Protein‐Loaded Cellular Nanosponges for Dual‐Biomimicry Neurotoxin Countermeasure

Abstract Neurotoxins present a substantial threat to human health and security as they disrupt and damage the nervous system. Their potent and structurally diverse nature poses challenges in developing effective countermeasures. In this study, a unique nanoparticle design that combines dual‐biomimicry mechanisms to enhance the detoxification efficacy of neurotoxins is introduced. Using saxitoxin (STX), one of the deadliest neurotoxins, and its natural binding protein saxiphilin (Sxph) as a model system, human neuronal membrane‐coated and Sxph‐loaded metal–organic framework (MOF) nanosponges (denoted “Neuron‐MOF/Sxph‐NS”) are successfully developed. The resulting Neuron‐MOF/Sxph‐NS exhibit a biomimetic design that not only emulates host neurons for function‐based detoxification through the neuronal membrane coating, but also mimics toxin‐resistant organisms by encapsulating the Sxph protein within the nanoparticle core. The comprehensive in vitro assays, including cell osmotic swelling, calcium flux, and cytotoxicity assays, demonstrate the improved detoxification efficacy of Neuron‐MOF/Sxph‐NS. Furthermore, in mouse models of STX intoxication, the application of Neuron‐MOF/Sxph‐NS shows significant survival benefits in both therapeutic and prophylactic regimens, without any apparent acute toxicity. Overall, the development of Neuron‐MOF/Sxph‐NS represents an important advancement in neurotoxin detoxification, offering promising potential for treating injuries and diseases caused by neurotoxins and addressing the current limitations in neurotoxin countermeasures.