Breakthrough in Cancer Treatment! The "Route-Recognizing" mRNA Smart Switch is Here!

During the global COVID-19 pandemic, mRNA vaccines gained worldwide recognition for their high efficiency and safety, showcasing the tremendous potential of mRNA technology. However, the applications of mRNA extend far beyond vaccines. In treating complex diseases like cancer, precisely delivering drugs to diseased cells while avoiding damage to healthy tissues has long been a major challenge in the medical field. Currently, although technologies like lipid nanoparticles (LNP) are widely used for mRNA delivery, their targeting capabilities remain limited, often leading to drug accumulation in non-target organs like the liver, causing potential side effects.

According to WHO data, cancer is the second leading cause of death globally, with approximately 10 million people dying from cancer in 2020. Breast cancer and colorectal cancer are particularly common and highly prevalent cancers, often accompanied by severe side effects during treatment that significantly impact patients' quality of life. Can mRNA drugs function like "smart missiles" that activate only within tumor cells while remaining "silent" in healthy cells? Recently, in a research paper titled "A tumor-selective mRNA system enables precision cancer treatment" published in the international journal Molecular Therapy, researchers from the Icahn School of Medicine at Mount Sinai provided an encouraging answer.

mRNA Technology Enters a New Era of "Precision Treatment"

Researchers have developed a novel mRNA platform called the cell-selective modified RNA translation system (cSMRTS, also known as SMRTS). This system functions like a built-in switch that recognizes specific cell types and precisely activates therapeutic gene expression within target cells. The researchers noted that one exciting aspect of this study is its flexibility-it's not limited to a single disease or therapy and could theoretically be applied to various precision medicine scenarios ranging from cancer to inflammation and metabolic diseases.

How Does It Achieve "Targeting Only Tumors"?

The core design of cSMRTS draws inspiration from the natural regulatory mechanism within cells-microRNA. Different cell types possess unique microRNA "fingerprints", and tumor cells are no exception. Researchers ingeniously designed two mRNA segments: 1) The first segment carries instructions encoding the Cas6 enzyme (an enzyme that cleaves RNA), with embedded sites that can be recognized by tumor-associated microRNA; 2) The second segment carries the therapeutic gene, along with an RNA "hairpin" structure that Cas6 can recognize and cleave.

The working principle resembles a smart security system: 1) In tumor cells: specific microRNA binds to the Cas6 mRNA and "silences" it, preventing Cas6 production, thus allowing the therapeutic gene to be expressed normally and exert its therapeutic effects; 2) In healthy cells: Due to the absence of these tumor-specific microRNAs, Cas6 is produced normally and rapidly cleaves the mRNA carrying the therapeutic gene, preventing its activation in non-target cells.

Targeting Enhanced Over 100-Fold, Combination Therapy Achieves 93% Tumor Suppression

Researchers tested this system in 4T1 (breast cancer) and MC-38 (colon cancer) mouse models, delivering it systemically via standard lipid nanoparticles. The results showed:

(1) Extremely high targeting specificity: In tumor tissues, gene expression increased by 114-fold (breast cancer) and 141-fold (colon cancer) respectively; while off-target expression in major organs like the liver and spleen decreased by more than 380-fold.

(2) Significant tumor growth inhibition: Colon cancer-specific cSMRTS carrying the tumor suppressor gene PTEN alone inhibited tumor growth by 45%.

(3) Remarkable combination therapy effects: When combined with mRNA-encoded anti-checkpoint inhibitor antibodies (modRNabs), the tumor suppression rate reached up to 93%.

Figure 1. Systemic delivery of therapeutic cSMRTS, combined with αCTLA-4 modRNabs, effectively inhibits tumor growth in mouse models of breast and colon cancer. (Żak M M, et al., 2025)

From Heart to Cancer

Researcher Dr. Zangi stated, "We have been engaged in mRNA cardiovascular therapy research for over 15 years, traditionally relying on invasive delivery methods like direct intracardiac injections. What particularly interests me is that this technology holds promise for safely targeting specific cells or organs through non-invasive delivery methods, avoiding unnecessary gene expression." Currently, nanoparticle-based delivery technologies mostly confine mRNA therapies to the vaccine field. By engineering the mRNA carrier itself to confer cell selectivity, cSMRTS provides a novel strategy for reducing toxicity and expanding the scope of mRNA therapeutics.

This research not only demonstrates the enormous potential of cSMRTS in cancer treatment but also opens up a modular, programmable mRNA precision treatment platform. The researchers have filed patent applications for this technology and are advancing toward commercialization and preclinical development. Researchers indicate that for patients, this means the potential for more targeted, better-tolerated cancer treatment options. In the long term, this technology also has the potential to be adapted for more diseases.

Reference

Żak M M, et al. A tumor-selective mRNA system enables precision cancer treatment. Molecular Therapy, 2025.