Therapeutic Potential of Silver Nanoparticles in Hepatocellular Carcinoma: From Pathogenesis to Clinical Perspectives.

Hepatocellular carcinoma (HCC) is one of the deadliest malignancies worldwide, characterised by late-stage diagnosis, high recurrence rates, and limited responsiveness to conventional therapeutic strategies. Despite advancements in surgical interventions, locoregional therapies, and targeted drugs, survival outcomes remain unsatisfactory due to systemic toxicity, drug resistance, and tumour heterogeneity. In this context, nanotechnology-based therapeutic approaches have attracted considerable interest, particularly silver nanoparticles (AgNPs), owing to their unique physicochemical properties and multifaceted biological activity. AgNPs demonstrate distinct anticancer effects in hepatic cancer models through mechanisms involving reactive oxygen species generation, mitochondrial dysfunction, DNA damage, cell cycle arrest, and activation of apoptosis-related signalling pathways. Additionally, advances in green and biogenic synthesis methods have improved the biocompatibility and safety profile of AgNPs, enhancing their suitability for biomedical applications. Tumour-targeting strategies, including passive accumulation via the enhanced permeability and retention effect and active ligand-mediated targeting, further improve therapeutic selectivity in HCC. The emerging evidence also highlights the potential of AgNP-based systems in combination therapies and stimuli-responsive platforms to overcome therapeutic resistance. However, despite their promising anticancer activity, AgNPs exhibit dose-dependent toxicity profiles characterised by hepatic accumulation, oxidative stress induction, mitochondrial dysfunction, inflammatory cytokine release, and potential off-target organ deposition, particularly in the liver, spleen, and kidneys. Silver ion (Ag⁺) release kinetics, particle size, surface chemistry, and repeated exposure significantly influence systemic toxicity. While short-term studies often report tolerable safety margins at therapeutic concentrations, concerns regarding chronic accumulation, redox imbalance, immunotoxicity, and long-term hepatic injury remain incompletely resolved. Therefore, comprehensive pharmacokinetic evaluation and standardised toxicological profiling are essential for safe clinical translation. In this review, silver nanoparticles represent a promising yet safety-dependent nanoplatform for hepatic cancer therapy, warranting further investigation to facilitate their integration into future HCC treatment paradigms.