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Among affected organs, the lung is particularly vulnerable, with injury involving both immune\u2010mediated tissue damage and inflammation\u2010induced neuronal impairment. Yet, whether coordinated targeting of immune and neural compartments can achieve synergistic and durable therapeutic benefits remains unknown. Here, we report a rationally engineered, dual\u2010functional, enzyme\u2010responsive nanoplatform (SJNPs) that co\u2010delivers the glutamate production inhibitor JHU083 and the neuroprotective spermine (Spm) to reprogram macrophage\u2010neuron immunometabolic interactions. SJNPs suppressed pro\u2010inflammatory, M1\u2010associated macrophage activation while promoting M2 polarization, which in turn drove robust secretion of the neurotrophic factor nerve growth factor (NGF) and preserved pulmonary neuronal integrity. Mechanistically, inhibition of glutamate metabolism reprogrammed macrophage polarization and activated NGF\u2010mediated neurotrophic signaling, establishing NGF as a key mediator linking immune modulation to neural protection. In murine sepsis models, SJNPs attenuated systemic cytokine storms, mitigated alveolar damage, alleviated neurological injury, and improved survival. This study identifies macrophage\u2010neuron immunometabolic crosstalk as a previously underexplored therapeutic target for septic lung injury characterized by neuronal damage, and establishes metabolic reprogramming of macrophages as a promising strategy for integrated immunomodulatory and neuroprotective therapy in sepsis.<\/jats:p>","DOI":"10.1002\/advs.202520665","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T19:59:01Z","timestamp":1771271941000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanotherapeutic Macrophage\u2010Neuro Reprogramming Through Immunometabolic Crosstalk Mitigates Sepsis\u2010Induced Lung Injury and Neurologic Damage"],"prefix":"10.1002","volume":"13","author":[{"given":"Wenhui","family":"Wang","sequence":"first","affiliation":[{"name":"Laboratory of Cellular Metabolism and Precision Therapeutics School of Life Science and Technology Northwestern Polytechnical University  Xi'an P. 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