Introduction: Fusobacterium nucleatum, a Gram-negative anaerobic bacterium, has recently been recognized as a critical microbial factor in colorectal cancer (CRC) initiation and progression. It promotes tumorigenesis by sustaining chronic inflammation, altering immune responses, and modulating the expression of oncogenic microRNAs involved in cell proliferation, apoptosis, and migration. F. nucleatum has also been linked to epithelial-to-mesenchymal transition (EMT) and the development of chemoresistance, thereby worsening disease prognosis. Conventional CRC therapies such as surgery, chemotherapy, and radiotherapy, although beneficial, are often limited by systemic toxicity, resistance, and insufficient tumor specificity. Nanotechnology, and particularly gold nanoparticles (AuNPs), provides innovative opportunities to overcome these barriers. With biocompatibility, tunable surface chemistry, and capacity to transport nucleic acids, AuNPs are emerging as efficient carriers for small interfering RNAs (siRNAs) or anticancer drugs, enabling precise modulation of molecular pathways influenced by F. nucleatum.
Methods: AuNPs of approximately 20–40 nm were synthesized with citrate-based reduction and stabilized with polyethylene glycol (PEG) to enhance circulation and reduce aggregation. They were functionalized with siRNAs targeting oncogenic microRNAs implicated in CRC. Human colorectal cancer cell lines (HCT116 and SW480) were treated with AuNP–siRNA complexes. Cellular uptake was tracked using fluorescence microscopy, while effects on proliferation, apoptosis, and migration were evaluated through MTT assays, Annexin V staining, and wound healing assays. Gene expression changes were analyzed by quantitative PCR. For in vivo studies, mouse CRC models received intravenous injections of AuNP–siRNA complexes. Tumor growth was monitored, colonic inflammation was examined histologically, and the abundance of F. nucleatum in gut microbiota was measured by qPCR. Systemic safety was evaluated by monitoring body weight, behavior, and histological analysis of liver, kidney, and spleen.
Results: AuNPs efficiently delivered siRNAs into CRC cells, resulting in significant downregulation of oncogenic microRNAs and reactivation of tumor suppressor pathways. Treated cells showed reduced proliferation, increased apoptosis, and impaired migration compared to untreated and control groups. In vivo, mice receiving AuNP–siRNA complexes demonstrated reduced tumor volume, attenuated colonic inflammation, and lower F. nucleatum colonization in the gut. Importantly, systemic toxicity was minimal: animals maintained stable weight, normal behavior, and no histological abnormalities were detected in vital organs. These findings demonstrate that AuNP-based therapy can simultaneously counteract microbial-driven tumor promotion and abnormal host signaling at cellular and tissue levels.
Conclusion: Gold nanoparticles represent a versatile therapeutic platform for colorectal cancer influenced by Fusobacterium nucleatum. By enabling precise siRNA delivery, AuNPs effectively suppress oncogenic microRNAs, restore tumor suppressor activity, and reduce bacterial-associated inflammation. Their dual impact on tumor biology and microbial burden offers a significant advantage over conventional chemotherapy, which lacks such specificity. Furthermore, the low systemic toxicity observed suggests AuNPs may provide a safer alternative with improved efficacy. Integration of AuNP-based strategies with current CRC treatments could enhance clinical outcomes while minimizing adverse effects. Future research should focus on optimizing nanoparticle formulations, evaluating long-term safety, and exploring clinical translation to fully realize the potential of nanotechnology in microbiota-driven colorectal cancer.