Optoregulated mRNA Delivery Controls Pleiotropic Immune Signaling for Tumor‐Targeted Therapy

Chen, Pengwen and Hu, Guanghao and Nakashima, Yuki and Xu, Zhining and Watanabe, Takayoshi and Kondo, Soichiro and Kovács, Ervin and Cabral, Horacio (2025) Optoregulated mRNA Delivery Controls Pleiotropic Immune Signaling for Tumor‐Targeted Therapy. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION. ISSN 1433-7851 (In Press)

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Abstract

Spatiotemporal control of protein expression remains a critical challenge in messenger RNA (mRNA) therapeutics, particularly for tumor‐targeted therapy. Here, we introduce a Light‐Induced Transfection System (LITS) leveraging photosensitizing polymers to deliver mRNA systemically and activate its translation via light‐triggered endosomal escape. This system enables localized protein expression in any irradiated tissue, allowing for spatial control of therapeutic effects. Using interleukin‐2 (IL‐2) as a model, we demonstrate that LITS can trigger proinflammatory cytokine levels in irradiated tumors, while inducing tolerogenic IL‐2 levels in nonirradiated healthy tissues. This modulation of IL‐2′s pleiotropic effects provides both potent antitumor activity and reduced toxicity. Furthermore, by optimizing light exposure, LITS synergizes IL‐2 efficacy by driving immunogenic cell death to eradicate lung metastasis in a breast cancer model. Our findings establish LITS as a programmable mRNA delivery platform for on‐demand targeted and safe therapies.

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