Compare the differences in gene expression of TAMs in mouse tumor tissues treated with AdV-Fe3O4@PACM and AdV-iCD47-Fe3O4@PACM.

Oncolytic adenoviruses (AdVs) represent a promising immunotherapeutic approach against cancer, yet their clinical translation is hindered by rapid systemic clearance, poor tumor accumulation, limited extravasation across the endothelial barrier, and an immunosuppressive tumor microenvironment. To overcome these challenges, we developed a biomimetic nanocomplex, AdV-iCD47-Fe₃O₄@PACM, consisting of an oncolytic adenovirus chemically conjugated with chemically modified CD47 siRNA and loaded with Fe₃O₄ nanoparticles, all encapsulated within a palmitoylated cancer cell membrane (PACM). Upon intravenous administration, the PACM coating enables immune evasion and prolonged circulation. Application of an external magnetic field promotes active tumor targeting via Fe₃O₄, while palmitic acid moieties transiently increase vascular permeability by downregulating tight junctions, facilitating nanocomplex extravasation into the tumor interstitium. Once inside tumor cells, the oncolytic AdV induces direct cytolysis, and the released chemically modified siRNA achieves sustained CD47 silencing, blocking the “don’t eat me” signal and enhancing macrophage-mediated phagocytosis. This dual mechanism—direct oncolysis combined with innate immune checkpoint blockade—elicits a robust antitumor immune response. Both in vitro and in vivo evaluations demonstrate that the AdV-iCD47-Fe₃O₄@PACM platform effectively overcomes key barriers of systemic delivery and immunosuppression, offering a promising strategy for enhanced cancer immunotherapy.