Tuning Mechanoreceptor Signaling Enhances the Adjuvant Effect of Biomaterial Vaccines

ABSTRACT By providing slow‐release antigen depots, injectable hydrogels, including granular hydrogels, represent promising vaccine platforms to promote durable humoral immunity against pathogens. Increasing hydrogel crosslinking further slows antigen release and increases mechanical rigidity. Herein, we tested whether upon enhancing mechanical stiffness of vaccine microporous annealed particle (Vax‐MAP), granular hydrogel vaccines could provide enhanced adjuvant effects through activation of Piezo1 and/or the Yap/Taz mechanotransduction pathways in immune cells. Indeed, regardless of the presence of an antigen, increasing hydrogel rigidity through polymer crosslinking dramatically enhanced innate immune cell recruitment and activation. Deletion of either Yap/Taz or Piezo1 in myeloid cells impaired this stiffness‐induced immune cell recruitment in response to antigen‐free formulations. Pharmacological inhibition of Yap/Taz, but not global deletion of Piezo1, reduced the enhanced production of low and high affinity antibody responses to stiffer Vax‐MAP formulations by preventing T follicular helper cell expansion in draining lymph nodes. Conversely, Yap/Taz and Piezo1 agonists elicit dendritic cell maturation in vitro and their addition to traditional alum‐based immunizations enhanced adaptive immune cell activation and antigen‐specific induced high‐affinity antibody production. These findings demonstrate that directly targeting mechanotransduction pathways represents a powerful strategy for tuning vaccine efficacy.