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

ABSTRACT 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.