Advanced functional lipid nanomaterials with precise structure-function relationships are pivotal to overcome extrahepatic delivery barriers in mRNA therapy. Here, we develop a chloroquine-inspired spleen-targeting system (CISTS) through rational molecular hybridization and combinatorial screening of quinoline-derived lipids. Computational simulations revealed enhanced mRNA binding via hydrogen bonding networks and TLR4/TLR7-targeting capacity inherent to chloroquine-mimetic headgroups. This molecular design enables CISTS to exhibit unique self-assembly behavior, as validated by cryo-EM and molecular dynamics, which promotes high-efficiency mRNA encapsulation and endosomal escape. Upon intravenous administration, CISTS achieves spleen-biased mRNA transfection while concurrently activating TLR-mediated immune pathways, conferring self-adjuvanting activity that drives potent Th1-biased responses. In murine melanoma models, CISTS-delivered ovalbumin mRNA elicited robust antigen-specific immunity, significantly suppressing tumor growth and extending survival. This work establishes a new paradigm of hybrid lipid nanomaterials that intrinsically integrates targeted delivery and immunostimulation, advancing next-generation mRNA vaccine design.
LI et al. (Sat,) studied this question.