Dual-function oral nanotherapeutic mitigates sepsis-like multi-organ failure by targeting inflammatory and fibrotic pathways

Sepsis, a life-threatening condition, often leads to multi-organ failure and has limited treatment options. We developed a novel dual-function nanoparticle, P2Ns-NAR(NAR), which utilizes naringenin (NAR) as both a targeting ligand for gut folate receptors and an encapsulated therapeutic agent to overcome its poor oral bioavailability. Here, we investigated the efficacy of this oral formulation in a mouse model of lipopolysaccharide-induced sepsis. We observed a significant reduction in the mRNA expression of pro-inflammatory ( Tlr4, NF-κB, and IL-18 ), apoptotic ( p53 , and Fas ), fibrosis ( TGFβ1 and Smad3 ) and inflammasome-related ( P2x7, gasdermin D, Nlrp3, Caspase 1, Nek7 ) markers. Histological analyses showed a prevention of tissue injury in the lungs, liver, kidney, heart, brain, intestines, and spleen. Additionally, Masson's trichrome staining revealed a remarkable reduction in collagen deposition, a hallmark of fibrosis, across multiple organs such as the lungs, liver, kidney, and heart. Our findings establish this dual-function nanoparticle platform as a highly effective oral therapy to prevent multi-organ failure. • P2Ns-NAR(NAR) is a dual-function nanoparticle that uses naringenin (NAR) as a gut-targeting ligand and sepsis therapeutic. • The nanoparticle reduced gene expressions linked to inflammation, cell death, fibrosis, and inflammasomes. • It prevented tissue injury and decreased collagen deposition in lungs, liver, kidneys, and heart. • This nanoparticle platform is a highly effective oral therapy for preventing multi-organ failure in sepsis.