UC San Diego

Neurotoxins pose a significant threat to public health and national security due to their extreme toxicity. Advancing neurotoxin defense is an urgent task that requires immediate research efforts. Traditional toxin defense requires the identification of unique toxin structures to further develop antidotes or antibodies. Studies on toxin-resistant species revealed toxin-neutralizing proteins encoded by their genome. Moreover, the development of neurotoxin-binding aptamers using high throughput selection methods expanded the biomacromolecule pools of drug candidates for neurotoxin defense. With the increasing number of related biomacromolecules discovered or developed, a proper delivery vehicle is desired to maintain prolonged blood circulation or deliver these molecules to target sites. Recently, biomimetic Neuron nanoparticle (Neuron-NP), fabricated by cloaking synthetic polymeric cores with neuron cell membranes, emerged as a novel platform for broad-spectrum neurotoxin detoxification. These Neuron-NPs possess the same surface proteins as host neuron cell membranes and act as decoys for these cells to bind neurotoxic agents and protect the nervous system. This strategy leverages host cell functionality to achieve effective neutralizations, bypassing the difficulty in identifying unique structures of the vast, diverse, and complex neurotoxins. This dissertation will study the combination of two strategies to advance neurotoxin defense: 1. Highly specific neurotoxin neutralizations with biomacromolecules; 2. Broad-spectrum neurotoxin neutralizations with neuron nanoparticles. Chapter 1 comprehensively reviews metal-organic frameworks (MOFs) as a delivery platform for biomacromolecules. MOFs are highlighted for their ability to encapsulate biomacromolecules effectively, protect these cargos against harsh conditions, and preserve their bioactivities. This chapter then reviews current cellular nanoparticle platforms used as medical countermeasures and discusses the potential to combine cellular nanoparticle platforms with biomacromolecules. Chapter 2 studies the use of enzyme-encapsulated cellular nanoparticles for continuous neurotoxin neutralization. How this design enhances detoxification efficacy is discussed. Chapter 3 examines the use of aptamer-encapsulated cellular nanoparticles for neurotoxin neutralization. The robustness and versatility of the newly established platform are demonstrated in different neurotoxin targets. The work in the dissertation underscores the potential of combining biomacromolecules with cellular nanoparticle platforms to create more effective and resilient therapeutic countermeasures for neurotoxins and thereby contribute to the broader neutralization field.