Journal of controlled release : official journal of the Controlled Release SocietyOct 2, 2026

A nanomaterial that stays local to improve mRNA immune treatment without entering the bloodstream

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 3, 2026

Abstract

Intraperitoneal administration of SEAL LNPs significantly reduces unintended mRNA expression in the liver and spleen.

A new nanoplatform, SEAL, enables efficient mRNA delivery specifically to peritoneal tumors while limiting systemic exposure.
Robust protein expression is maintained in peritoneal tumors with minimal off-target effects on the liver and spleen.
The inclusion of a cationic helper lipid is crucial for the SEAL platform's ability to reduce systemic exposure.
SEAL LNPs promote a specific cellular uptake mechanism that limits their ability to cross the mesothelium for lymphatic transport.
Using the SEAL platform to deliver IL-12 mRNA leads to localized expression and reduced systemic toxicity, resulting in significant antitumor effects in mice with colorectal cancer.

Simplified

Rapid transport of locally delivered mRNA lipid nanoparticles (mRNA-LNPs) into systemic circulation induces off-target protein expression and undesired side effects. Here we describe a systemic-absorption-blocked (SEAL) nanoplatform that achieves efficient mRNA delivery to disseminated peritoneal tumors using LNPs with minimized systemic exposure. Intraperitoneal administration of SEAL LNPs significantly reduces unintended mRNA expression in the liver and spleen, while maintaining robust protein expression in peritoneal tumors. Incorporation of cationic helper lipid is demonstrated essential for SEAL LNPs to minimize their systemic exposure. Using an in vitro transwell model to simulate the mesothelial barrier, we further elucidate that SEAL LNPs favor clathrin-mediated endocytosis and Golgi apparatus less involved intracellular trafficking in mesothelial cells, leading to reduced capability to penetrate the mesothelium for lymphatic transport. Intraperitoneal delivery of IL-12 mRNA (mIL-12) using the SEAL platform generates localized IL-12 expression with reduced systemic toxicity, leading to potent antitumor effects in mice bearing colorectal cancer (CRC) peritoneal dissemination. Delivery of mRNA-encoded therapeutic proteins using this platform presents a promising strategy to address peritoneal carcinomatosis.

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A nanomaterial that stays local to improve mRNA immune treatment without entering the bloodstream

Abstract

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