Drilling dendritic cell activation: Engineering interfacial mechano-biochemical cues for enhanced immunotherapy

A 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, were heralded to promote an enlarged contact area with dendritic cells (DCs) during endocytosis, transmitting localized stress that activates PIEZO1-mediated calcium/mitogen-activated protein kinase (MAPK) signaling. This enhances antigen cross-presentation and Th1 immunity. Co-delivering a TLR4 agonist (monophosphoryl lipid A [MPLA]) further boosted immunogenicity in a varicella-zoster virus vaccine among aged mice, outperforming alum+MPLA (AS04). In antigen-pulsed DC therapy combined with PD-1 blockade, ASPE-M-treated DCs achieved a 2.11-fold greater tumor suppression compared with tumor lysate-M-based clinical approaches. These findings demonstrate how tuning the interfacial mechanics of approved materials can unlock mechano-immunotherapy with translational potential.