Design, Synthesis, and Biological Evaluation of BODIPY-Caged Resiquimod as a Dual-Acting Phototherapeutic

Resiquimod, an imidazoquinoline scaffold, exhibits potent immunotherapeutic activity but is associated with off-target effects, limiting its clinical utility. To address this limitation, we developed a novel BODIPY-caged resiquimod that is responsive to red light, combining photocaging and photodynamic therapy functionalities. Molecular docking studies guided identification of the optimal caging site for resiquimod, effectively masking its immune activity. BODIPY-caged resiquimod remained inactive under dark conditions, effectively masking resiquimod's immunostimulatory effects. However, red light irradiation precisely uncaged resiquimod, inducing robust immune activation, even in the presence of N-acetyl cysteine as an antioxidant. Notably, the attachment of resiquimod to BODIPY reduced the dark toxicity typically associated with BODIPY as a photosensitizer. In 3D spheroid models of HeLa and A549 cells, BODIPY-caged resiquimod demonstrated spatiotemporal control over cytotoxicity, significantly enhancing cell death only upon irradiation. This dual-function therapeutic approach highlights a "win-win" strategy: precise, red-light-mediated control of immune activation and photodynamic efficacy with reduced collateral toxicity.