicines for the brain and open new possibilities for therapeutic strategies in neurodegenerative diseases. We expect that the knowledge and technologies developed in this ERC-COG project will support future translation toward more effective and targeted treatments for conditions such as Parkinson’s and Alzheimer’s disease.
In addition, we developed brain-targeted lipid nanoparticles carrying mRNA, introducing a new approach for selective gene delivery to the central nervous system. These nanoparticles demonstrated cell-type specificity, and an AI-based predictive model supported the identification of effective ligands, underscoring the potential of combining computational approaches with experimental screening to guide nanoparticle design.
Taken together, these results provide valuable scientific insights into the design of nanomedicines for the brain and open new possibilities for therapeutic strategies in neurodegenerative diseases. We expect that the knowledge and technologies developed in this ERC-COG project will support future translation toward more effective and targeted treatments for conditions such as Parkinson’s and Alzheimer’s disease.