An Mn2+-coordinated glycyrrhizic acid self-adjuvating hydrogel for sustained codelivery of an antigen and Mn2+ for a potent immune response

Abstract

The development of vaccine platforms that enable sustained codelivery of antigens and adjuvants remains a major challenge in modern vaccinology. Herein, we constructed a self-adjuvating hydrogel (GA@Mn) via the self-assembly of natural glycyrrhizic acid (GA) and subsequent coordination with Mn²⁺. This coordination facilitates gradual Mn²⁺ release during hydrogel degradation, overcoming the rapid clearance and poor bioavailability of soluble Mn²⁺in vivo. Notably, Mn²⁺ coordination drastically increased the crosslinking density of the GA hydrogel (GAgel) network, enhancing the storage modulus of GA@Mn by three orders of magnitude compared to the native GAgel. This superior mechanical stability allows GA@Mn to serve as an efficient antigen depot, prolonging the retention of both Mn²⁺ and the antigen at the injection site for up to 14 days. Meanwhile, GA@Mn promoted robust local immune cell recruitment, establishing an antigen-presenting cell (APC)-rich microenvironment. Subsequently, GA@Mn activation of the STING pathway enhanced the dendritic cell (DC) maturation and antigen uptake by 2.4-fold and 1.8-fold, respectively. In mice, a single injection of GA@Mn significantly potentiated antigen-specific humoral and cellular immune responses, leveraging a synergistic effect between the STING-activating capacity of Mn²⁺ and the depot-forming ability of the hydrogel. In summary, this study presents a facilely fabricated GA@Mn hydrogel vaccine platform that enables sustained codelivery of the antigen and adjuvant (Mn²⁺) for robust immune enhancement. This work provides a new paradigm for the rational design of metal ion-coordinated hydrogel vaccines.