Engineering DNA Origami Captors for TGFβ1 Sequestration to Enhance Tumor Immune Modulation and Therapy.

Abstract

Efficient modulation of pivotal immune-regulatory molecules to leverage the tumor microenvironment (TME) and enhance therapeutic effects remains an ideal yet challenging goal. TGFβ1 represents a critical therapeutic target as a key cytokine involved in immune suppression and tumor progression. Here, a DNA origami-based framework functionalized with anti-TGFβ1 aptamers is developed to act as a captor for efficient TGFβ1 sequestration and fast clearance, thereby improving anti-tumor immunity. By engineering the geometric shapes and pore sizes of three DNA framework captors (DFCs), the superior efficacy of a barrel-shaped captor (DBC) in regulating TGFβ1 levels is demonstrated. In cell culture, DBCs significantly enhance T cell-mediated tumor cytotoxicity, while systemic administration effectively inhibits tumor growth in the mouse model. Moreover, DBCs demonstrate a synergistic effect with PD-L1 antibody to enhance anti-tumor efficacy. Immunohistochemistry (IHC) further confirmes the DBC-mediated reduction of TGFβ in tumor tissue and its biodistribution fate. These findings underscore the importance of cytokine regulation in cancer immunotherapy and provide valuable insights for the rational design and application of structural DNA nano-devices as a transformative tool for precise immunomodulation.