Redox-responsive cisplatin-loaded cerium oxide nanozymes for oral squamous cell carcinoma: oxidative stress modulation, anti-inflammatory activity, and enhanced cytotoxicity

Oral squamous cell carcinoma (OSCC) is known to inadequate therapies outcomes due to low efficacy and inflammatory toxicity of conventional chemotherapy. Herein, this study was developed cisplatin-loaded cerium oxide nanozymes (Cis@CeO₂ NZs) as a multi-functional platform to improve the anticancer properties by modulating redox and regulating anti-inflammatory responses. Cerium oxide nanozymes were successfully synthesized using controlled precipitation method and it showed high efficiency in Cis loading (encapsulation efficiency ~ 68–75%, drug loading ~ 12–18%) with sustained release of the drug (~ 75–80% in 48 h). In vitro studies conducted on SCC-9 and CAL-27 cells revealed a significant improvement in the cytotoxic potential of Cis@CeO₂ NZs compared to Cis, with a ~ 1.8-2.0-fold decrease in IC₅₀ values. Cis@CeO₂ NZs caused substantial oxidative stress, as indicated by a 3.5-4.0-fold increase in intracellular ROS and a ~ 60–70% reduction in antioxidant enzymes (SOD, CAT, GSH). These changes led to substantial mitochondrial membrane potential depolarization (JC-1 red/green ratio decreased to ~ 0.31) and increased apoptosis, with ~ 65–75% apoptotic/necrotic cells observed by AO-EB staining and ~ 70% apoptotic nuclei detected by DAPI staining. Moreover, Cis@CeO₂ NZs caused significant inhibition of cancer cell migration, with a ~ 17–19% wound closure area compared to ~ 75–80% in control cells. Notably, Cis@CeO₂ NZs attenuated Cis induced inflammation and downregulating TNF-α, IL-6, and NF-κB expression by ~ 70–80% at the transcriptional level. Hence, these findings shed light on Cis@CeO₂ NZs delivery as a potent, mechanism-driven strategy for improving OSCC chemotherapy.