Edge Length-Programmed Single-Stranded RNA Origami for Predictive Innate Immune Activation and Therapy

Area of Science:

• Biotechnology
• Immunology
• Materials Science

Background:

• Nucleic acid-sensing receptors are crucial for innate immunity, antiviral, and antitumoral therapies.
• Current ligand design faces challenges in stability, targeted delivery, and predictable immunogenicity due to complex sensing mechanisms.

Purpose of the Study:

• To develop structurally designed single-stranded RNA (ssRNA) origami as ligands for nucleic acid sensors.
• To enhance biostability, achieve organelle-level targeting, and enable predictive immunogenicity for therapeutic applications.

Main Methods:

• Utilized ssRNA self-folding into compact, structurally defined nanoparticles (origami).
• Investigated ssRNA origami biostability against RNase digestion and endolysosomal retention in macrophages.
• Programmed ssRNA origami edge length to modulate macrophage activation via toll-like receptor pathways.

Main Results:

• ssRNA origami demonstrated enhanced biostability and prolonged retention in macrophage endolysosomes.
• ssRNA origami structure-based programming precisely regulated macrophage activation through toll-like receptors.
• ssRNA origami ligands induced anti-tumoral immune responses from macrophages and neutrophils, retarding tumor growth in a pancreatic tumor model.

Conclusions:

• ssRNA origami offers a novel strategy for designing nucleic acid sensor-based ligands with improved properties.
• This approach enables predictive immune activation for biomedical applications, including cancer therapy.
• Structured RNA ligands present a new solution for advancing nucleic acid sensor-based therapeutic development.