Nanotherapeutic Macrophage‐Neuro Reprogramming Through Immunometabolic Crosstalk Mitigates Sepsis‐Induced Lung Injury and Neurologic Damage

ABSTRACT Sepsis remains a leading cause of mortality in intensive care units, with its associated organ dysfunction primarily driven by uncontrolled inflammation and neuroimmune dysregulation. Among affected organs, the lung is particularly vulnerable, with injury involving both immune‐mediated tissue damage and inflammation‐induced 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‐functional, enzyme‐responsive nanoplatform (SJNPs) that co‐delivers the glutamate production inhibitor JHU083 and the neuroprotective spermine (Spm) to reprogram macrophage‐neuron immunometabolic interactions. SJNPs suppressed pro‐inflammatory, M1‐associated 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‐mediated 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‐neuron 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.