Host-pathogen hybrid glycocalyx mimicking lipid nanoparticles induce trained immunity as a promising platform for universal vaccines.

Given the challenge of antigen selection in universal vaccine development, pathogenic microorganisms involved in diverse disease progressions have emerged as promising targets. Certain components of their glycocalyx can induce trained immunity, making them highly attractive for universal vaccine construction. Considering the limitations of current glycocalyx-mimicking strategies based on single glycans, we propose and construct host-pathogen hybrid glycocalyx-mimicking lipid nanoparticles incorporating endogenous sialic acid and exogenous lipopolysaccharide (SA-LPS@LNPs). By tuning the SA-to-LPS ratio, we balanced "self" and "non-self" features, enabling SA-LPS@LNPs to achieve efficient immune recognition, targeted uptake, and autonomic lysosomal escape, thus promoting trained immunity. SA-LPS@LNPs exhibited significant therapeutic efficacy in both solid tumors and liquid tumors (acute myeloid leukemia, AML), inhibited tumor metastasis. A 100 % cure rate in early-stage AML and improved survival after tumor rechallenge, with significantly improved survival in sepsis (87.5 % vs. 0 %-25 %) were observed in SA-LPS@LNPs group. We propose the Enhanced Level Evaluation Via Anatomic Tissue Weight (ELEVATE) index for quantifying anti-metastatic effects more scientifically. Besides, SA-LPS@LNPs provided prophylactic protection against sepsis in both healthy and tumor-bearing mice. To our knowledge, this is the first study to introduce the hybrid glycocalyx-mimicking concept in nanoparticle vaccine design, offering a new perspective for both glycocalyx-based formulation strategies and the advancement of universal vaccines.