An endogenous metabolite nanomedicine restores pulmonary neuroimmune homeostasis in septic lung injury

Septic lung injury is a major cause of mortality in critically ill patients, yet targeted therapies remain lacking. Although current therapeutic efforts have largely focused on controlling macrophage-driven inflammation, septic lung injury is increasingly recognized as more than an inflammatory disorder alone, highlighting disrupted pulmonary neuroimmune regulation as an underappreciated therapeutic dimension. Here, we developed a liposomal nanoplatform co-delivering two endogenous metabolites, 5-hydroxyindoleacetic acid (5-HIAA) and spermine (SPM), termed HSLPs, to achieve coordinated regulation of inflammatory macrophage programs and local tissue homeostasis in septic lung injury. In murine sepsis models, HSLPs improved survival, reduced systemic and pulmonary inflammation, alleviated multi-organ injury, and restored alveolar architecture, barrier function, and sensory nerve integrity within septic lungs. Mechanistically, HSLPs promoted macrophage phenotypic reprogramming in part through AhR-dependent signaling, while simultaneously restoring TRPV1⁺ sensory nerve structure and engaging a CGRP-dependent neuroimmune pathway. Together, these results establish HSLPs as an endogenous metabolite-based nanomedicine that protects against septic lung injury through coupled macrophage reprogramming and pulmonary sensory neuroimmune restoration. This study identifies sensory nerve dysfunction as a therapeutically relevant component of septic lung injury and supports endogenous metabolite-based nanomedicine as a strategy for coordinated immune and neural restoration in sepsis.