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To investigate the efficacy of Ag2Se nanoparticles for eliminating intracellular Porphyromonas gingivalis (P. gingivalis) in esophageal cancer and examine the effect of P. gingivalis clearance on progression of esophageal cancer. Ag2Se nanoparticles were synthesized via a chemical synthesis method. The effects of Ag2Se nanoparticles on P. gingivalis viability and colony-forming ability were assessed using fluorescence staining and colony formation assays. In a mouse model bearing subcutaneous murine esophageal cancer cell allograft with P. gingivalis infection, the effect of treatment with Ag2Se nanoparticles on the abundance of P. gingivalis in the tumor tissues was quantified using RNAscope in situ hybridization and quantitative polymerase chain reaction (qPCR), and the changes in tumor volume were monitored. The biosafety of Ag2Se nanoparticles was assessed by examining liver and kidney functions and pathological changes in the major organs of the mice. Transmission electron microscopy revealed that the synthesized Ag2Se nanoparticles were uniformly dispersed spherical particles with a diameter around 50 nm. In vitro experiments demonstrated that exposure to Ag2Se nanoparticles significantly reduced the viability and clonal proliferation capacity of P. gingivalis in a dose-dependent manner. In the tumor-bearing mice, treatment with Ag2Se nanoparticles significantly reduced the abundance of P. gingivalis in tumor tissues and suppressed tumor cell proliferation. No significant damages to the liver and kidney functions or the major organs were observed in Ag2Se nanoparticle-treated mice, demonstrating good biocompatibility of Ag2Se nanoparticles. Ag2Se nanoparticles exhibit significant bactericidal and inhibitory effects against P. gingivalis, and can effectively eliminate intracellular P. gingivalis to suppress the growth of esophageal cancer allograft in mice, suggesting the potential of Ag2Se nanoparticles in the treatment of esophageal cancer.