Inhibiting Senescence‐Associated Macrophage‐Epithelia Cell Communication via siPLAU Gene‐Patch for Colorectal Cancer Treatment

Abstract The interaction between immune cells, particularly macrophages, and tumor cells plays a pivotal role in cancer progression. Single‐cell RNA sequencing is conducted on 51 colorectal cancer (CRC) samples to identify senescence‐associated macrophages (SAMs) orchestrating tumor‐stroma crosstalk. Mechanistically, PLAU/PLAUR mediates bidirectional communication between SAMs and CRC cells by activating NF‐κB signaling through NFKBIA phosphorylation, thereby promoting CRC proliferation, metastasis, and heterogeneity. Multi‐color immunofluorescence staining validates the role of PLAU in regulating cellular senescence and immune infiltration. Finally, the study engineers the siPLAU gene‐patch based on Poly(amidoamine), modified with oxidized methacrylic acid‐modified hyaluronic acid and photo‐crosslinking. In vitro, the siPLAU gene‐patch significantly suppresses CRC progression by downregulating NF‐κB/EMT signaling. In vivo, the siPLAU gene‐patch effectively inhibits orthotopic tumor growth and lung metastasis while significantly enhancing the infiltration of CD4+/CD8+ T cells, IFN‐γ+ cytotoxic T cells, and M1 macrophages, thereby improving the efficacy of immunotherapy. This study highlights the substantial potential of impeding senescence‐associated targets for CRC therapy.