pH-Isomerizable Acylhydrazone-Based Ionizable Lipids for Spleen-Targeted mRNA Vaccines

Effectively and safely amplifying systemic immunity against heterogeneous and immunosuppressive cancers remains highly challenging. Here, we report a library of acylhydrazone-based ionizable lipids (AHzILs) that exploit pH-responsive E/Z isomerization to dynamically tune the membrane properties of mRNA-encapsulated lipid nanoparticles (LNPs), thereby achieving spleen targeting, efficient endosomal escape, and robust immune activation. These isomerizable mRNA vaccines acquired a protein corona enriched in mannose-binding protein A and vitronectin, promoting preferential uptake by antigen-presenting cells and granulocytes and facilitating immune-cell-mediated trafficking to the spleen. Once internalized, the acidic endosomal milieu triggered rapid pH-dependent E/Z isomerization of the acylhydrazone motif, inducing a cone-shaped lipid geometry that accelerated endosomal membrane destabilization. This disruption not only enabled efficient mRNA release and antigen expression but also activated the NLRP3 inflammasome pathway, thereby orchestrating both innate and adaptive immunity. Systemic immune activation expanded cDC1 subsets, enhanced antigen presentation, and T cell priming, thereby increasing the pool of antigen-specific TCF-1⁺PD-1⁺CD8⁺ T cells. This stem-like T cell subset synergized with anti-PD-1 checkpoint blockade to remodel the tumor microenvironment and ultimately confer durable systemic antitumor protection in a melanoma mouse model. Compared with conventional LNPs, our isomerizable vaccines uniquely integrate high transfection efficiency, intrinsic adjuvanticity, and spleen tropism, offering great promise for cancer immunotherapy and establishing a versatile modular platform adaptable to gene editing, T cell engineering, and targeted drug delivery against diverse malignant diseases.