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

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.