A modular mRNA platform for programmable induction of tumour-specific immunogenic cell death

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Messenger RNA (mRNA) therapeutics show promise in oncology but face challenges with systemic off-target effects and immunosuppressive tumor microenvironments.
• Current delivery methods often lead to toxicity and limited efficacy in solid tumors.

Purpose of the Study:

• To develop a tumor-customizable mRNA nanomedicine platform (TITUR) for enhanced tumor-selective delivery and expression.
• To investigate the potential of TITUR to induce immunogenic cell death and overcome tumor immunosuppression.

Main Methods:

• TITUR platform integrates tumor-customizable ionizable lipids (TIs) and tumor-specific untranslated regions (TURs).
• Intratumoral delivery of mRNA encoding 4HB, an immunogenic cell death-inducing protein, in murine models of melanoma and triple-negative breast cancer.
• Combination therapy with immune checkpoint inhibitors.

Main Results:

• TITUR achieved precise intratumoral expression of 4HB, mitigating systemic toxicities.
• 4HB delivery induced tumor-specific immunogenic cell death, remodeled the tumor microenvironment, and enhanced immune cell infiltration.
• Combination therapy suppressed primary and metastatic tumor growth, reduced recurrence, and elicited systemic anti-tumor immunity.

Conclusions:

• TITUR is a versatile platform for targeted mRNA delivery in oncology.
• This approach enhances immunotherapy efficacy and safety, offering a potential for personalized mRNA nanomedicines.
• TITUR demonstrates potential to overcome limitations of current immunotherapies.