Programmable nucleic acid origami nanostructures for immunotherapy

Immunotherapy has emerged as a pivotal strategy for restoring immune balance in diseased tissues, harnessing the immune system to eliminate malignant cells and suppress aberrant inflammatory responses at lesional sites while sparing healthy adjacent tissues. Programmable nucleic acid origami nanostructures can be precisely modified with diverse biomolecules at designated sites, making them superior delivery carriers for immune modulation. This review highlights the transformative therapeutic potential of nucleic acid origami nanostructures in the immunotherapy of cancer, inflammatory, and autoimmune diseases through regulation of both innate and adaptive immune pathways. Particular attention is given to their applications in antigen/adjuvant co-delivery for vaccine design, cytokine delivery, adoptive cell therapies, and combination immunotherapies. We further summarize current biomedical applications and clinical translation efforts, critically evaluating both opportunities and limitations. Overall, this review underscores the promise of nucleic acid origami nanostructures to redefine personalized immunotherapy and provides perspectives for future research directions. • Precision Immunomodulation: Nucleic acid origami nanostructures offer unparalleled spatial control for the precise delivery and presentation of immunotherapeutic agents, enabling targeted immune activation or suppression while sparing healthy tissues. • Multifunctional Therapeutic Platforms: Nucleic acid origami nanostructures function not merely as passive carriers but as active scaffolds that can directly engage and modulate innate and adaptive immune pathways. • Broad Application Potential: The nucleic acid origami technology holds transformative promise for treating a wide range of conditions, including cancer, inflammatory, and autoimmune diseases, through applications in vaccine design, adoptive cell therapy, and chemo-combination immunotherapies.