Sepsis, a syndrome of acute organ dysfunction induced by various infections, could lead to a very high mortality in hospitals despite the development of advanced medical technologies. Herein, a type of two-phase releasing immune-stimulating composite is developed by mixing alginate (ALG) with muramyl dipeptide (MDP) and the nanoparticle formulation of monophosphoryl lipid A (MPLA), the latter two are immunomodulatory agents with different release rates from the formed ALG hydrogel. The obtained two phase-releasing composite could provide instantaneous sepsis protection by the rapid release of MDP to enhance the phagocytic and bactericidal function of macrophages. Later on, such composite could further offer long-term sepsis protection by the sustained release of MPLA to continuously activate the immune system, via up-regulating the production of various pro-inflammatory cytokines, promoting the polarization of macrophages, and increasing the percent of natural killer (NK) cells in the lesion after sepsis challenge. Mice survived from sepsis challenge after such treatment could resist a second infection. Notably, treatment with our composite could increase the mouse survival rate in a cecal ligation and puncture (CLP) induced polymicrobial sepsis model. This work provides an easy-translatable immune-stimulating formulation for effective protection against sepsis under various triggering causes. Our strategy may be promising for long-term broad prevention against various infections, and could potentially be used to protect medical workers under a new pandemic before a reliable vaccine is available.

脓毒症是一种由各种感染引起的急性器官功能障碍综合征，尽管先进的医疗技术得到发展，但仍可能导致医院的死亡率非常高。在此，通过将海藻酸盐(ALG) 与胞壁酰二肽 (MDP) 和单磷酰脂质 A的纳米颗粒制剂混合，开发了一种两相释放免疫刺激复合物(MPLA)，后两者是免疫调节剂，从形成的 ALG 水凝胶中具有不同的释放速率。获得的两相释放复合物可以通过快速释放MDP来增强巨噬细胞的吞噬和杀菌功能，从而提供瞬时的败血症保护。后来，这种复合材料可以通过持续释放 MPLA 来持续激活免疫系统，从而进一步提供长期的败血症保护，通过上调各种促炎细胞因子的产生，促进巨噬细胞的极化，并增加脓毒症攻击后病变中自然杀伤 (NK) 细胞的百分比。在这种治疗后，小鼠从败血症攻击中存活下来，可以抵抗二次感染。值得注意的是，在盲肠结扎和穿刺 (CLP) 诱导的多微生物败血症模型中，使用我们的复合材料进行治疗可以提高小鼠的存活率。这项工作提供了一种易于翻译的免疫刺激配方，可在各种触发原因下有效预防败血症。我们的策略可能有希望对各种感染进行长期广泛的预防，并且有可能在新的大流行病出现之前保护医务人员，然后再获得可靠的疫苗。