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

Polysaccharides modulate immune responses by engaging pattern recognition receptors (PRRs) to induce T‐cell activation. In vaccine design, their particle size critically influences lymph node targeting and activation mechanisms. By engineering structural complexity and multivalent PRR engagement, polysaccharides enable precise modulation of immune signaling, offering versatile potential for diverse biomedical applications. 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. Polysaccharides modulate immune responses by engaging pattern recognition receptors (PRRs) to induce T-cell activation. In vaccine design, their particle size critically influences lymph node targeting and activation mechanisms. By engineering structural complexity and multivalent PRR engagement, polysaccharides enable precise modulation of immune signaling, offering versatile potential for diverse biomedical applications. 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. Advanced Science, Volume 12, Issue 48, December 29, 2025.