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.