Toward Nano-Nutritional Medicine: A Remotely Activated Trans-Vaccenic Acid-Based Lipid Nanoparticles for Enhancing Immune Checkpoint Blockade Therapy.

Using nutrients to modulate anti-tumor immunity offers clear advantages over developing new immunotherapy drugs, yet its clinical translation is hampered by low oral delivery efficiency. Herein, we propose concept of nano-nutritional medicine (NNM), encapsulating IR780 in lipid nanoparticles (IR780@TVA LNPs) containing a eutectic mixture of trans-vaccenic acid (TVA) and stearic acid. Eutectic mixture (melting point: 40.5°C) functions as gated phase-change material, triggered by near-infrared light to release TVA. Compared to oral free TVA, IR780@TVA LNPs increase intratumoral TVA concentration by 21.86-fold. IR780@TVA LNPs demonstrate excellent photothermal ablation and induce adaptive immunity. Subsequently, the released TVA not only reduces CD8+ T cell exhaustion by activating cAMP-PKA-CREB axis, but downregulates PD-1 levels in T cells and upregulates PD-L1 levels in tumor cells, thereby potentiating PD-L1 blockade therapy in both "hot" and "cold" tumor models, achieving complete responses in some instances. These cured mice establish long-term immune memory, enabling them to resist tumor rechallenge. Furthermore, IR780@TVA LNPs suppress advanced large tumors and prevent lung metastasis, demonstrating superior efficacy compared to first-line therapy (radiotherapy + PD-L1 blockade). Overall, this work establishes first platform for targeted delivery and on-demand release of dietary immunonutrients, paving the way for NNM as a new direction in cancer immunotherapy.