Dual Graphene Oxide–Based Multigene Delivery for Cancer Elimination via Stromal and Immune Reprogramming

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Cancer therapies are often limited by poor cellular specificity and tumor microenvironment‐mediated immunosuppression. We developed a dual‐function graphene oxide (GO)–based gene delivery platform combining direct cancer cell elimination with stromal and immune reprogramming. CD47‐targeting siRNA and ANT1‐encoding plasmid DNA selectively induced apoptosis in tumor cells, while TGFβ‐targeting siRNA altered cancer‐associated fibroblasts (CAFs) phenotype and was associated with a shift in macrophage polarization toward a pro‐inflammatory, tumor‐restraining phenotype. We evaluated this approach in a 3D multicellular lung cancer model consisting of A549 cells, human lung fibroblasts, and THP1‐derived macrophages. TGFβ silencing alone modulated stromal and immune features without direct cytotoxicity, whereas CD47/ANT1 modulation reduced overall cell viability to ∼51%. When both therapeutic functions were applied together, overall cell viability was further reduced to ∼29%. EGFR‐targeted GO‐CD47‐ANT1 (GE11‐peptide modified formulation) enhanced tumor‐cell uptake and selective apoptosis in CK7 + cancer cells to 91%, while sparing CK7 − nonmalignant populations (16%). Mechanistically, combined therapy suppressed immunosuppressive macrophage markers (CD163, IL10, TGFβ), restored epithelial integrity (E‐cadherin 3.5‐fold), and attenuated CAF activation (αSMA 0.3‐fold; vimentin 0.6‐fold). GE11 peptide functionalization shifted nanocarrier internalization toward EGFR‐mediated cancer cell uptake, minimizing off‐target delivery to fibroblasts and macrophages. These findings demonstrate that synergistic modulation of cancer cells and the tumor microenvironment is essential for robust and selective tumor elimination. Our study establishes a modular, mechanism‐informed GO platform integrating dual therapeutic functions—targeted cancer cell killing and microenvironmental reprogramming—highlighting its translational potential in physiologically relevant tumor models.

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