Abstract C078: DNA Nanocarrier-mediated Co-Delivery of Cisplatin and Silibinin for enhanced treatment of Oral Squamous Cell Carcinoma

Abstract Background: Oral Squamous Cell Carcinoma (OSCC) is a major public health burden in Asia, primarily due to tobacco use, with a 5-year survival rate of ∼50%. This poor prognosis stems from minimal residual disease (MRD), driven by therapy-resistant cancer stem cells (CSCs) that survive treatment and promote recurrence. Effective MRD targeting demands precise delivery systems to overcome resistance. DNA tetrahedrons (TDNs), due to their biocompatibility, stability, and programmability, offer a promising platform for drug delivery. This study presents a TDN-based nanocarrier co-delivering cisplatin and silibinin (TDN-Cis-Sil) to address OSCC therapy. Methods: TDNs encapsulating cisplatin and silibinin were synthesized and characterized by FTIR, native PAGE, nanoparticle tracking analysis (NTA), UV–Vis spectroscopy, and atomic force microscopy (AFM). Drug loading efficiency, release kinetics, and in vitro stability were evaluated. Cellular uptake was assessed in OECM1 OSCC cells, followed by functional assays examining cell proliferation, apoptosis, mitochondrial membrane potential (ΔΨm), cell cycle progression, migration, invasion, and reactive oxygen species (ROS) generation. Therapeutic efficacy was validated in a xenograft mouse model. Results: TDN-Cis-Sil exhibited loading efficiencies of 71.5% (cisplatin) and 76% (silibinin), with stability up to 10 hours and sustained drug release over 24 hours. Internalization by OECM1 cells was evident within 3 hours. The dual-loaded nanocarrier showed significantly lower IC50 (50 nM) compared to cisplatin (200 nM) and silibinin (1500 nM) alone. Cell cycle analysis indicated G2/M arrest, consistent with late apoptosis. Annexin V/PI staining confirmed 40% apoptotic cells. Invasion potential was reduced twofold (p < 0.05), and JC-1 staining revealed a notable decline in mitochondrial membrane potential (red/green ratio ∼0.5). ROS levels were markedly elevated in the TDN-Cis-Sil group compared to single-agent treatments. In vivo, the nanocarrier significantly regressed tumour growth in xenograft models, demonstrating the synergistic effect of co-delivery. Conclusion: This study establishes a DNA tetrahedron-based nanoplatform for co-delivering silibinin and cisplatin in OSCC. By targeting therapy-resistant and bulk tumour populations simultaneously, the TDN-Cis-Sil system induces apoptosis, inhibits invasiveness, and elevates ROS, resulting in pronounced tumour regression. These findings support the potential of programmable DNA nanocarriers as next-generation therapeutics for treatment-resistant and recurrent oral cancers. Citation Format: Kanisha Shah, Shreya Lotia, Vaishnavi Patel, Aditi Patel, Shanaya Patel, Payal Vaswani, Dhiraj Bhatia, Vivek Tanavde. DNA Nanocarrier-mediated Co-Delivery of Cisplatin and Silibinin for enhanced treatment of Oral Squamous Cell Carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C078.