Systemic Delivery of an mRNA-Encoding, Tumor-Activated Interleukin-12 Lock to Eliminate Tumors and Avoid Immune-Related Adverse Events

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.