Silver Nanoparticles in Oral Squamous Cell Carcinoma Therapy: A Systematic Review of Preclinical Evidence

Oral squamous cell carcinoma (OSCC) constitutes a significant global health challenge, particularly in low- and middle-income countries, where late-stage diagnoses and therapeutic resistance are prevalent. Conventional treatments, including surgery, chemotherapy, and radiotherapy, are constrained by substantial toxicity, disfigurement, and the emergence of drug resistance. This systematic review evaluates the therapeutic potential of silver nanoparticles (AgNPs) in oral cancer therapy by analyzing 42 preclinical studies published between 2013 and 2025. AgNPs demonstrate multifaceted anticancer activity through polypharmacological mechanisms such as reactive oxygen species (ROS) generation, mitochondrial disruption, DNA damage, and induction of apoptosis via both intrinsic and extrinsic pathways. Additional effects include anti-angiogenic, anti-metastatic, and immunomodulatory properties. AgNPs exhibit selective cytotoxicity toward cancer cells, which is enhanced by their nanoscale dimensions and targeted surface functionalization with ligands such as folic acid. Green synthesis methods provide cost-effective and biocompatible alternatives to conventional chemical synthesis, although issues with batch reproducibility and clinical scalability remain. While in vitro and in vivo studies indicate promising efficacy, concerns persist regarding long-term toxicity, bioaccumulation, and regulatory approval. To date, no AgNP-based formulations have advanced to clinical trials for OSCC. This review highlights critical knowledge gaps and outlines future research priorities to optimize AgNP synthesis, ensure safety, and facilitate clinical translation. AgNPs thus represent a promising multifunctional nanomedicine platform with the potential to advance oral cancer therapeutics through targeted, sustainable, and synergistic strategies.