Oral Multi-Enzymatic Manganese–Carbon Dots Alleviate Sepsis-Associated Lung Injury via the Gut–Lung Axis

Sepsis-induced pulmonary injury represents a life-threatening global health challenge due to poorly defined pathological mechanisms. The gut-lung axis has been proven to be widely involved in sepsis-induced lung injury, yet effective interventions targeting gut microbiota homeostasis remain unknown. Single-cell sequencing revealed increased alveolar apoptosis and impaired macrophage efferocytosis during sepsis pathogenesis. Thus, we designed oral manganese-doped carbon dots (Mn-CDs) to alleviate septic lung injury by remodeling gut microbiota homeostasis and targeting the gut-lung axis. Biochemical characterization demonstrated Mn-CDs possess multienzyme mimetic activities (SOD-, CAT-, POD-, GPx-like) and potent ROS scavenging capacity. In murine sepsis models, Mn-CDs significantly improved systemic indices and were associated with macrophage anti-inflammatory states with enhanced efferocytosis, as evidenced by transcriptomic profiling. Integrated metagenomic/metabolomic analyses identified Mn-CDs-mediated enrichment of <i>g_Clostridium</i> and <i>g_Bacteroides</i>, concomitant with elevated indole-3-propionic acid (IPA) production. Subsequent in vitro studies demonstrate that IPA likely binds primarily to the aryl hydrocarbon receptor (AHR), promoting both efferocytosis and anti-inflammatory polarization in macrophages, thereby mitigating septic lung injury. Notably, the fecal microbiota transplantation (FMT) from Mn-CDs-treated mice not only alleviated systemic symptoms but also effectively promoted efferocytic polarization of pulmonary macrophages in septic mice. Depletion of the gut microbiota resulted in a significant loss of the protective efficacy of Mn-CDs in a murine model of septic lung injury. Collectively, the gut-lung axis mediated by microbiota-derived IPA and macrophage efferocytosis contributes to the remediation of septic lung injury, highlighting the potential of Mn-CDs in microbiome-directed critical care.