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Hydrogen Gas from Inflammation Treatment to Cancer Therapy Ying Wu,† Meng Yuan,† Jibin Song,*,† Xiaoyuan Chen,*,‡ and Huanghao Yang*,† †

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MOE Key Laboratory for Analytical Science of Food Safety and Biology, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350116, P.R. China ‡ Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) Bethesda, Maryland 20892, United States ABSTRACT: Hydrogen (H2) therapy is a highly promising strategy against several diseases due to its inherent biosafety. However, the current H2 treatment modalities rely predominantly on the systemic administration of the gas, resulting in poor targeting and utilization. Furthermore, although H2 has significant anti-tumor effects, the underlying mechanisms have not yet been elucidated. Due to their ultrasmall size, nanomaterials are highly suitable drug-delivery systems with a myriad of biomedical applications. Nanocarrier-mediated H2 delivery, as well as in situ production of H2 by nanogenerators, can significantly improve targeted accumulation of the gas and accelerate the therapeutic effects. In addition, nanomaterials can be further modified to enhance passive or active accumulation at the target site. In this Perspective, we summarize the mechanism of H2 therapy and describe possibilities for combining H2 therapy with nanomaterials. We also discuss the current challenges of H2 therapy and provide some insights into this burgeoning field. H2.8 The most common routes of H2 therapy include inhalation of hydrogen-containing air (HCA),9,10 oral intake of hydrogen-rich water (HRW),11 and injection of a hydrogenrich physiological solution (HRS),12 each of which are suitable for specific applications. For example, HCA inhalation is more effective in relieving acute oxidative stress conditions such as systemic inflammatory response syndrome, whereas drinking HRW increases the concentration of H2 in the atria by 10-fold compared to that in the arteries.13 However, it is not possible to control gas delivery to the diseased areas accurately with macroscopic administration. Theoretically, if H2 production could be controlled at the disease site for sustained and powerful release, the treatment efficacy would be greatly improved. In this Perspective, we discuss the therapeutic utility of H2 and its possible mechanisms, primarily focusing on the possibility of using targeted H2 delivery through nanocarriers for cancer treatment (Figure 1).

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ince the treatment of cardiovascular disease with nitric oxide was acknowledged with the Nobel Prize in Physiology or Medicine in 1998, gas therapy has gained increasing attention in the scientific community. By tightly regulating their concentrations, macroscopically toxic gases such as NO,1,2 CO,3 SO2,4 H2,5 etc. can be harnessed into powerful weapons to kill malignant cells. Some of these gases are present as trace elements in the human body and act as messenger molecules in various signaling pathways. In addition, their byproducts have few side effects, making gas therapy a safe and effective option for clinical applications. Hydrogen gas (H2) can penetrate bacterial biofilms, easily diffuse into the nucleus and mitochondria, and even penetrate the blood−brain barrier. Hydrogen has long been regarded as a relatively unreactive gas that does not affect metabolic redox reactions or reactive oxygen species (ROS). However, recent studies have found that H2 can interact with and scavenge free radicals such as hydroxyl (•OH) and peroxynitrite (ONOO−) anions.6 Furthermore, H2 concentration in tissues can be monitored in real time through electrodes, with its byproduct being harmless water. These features make H2 a promising therapeutic gas that can be developed for diverse clinical applications. The first therapeutic use of H2 was reported in 1975 by Dole et al., who found that high-pressure application of the gas in tumor-bearing hairless albino mice caused the squamous cell carcinoma growth to subside.7 Since then, numerous studies in animal models and clinical trials have reported antioxidant, anti-inflammatory, anti-apoptotic, and anti-tumor functions of © XXXX American Chemical Society

OPTIMUM CONCENTRATION AND ROUTE OF HYDROGEN ADMINISTRATION The H2 concentration in inhaled HCA presently does not exceed 4%. Because the solubility of H2 in water is constant at a certain temperature and pressure, a limited amount of the gas can be injected into the body per unit time via HRW or HRS. Low H2 concentrations have shown therapeutic effects against local inflammation of the eye,14 ear,15 nose,16 and liver17 as well as a treatment for pancreatitis,18 systemic inflammatory

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Figure 1. Schematic showing H2 carriers and generators, the therapeutic utility of H2, and its possible mechanisms. 2D: Two-dimensional; ROS: Reactive oxygen species.

Therefore, it is possible that the •OH and •H radicals react to form water (eq 3):

We discuss the therapeutic utility of H2 and its possible mechanisms, primarily focusing on the possibility of using targeted H2 delivery through nanocarriers for cancer treatment.

•OH + •H → H 2O

Although this partly explains the oxidation resistance of H2, the mechanistic basis of its other effects is still unknown. Because H2 also acts as a messenger in certain signaling pathways,21 it is possible that it activates apoptosis in cancer cells. We discuss some of the possible mechanisms of H2 action in the following sections.

syndrome,13 sepsis,19 and neurodegenerative diseases.20 Dole et al. showed in 1975 that high concentrations of H2 can inhibit the growth of tumors. A high concentration of H2 at the site of the lesion can be achieved by either targeted delivery of the gas via a carrier or continuous generation at the site through a biochemical generator. In recent years, researchers have used nanomaterials to construct H2 carriers and generators, which have the advantages of in vivo cycling, passive targeting, and biocompatibility.

