mRNA vaccine developed for sequential selective organ-to-cell targeting of glioma.

Messenger RNA (mRNA)-based therapeutics hold great potential for effectively treating various diseases. However, the targeting of mRNA delivered by systemically administered lipid nanoparticles (LNP) is currently limited to the liver. Safe and efficient systemic delivery of mRNA to specific organs and cells remains a major challenge, and it is still unclear whether the positional isomerism of individual compounds within LNP affects their activity. Here, we synthesize a library of meta/ortho/para-ionizable lipidoids and prepare three-component lipid nanoparticles (tLNP) without PEG-lipids. Our findings show that tLNP containing meta-ionizable lipidoids (meta-tLNP) exhibits higher mRNA delivery efficiency than those containing ortho-/para-ionizable lipidoids (ortho-/para-tLNP). Additionally, we report a strategy termed Sequential Selective Organ-to-Cell Targeting (SSOCT), which enables the systemic administration of meta/ortho/para-tLNP to first achieve selective mRNA expression in the spleen, followed by targeted mRNA expression in dendritic cells within the spleen. Notably, we demonstrate that delivering the mRNA vaccine (mXO10 tLNP@mIDH1) using meta-tLNP effectively treats glioma in mice, particularly when combined with Anti-PD-1 therapy. This combination further enhances therapeutic efficacy, even completely eradicating glioma, reducing hepatotoxicity, and minimizing PEG-lipid-induced allergic reactions. This study establishes that mRNA therapy, developed by selectively targeting splenic dendritic cells via SSOCT, represents a promising therapeutic intervention for glioma.