Bioengineered hybrid spheroids integrating mesenchymal stem cells and metformin-loaded microspheres for the treatment of sepsis-induced liver injury.

Sepsis is a complex and heterogeneous inflammatory and immune response, causing multi-organ dysfunction and accounting for approximately 20% of all global deaths. Currently, antibiotics and organ-supportive therapy are the major available supportive treatments for sepsis, which may be due to multiple pathways of disease progression that make them highly evasive. Besides, Food and Drug Administration-approved drugs, cells, or biologics for sepsis treatment are unavailable, and preclinical data do not seem to reduce mortality in clinical trials, indicating the need for an alternative therapeutic approach. Here, we introduce bioengineered cell-particle hybrid spheroids (HS), composed of mesenchymal stem cells (MSCs) and metformin-loaded poly (lactic-co-glycolic acid) microspheres (Met-MS) as MSCargo, which exhibit synergistic and enhanced antioxidants, anti-inflammatory, and immunomodulatory activities. We demonstrated that MSCargo significantly enhances cell viability and functionality of hepatocytes, thereby protecting them from oxidative stress and inflammatory cytokine-induced damage. Furthermore, MSCargo post-transplantation via the hepatic portal vein remarkably reduced sepsis-associated organ dysfunction, including liver, kidney, and lungs through the modulation of TLR4/NF-kB signaling pathways as well as enhancing hepatic regeneration. In summary, MSCargo holds a promising therapeutic alternative for treating sepsis as well as other inflammatory diseases by integrating immune modulation, anti-inflammatory, and regenerative effects.