Abstract

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.

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