A single oral administration of resveratrol cocrystals enables potent antisepsis therapy via interfering neutrophil extracellular traps formation

Sepsis is a life-threatening syndrome characterized by organ dysfunction resulting from host response disorders and is a common complication in patients suffering from clinical trauma, burns, and infections. Resveratrol, a natural polyphenol compound, possesses anti-inflammatory, antiviral, antibacterial, and antifungal properties, as well as cardiovascular and anti-tumor protective effects. However, its therapeutic applications have been limited due to low bioavailability, poor aqueous solubility, and rapid metabolism. To address these limitations, this study focused on the preparation of resveratrol (RES) cocrystal with nicotinamide (NCA) and RES polymorphs through recrystallization for oral application. The identity of the new crystalline forms was confirmed using powder X-ray diffraction (PXRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and single-crystal X-ray diffraction (SCXRD). Physicochemical evaluations revealed that the RES polymorphs and RES-NCA cocrystal exhibited higher solubility and dissolution rates compared to pristine RES. In vitro experiments with LPS-stimulated HL-60 cells demonstrated that the RES-NCA cocrystal effectively inhibited neutrophil extracellular traps (NETs) formation by targeting peptidylarginine deiminase 4 (PADI4) and reducing inflammatory markers. Additionally, in vivo studies using a cecal ligation and puncture (CLP)-induced sepsis model in mice showed that oral administration of the RES-NCA cocrystal significantly reduced NETs formation, organ injury, and mortality. These findings suggest that orally administered RES-NCA cocrystal holds promise as a therapeutic agent for sepsis treatment, offering enhanced solubility and bioavailability, along with potent effects in inhibiting NETs formation and reducing sepsis-induced organ injury.