Drilling Dendritic Cell Activation: Engineering Interfacial Mechano-Biochemical Cues for Enhanced Immunotherapy

AbstractA key challenge in immunotherapy is enhancing immune responses without introducing new molecular entities that trigger regulatory hurdles. While the size, shape, and composition of approved adjuvants have been optimized, their mechanical properties remain underexplored. Here, we repurpose approved aluminum-based adjuvants (alum) by engineering alum-stabilized Pickering emulsions (ASPEs) to synergize mechanical (PIEZO1) and biochemical (TLR4) cues. ASPEs, featuring interfacial alum with optimal rigidity, was heralded to promote multivalent dendritic cell (DC) engagement and dynamic three-dimensional membrane contact during endocytosis, transmitting localized stress that activates PIEZO1-mediated calcium/MAPK signaling. This enahnces antigen cross-presentation and Th1 immunity. Co-delivering a TLR4 agonist (MPLA) further boosted immunogenicity in a varicella-zoster virus vaccine, outperforming alum+MPLA (AS04). In antigen-pulsed DC therapy combined with PD-1 blockade, ASPE-treated DCs achieved a 2.11-fold greater tumor suppression compared to tumor lysate-based clinical approaches. These findings demonstrate how tuning interfacial mechanics of approved materials can unlock mechano-immunotherapy with high translational potential.