Innovative DNA tetrahedron inspired by ancient mortise-and-tenon technique offers new immunotherapy strategy for metastatic breast cancer.

Framework nucleic acids effectively meet the demands for precise size control and accurate targeting in the design of drug delivery systems, while developing a controllable drug delivery system with low immunogenicity and high efficiency for delivering nucleic acid drugs to the tumor immune microenvironment (TIME) remains significant challenge. Inspired by ancient Chinese mortise and tenon joint structures, this study develops an intelligent self-assembling DNA tetrahedron (TDN@siCSF-1R), which consists of a gapped DNA tetrahedron (TDN) and a therapeutic siRNA against Colony-Stimulating Factor-1 Receptor (siCSF-1R) that non-covalently bind with TDN via its gap, aiming to target tumor-associated macrophages (TAMs) and inhibit the CSF-1R pathway. Additionally, a CD206 mRNA-responsive sequence is introduced into the gapped TDN, triggering the site-specific release of siCSF-1R in M2-like TAMs, thereby achieving the precise targeting of CSF-1R in M2-like TAMs and reducing off-target effect. The mortise-and-tenon-like TDN@siCSF-1R synchronously combines the self-assembly flexibility and structural stability, significantly inhibiting 4T1 tumor growth, lung metastasis, and tumor recurrence after resection in vivo. Furthermore, it repolarizes M2-like TAMs and activates infiltrating T cells in TIME, thereby reshaping the immunosuppressive microenvironment, and offering a promising strategy for the clinical application of cancer immunotherapy.