Self-Assembled Peptide-Gold Nanoclusters with SiRNA Targeting Telomeric Response to Enhance Radiosensitivity in Lung Cancer Cells.

Lung cancer cells resistant to radiotherapy present a significant clinical challenge. Stable telomeric structures, maintained by the TRF2 protein, play a critical role in protecting cells from ionizing radiation. Reduced TRF2 expression increases DNA damage and radiosensitivity. We designed a self-assembling system utilizing ultra-small luminescent gold nanoclusters (AuNCs) with radiosensitizing properties, combined with siRNA targeting TRF2. The system forms ≈100  nm non-spherical structures with AuNCs enriched in the outer layer, exhibiting a 17.6-fold enhancement in red photoluminescence due to aggregation-induced effects. This nanoplatform efficiently penetrates lung cancer cells, reducing TRF2 expression by 50%. Under 5 Gy radiotherapy, cells treated with this system show a 1.5-fold radiosensitivity increase from AuNCs and a 2.3-fold reduction in clonogenic survival due to telomere deprotection. The AuNC-siRNATRF2 system combines enhanced optical properties with biological functionality, offering a promising approach to augment radiotherapy efficacy by disrupting telomeric protective mechanisms in cancer cells.