**Background:** Enteritis caused by Gram-negative bacterial infection is a major problem in livestock and poultry production. Schisandra chinensis polysaccharide (SCP) has shown therapeutic potential for enteritis, but its high molecular weight limits bioavailability. Selenium nanoparticles (Se NPs) can enhance polysaccharide bioactivity, but bare Se NPs aggregate rapidly. Conjugating polysaccharides with Se NPs may overcome both limitations. This study aimed to synthesize SCP-Se NPs for the first time and evaluate their protective effects against LPS-induced intestinal injury in mice.
**Methods:** SCP was extracted from Schisandra chinensis via water extraction and alcohol precipitation, purified using a DEAE-52 cellulose column, and characterized for monosaccharide composition by HPLC. SCP-Se NPs were synthesized by reducing sodium selenite with ascorbic acid in the presence of SCP. The synthesis was optimized by testing SCP concentrations from 0 to 2.00 mg/mL, using UV-Vis spectroscopy (A410/A490 ratio), dynamic light scattering (particle size, PDI, Zeta potential), and TEM, XRD, EDX, and FTIR for characterization. Stability was assessed at 4°C and room temperature over 14 days. For in vivo evaluation, 28 SPF male KM mice were divided into four groups: blank control (BC), LPS model, SCP (10.0 mg/kg), and SCP-Se NPs (10.0 mg/kg). After 14 days of oral gavage, mice (except BC) received 20.0 mg/kg LPS intraperitoneally. Disease activity index (DAI) was scored over 6 hours. Jejunum tissue was analyzed by H&E staining (villus height, crypt depth, V/C ratio), IHC for ZO-1 tight junction protein, and qRT-PCR for TNF-α, IL-1β, and IL-6 mRNA. Serum cytokines were measured by ELISA.
**Key Results:** Purified SCP had 89.2% carbohydrate content and consisted of mannose, ribose, rhamnose, glucuronic acid, galacturonic acid, glucose, xylose, and arabinose in a molar ratio of 6.93:1.00:14.7:1.71:29:13.0:21.3:23.1. Optimal SCP-Se NPs were obtained at 0.100 mg/mL SCP, yielding uniform spherical amorphous particles of ~121 nm diameter (PDI 0.170, Zeta potential −28.9 mV). EDX showed 18.5% selenium content. FTIR revealed O-H···Se and C-O···Se bond formation. The colloidal solution was stable at 4°C for at least 14 days but aggregated at room temperature (particle size increased to 516 nm by day 14). In vivo, LPS induced severe enteritis with significantly elevated DAI scores, villus atrophy (decreased villus height, increased crypt depth, reduced V/C ratio, all p < 0.05), ZO-1 downregulation (p < 0.05), and elevated serum and mRNA levels of TNF-α, IL-1β, and IL-6 (p < 0.05). Both SCP and SCP-Se NPs significantly attenuated these changes. SCP-Se NPs showed superior effects: DAI scores were lower than SCP (though not statistically significant, p > 0.05); ZO-1 expression was significantly higher than in the SCP group and approached BC levels (p < 0.05); serum TNF-α, IL-1β, and IL-6 were significantly lower than both LPS and SCP groups (p < 0.05); and all three cytokine mRNA levels returned to levels not significantly different from BC (p > 0.05), whereas IL-6 mRNA was significantly lower than the SCP group (p < 0.05).
**Clinical Implications:** This study demonstrates that SCP-Se NPs are more effective than SCP alone in protecting against LPS-induced intestinal injury in mice, likely through enhanced anti-inflammatory activity and preservation of intestinal barrier integrity. The nanoparticle formulation overcomes the bioavailability limitations of native SCP while also stabilizing selenium nanoparticles. These findings support SCP-Se NPs as a promising antibiotic alternative for preventing and treating enteritis in livestock and poultry, addressing the urgent need for safe, non-antibiotic therapies in animal production. Further research is needed to evaluate efficacy in target species and elucidate the precise molecular mechanisms.