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

## TL;DR

This study develops an mRNA vaccine that targets glioma by delivering mRNA to specific cells in the spleen using a new delivery strategy called SSOCT.

## Contribution

The study introduces a new sequential targeting strategy (SSOCT) and shows that meta-ionizable lipidoids improve mRNA delivery efficiency and therapeutic outcomes.

## Key findings

- meta-tLNP shows higher mRNA delivery efficiency compared to ortho-/para-tLNP.
- SSOCT enables selective mRNA expression in the spleen and then in dendritic cells.
- The mRNA vaccine combined with Anti-PD-1 therapy effectively treats glioma in mice.

## Abstract

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.

Targeted delivery of mRNA with lipid nanoparticles has potential in cancer therapy. Here this group reports a sequential selective organ-to-cell targeting strategy which enables selective mRNA expression in dendritic cells within the spleen.