Overcoming Matrix Barriers for Enhanced Immune Infiltration Using siRNA-Coated Metal-Organic Frameworks.

The extracellular matrix (ECM) of solid tumor constitutes a formidable physical barrier that impedes immune cell infiltration, contributing to immunotherapy resistance. Breast cancer, particularly triple-negative breast cancer (TNBC), is characterized by a collagen-rich tumor microenvironment, which is associated with T cell exclusion and poor therapeutic outcomes. Discoidin domain receptor 2 (DDR2) and integrins, key ECM regulatory receptors on cancer cells, play pivotal role in maintaining this barrier. In this study, we developed a dual-receptor-targeted strategy using metal-organic frameworks (MOFs) to deliver DDR2-specific siRNA (siDDR2) and ITGAV-specific siRNA (siITGAV) to disrupt the ECM barrier. siDDR2 modulates immune infiltration by regulating collagen-cell interactions, while siITGAV suppresses TGF-β1 activation. The MOF@siDDR2+siITGAV complex significantly reduced collagen deposition, enhanced CD8+ T cell infiltration, and downregulated programmed cell death ligand 1 (PD-L1) expression in TNBC. Consequently, this approach markedly inhibited tumor growth. Our findings demonstrate that dual-receptor-targeted MOF-based nanocarriers (MOF@siDDR2+siITGAV) can effectively reprogram the tumor ECM to enhance immune cell access, offering a promising prospect for synergistic cancer immunotherapy. STATEMENT OF SIGNIFICANCE: : A dual-receptor-targeted MOF nanocarrier is developed to improve immune accessibility in tumors. Concurrent blockade of DDR2 and ITGAV effectively decreases collagen deposition, increases CD8+ T cell infiltration, and suppresses PD-L1 expression. Modulating the mechanical properties of the extracellular matrix (ECM) to enhance immune accessibility offers an innovative strategy for cancer treatment.