Optoregulated mRNA Delivery Controls Pleiotropic Immune Signaling for Tumor-Targeted Therapy

Area of Science:

• Biotechnology
• Therapeutics
• Molecular Biology

Background:

• Spatiotemporal control of protein expression is crucial for mRNA therapeutics, especially in tumor-targeted treatments.
• Current methods face challenges in achieving precise delivery and localized activation of mRNA therapies.

Purpose of the Study:

• To introduce a Light-Induced Transfection System (LITS) for spatiotemporal control of mRNA translation.
• To demonstrate LITS's capability for localized protein expression and modulation of therapeutic effects in targeted tissues.

Main Methods:

• Developed LITS using photosensitizing polymers for systemic mRNA delivery.
• Activated mRNA translation via light-triggered endosomal escape in irradiated tissues.
• Utilized interleukin-2 (IL-2) as a model therapeutic to assess LITS efficacy.

Main Results:

• LITS enabled localized protein expression in irradiated tumors, triggering proinflammatory cytokine levels.
• Nonirradiated healthy tissues showed tolerogenic IL-2 levels, reducing systemic toxicity.
• LITS synergized IL-2 efficacy, driving immunogenic cell death and eradicating lung metastasis in a breast cancer model.

Conclusions:

• LITS provides a programmable platform for on-demand, targeted mRNA therapies.
• The system offers precise spatial control over protein expression, enhancing therapeutic efficacy.
• LITS demonstrates potential for safe and effective cancer treatment by modulating IL-2's effects.