Polysaccharide Adjuvants as Innate Immune Trainers: Bridging Pattern Recognition Receptor (PRR) Activation and Metabolic Reprogramming for Synthetic Vaccine Design

Abstract The concept of trained immunity has redefined the understanding of innate immune memory and opened new opportunities for vaccine design. Polysaccharides, as naturally occurring pathogen‐associated molecular patterns (PAMPs), can activate pattern recognition receptors (PRRs) and induce durable immunomodulatory effects. This review examines the historical context of microbial immunotherapy, beginning with Coley's toxin, and traces its evolution toward the rational use of polysaccharides as vaccine adjuvants. Their mechanisms of action, ranging from PRR engagement to metabolic and epigenetic reprogramming, are discussed to support both innate training and adaptive immune activation. Emphasis is placed on how these materials interact with biological barriers, influence antigen processing, and enhance lymph node trafficking. By analyzing the immunological functions and material properties of β‐glucan, mannan, alginate, hyaluronic acid, chitosan, and others, the potential of polysaccharide‐based platforms is highlighted to improve the efficacy and breadth of synthetic vaccines.