Palladium Hydride Nanopocket Cubes and Their H₂‐Therapy Function in Amplifying Inhibition of Foam Cells to Attenuate Atherosclerosis

Abstract Foam cells formed by the imbalance between lipid uptake and efflux play a dominant role at all stages of atherosclerotic development. Lipid‐regulation by active agents can reduce atherosclerotic lesions, however only limited therapeutic efficacy has been achieved because of the low solubility. Herein, a “coupling hardness with softness” strategy is developed, for the first time, by using palladium hydride nanopocket cubes to regulate lipid uptake and efflux. The prepared palladium hydride nanopocket cubes have a molar ratio of H to Pd at 0.12: 1, thus denoted as PdH_0.12 NPCs. The palladium nanopocket cubes play the hardness role in efficiently scavenging reactive oxygen species (ROS) via their innate antioxidant enzyme activities. The hydrogen released from PdH_0.12 NPCs, controlled by near‐infrared‐II, upregulate peroxisome proliferator‑activated receptor gamma‐mediated cholesterol transport, which plays the softness role. Consequently, ROS scavenging reduces lipid uptake and promoted cholesterol transport increases lipid efflux, resulting in the amplified‐inhibition of foam cells. In vitro and in vivo tests show that PdH_0.12 NPCs significantly reduce lipid storage and plaque formation in Western diet‐fed apolipoprotein E‐deficient mice without obvious long‐term toxicity. The “coupling hardness with softness” strategy shows promising to be further developed as a high efficacy and low toxicity method to treat atherosclerosis.