Ming et al. generated oil-water emulsions stabilized by alum particles (ASPEs) to mechanically activate DCs. Increasing alum crystallinity increased ASPE interfacial stiffness, in turn increasing DC contact area, membrane tension, and internalization, leading to PIEZO1-induced calcium flux and MAPK activation, altogether improving DC activation. Admixed with Ag, ASPEs induced a stronger Th1 responses in C57 mice compared to standard alum, increasing with ASPE stiffness. A high-stiffness ASPE incorporating MPLA adjuvant also induced strong, Th1-biased immune responses and improved efficacy over MPLA alone when used to prepare a DC vaccine.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China
(2) University of
Author Info: (1) State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, P.R. China
(2) University of Chinese Academy of Sciences, Beijing 100049, P.R. China
(3) Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, P.R. China
(4) Lead contact
