Abstract

Sepsis is a critical global health challenge, characterized by dysregulated host responses and high mortality rates. Current treatment therapies inadequately address persistent immunoparalysis and adverse reactions, leaving survivors susceptible to recurrent infections. Herein, we developed the first β-glucan (BG) delivery system using self-assembling peptide hydrogels to combat immuneparalysis associated with sepsis. This hydrogel combines oxidized BG (BGA) and tuftsin-functionalized self-assembling peptides (t-RADA16) to create an injectable glycopeptide hydrogel (BGA@t-RADA16). Upon subcutaneous injection, the hydrogel forms a dual-functional platform consisting of a "sustained-release depot" of BGA and a local "trained immunity center", where the three-dimensional network of peptide nanofibers actively recruits and the BGA educates macrophages in-situ. This endows the macrophages with an immune memory function, generating a rapid and powerful defense against secondary infection, and achieving a "targeted-sustained-response" cascade treatment system. The results demonstrate that the glycopeptide hydrogel reduces organ damage, lowers sepsis mortality and confers protection against secondary infections by coordinating the activation of both innate and adaptive immune pathways. Furthermore, BGA-P@t-RADA16 simultaneously clears acute-phase pathogens and provides long-term immune training by loading polymyxin B within a single system, which truly addresses the dynamic nature of "immune imbalance" in the pathological process of sepsis. BGA@t-RADA16 provides a new tool for sepsis immunotherapy, pioneering an integrated strategy of "immune training, acute intervention and long-term defense". This strategy is expected to be an important breakthrough in the treatment of sepsis and related immune disorders.