Chitosan as a Vaccine Adjuvant: From Material Determinants to Innate Immune Activation and Formulation Optimization.

This review summarizes the current understanding of chitosan as a chemically tunable vaccine adjuvant, with a particular focus on the relationships between material determinants, innate immune activation, and translational formulation design. From a materials science perspective, we discuss how molecular weight, charge density, and composite construction with organic or inorganic components shape the physicochemical behavior of chitosan-based systems. It then summarizes, from an immunological perspective, the pathways through which chitosan-based adjuvants activate immune responses-including the cGAS-STING pathway, the NLRP3 inflammasome, and TLR2/TLR4-and how they balance humoral and cellular immunity. Finally, we also analyze the context-dependent applicability of various chitosan-based formulations, such as nanoparticles and hydrogels, along with the design rationale for synergistic "chitosan + X" (e.g, TLR agonists, cytokines) adjuvant systems. We highlight key translational challenges, including poor solubility at neutral pH, structural heterogeneity, endotoxin and impurity control, batch-to-batch reproducibility, and chemistry, manufacturing, and controls (CMC) requirements. Collectively, this review provides a theoretical framework for rational formulation selection, critical quality attribute standardization, and the prioritization of clinically feasible chitosan-based adjuvant platforms.