Nano lettersSep 10, 2025

Using mRNA to Deliver a Tumor-Activated Immune Protein That Kills Tumors While Reducing Side Effects

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

A tumor-activated mRNA-encoded IL-12 lock is proposed to deliver antitumor cytokine activity while limiting systemic toxicity.

Evidence

This cytokine-delivery platform study describes LNP-based systemic delivery of mRNA encoding an MMP-2-cleavable Lock-IL-12 fusion protein intended to activate in the tumor microenvironment.

Caveat

The abstract mainly presents the design and mechanism and does not provide detailed experimental tumor efficacy, toxicity, or clinical outcome data.

Simplified

Interleukin-12 (IL-12) is a robust proinflammatory cytokine that activates immune cells, such as T cells and natural killer cells, to induce antitumor immunity. However, the clinical application of recombinant IL-12 has been limited by systemic immune-related adverse events (irAEs) and rapid degradation. To address these challenges, we employed mRNA technology to encode a tumor-activated IL-12 "lock" fusion protein that offers both therapeutic efficacy and systemic safety. Lock-IL-12 mRNA encodes a sequence consisting of the IL-12 receptor-binding domain, a matrix metalloproteinase-2 (MMP-2)-cleavable linker, and two IL-12 subunits. Systemic delivery of the mRNA via lipid nanoparticles (LNPs) enables widespread systemically expression of Lock-IL-12 protein in the locked state, and maintaining an inactive state during circulation. Upon reaching the MMP-2-rich tumor microenvironment (TME), the fusion protein undergoes cleavage, activating IL-12 to initiate a powerful antitumor immune response. This strategy represents a promising approach for cytokine-based tumor therapy, combining efficient delivery with minimal systemic toxicity.