Multifunctional RNA G‑Quadruplex Ligand for Integrated Photodynamic Therapy and Oncoprotein Translation Inhibition in Cancer Cells

Targeting
RNA G-quadruplexes (rG4s) with photosensitizers offers
a mechanistically distinct approach for cancer therapy by integrating
molecular targeting with photodynamic activity. Here, we report TO-ISe, a selenium-containing rG4-targeting photosensitizer
designed for combined photodynamic therapy and immunomodulation. TO-ISe binds rG4s with high affinity (Kd = 860 nM) and exhibits pronounced Type I photodynamic activity.
rG4 complex formation enhances radical generation, resulting in selective
phototoxicity toward cancer cells (IC50 = 0.16–0.27
μM) with substantially lower toxicity in nonmalignant cells
(IC50 = 5.9–7.8 μM). Under dark conditions, TO-ISe suppresses rG4-regulated oncogenes (c-MYC, NRAS and hTERT), leading to mitochondrial
dysfunction, ferroptosis, and apoptosis. Upon white-light irradiation
(22.1 mW·cm–2), TO-ISe further
potentiates antiproliferative efficacy and induces immunogenic cell
death via activation of the cGAS–STING pathway. In an orthotopic
4T1 tumor model, TO-ISe (0.5 mg kg–1) with irradiation achieved up to 72.8% tumor growth inhibition.
These results highlight TO-ISe as a dual-function rG4-targeting
photodynamic immunotherapeutic agent.