ANTIOXIDANT MECHANISM OF HYDROGEN THERAPY Although the antioxidant effects of H2 were initially attributed to the selective removal of •OH and ONOO− as already discussed,6 recent studies show that H2 activates endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) and reduces the concentration of various oxidative stress markers such as myeloperoxidase, malondialdehyde, 8-isoprostaglandin F2a, and thiobarbituric acid in a dose-dependent manner in numerous human diseases and rodent models.12,22 It also participates in the p38 mitogenactivated protein kinase, extracellular signal-regulated protein kinase (ERK)1/2,18 nuclear factor kappa B (NF-κB),13 JNK,23 and nuclear factor-erythroid 2p45-related factor 2 (Nrf2) pathways24 and inhibits nuclear translocation of phospho-ERK, phospho-JNK, and phospho-p38. In addition, H2 also regulates transcription of certain genes via the Ca2+ signal transduction pathway by modulating free radical-dependent generation of oxidized phospholipids to mitigate oxidative stress damage.25,26

MECHANISMS OF HYDROGEN THERAPY The specific mechanism of the therapeutic action of H2 is largely ambiguous. Ohsawa et al. reported that H2 exerts its antioxidant effects by selectively reducing hydroxyl radicals (•OH) and peroxynitrite anion (ONOO−).6 Dole et al. hypothesized that it scavenges free radicals through an exothermic reaction (eq 1), following which the •H radicals scavenge the O−2 radicals (eq 2).7 This possibility, however, contradicts the surmise that H2 selectively removes the malignant free radicals. H 2 + •OH → H 2O + •H

•H +

O−2

→

HO−2

(ΔE ∼ 12kcal/mol)

(3)

(1) (2) B

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Figure 2. (a) Schematic illustration of the synthesis and near-infrared-controlled release of H2 and heat generation from PdH0.2 nanocrystals. H2 release in (b) stimulated body fluid and in (c) HeLa cells, detected using methylene blue (MB) as the oxidative probe for active H2 (*P < 0.05). Reprinted with permission from ref 32. Copyright 2018 Nature. (d) Schematic demonstration of the long-term elimination of •OH released from diseased cells into body fluids. Reprinted with permission from ref 34. Copyright 2019 Wiley-VCH. (e) The composition of a photodriven nanoreactor and the mechanism of in situ abatement of LPS-induced oxidative stress in mouse paws. (f) In vivo images and (g) the corresponding L-012 luminescence intensities of reactive oxygen species in the induced inflamed paws following treatment with BS and NR without/with laser irradiation. (h) Levels of IL-6 and IL-1β in the inflamed paws following various treatments without/with laser irradiation. *P < 0.05. Reprinted from ref 36. Copyright 2017 American Chemical Society.

ANTI-INFLAMMATORY MECHANISMS OF HYDROGEN THERAPY

ANTI-NEOPLASTIC MECHANISMS OF HYDROGEN THERAPY

H2 can inhibit inflammatory tissue damage caused by oxidative stress by down-regulating pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), other inflammation mediators such as macrophage chemoattractant protein 111 and intercellular cell adhesion molecules, and pro-inflammatory transcription factors such as high-mobility group box 1 (HMGB-1), NF-κB, and prostaglandin E2.12,27 Chen et al. found that H2 protected mice from chronic pancreatitis by restoring the loss of regulatory T cells.28 Furthermore, H2 can be regulated by Toll-like receptor 4 (TLR4)-mediated signaling to exert anti-inflammatory effects.29,30

Several studies published in recent years have shown an inhibitory effect of H2 on tumor growth.7,31 Runtuwene et al. injected hydrogen-rich water and 5-fluorouracil to colontumor-bearing mice and found that H2 enhanced apoptosis of cancer cells via the AMPK pathway, with a significant increase seen in the expression of p-AMPK, AIF, and caspase 3.31 Based on the known antioxidant and anti-inflammatory effects of H2, it can be surmised that H2 inhibits tumor growth by destroying the redox status of the tumor microenvironment, activating the caspase-independent apoptosis pathway, and reducing lipid oxidation. Further studies are needed to explore the anti-tumor effects of H2. C

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HYDROGEN THERAPY AGAINST CANCER AND OTHER DISEASES The therapeutic effects of low doses of H2 have been documented in both animal models and clinical trials. However, ingestion/inhalation of H2 is technically complicated, time-consuming, and inefficient. Therefore, it is necessary to design strategies for targeted H2 delivery and precision treatment. The ultrasmall size of nanoparticles enables passive targeting, and they are also highly amenable to modification for active targeting, making them ideal drugdelivery systems. There are two strategies of using nanomaterials in H2 therapy, as carriers and as generators, and the combination of nanomaterials and H2 therapy is highly promising.

could be regulated by controlling the thickness of the mesoporous silicon dioxide layer, and the H2 microdrug protected the cells from oxidative stress by scavenging the hydroxyl radicals (Figure 2d).34 In both studies, however, a therapeutically relevant amount of H2 was only produced with excessive amounts of the materials. This requirement limits in vivo applications, especially against deep-seated tumors, as well as targeted release. The limitations can be obviated by using nanoscale materials with larger surface areas, such as boron nitride, graphene, and other two-dimensional materials, which not only increase the loading rate of H2 at smaller amounts but also accumulate passively at the tumor site through the enhanced permeability and retention (EPR) effect. In addition, porous three-dimensional nanomaterials, such as mesoporous silica, fullerene, metal−organic frameworks, covalent−organic frameworks, etc., can be used to design nanocarriers that release H2 in response to exogenous or endogenous stimuli at the target site. External stimuli include light, ultrasound, magnetic fields, etc. A magnetic field can accurately steer the nanomaterial to the target site. In contrast, although ultrasound is difficult to focus, it is non-invasive, and thus, ultrasonic imaging-guided H2 therapy offers significant advantages. Light not only can be used to release H2 but also can produce the gas via photocatalytic hydrolysis. In addition, light irradiation enables synergistic H2 and photothermal therapy.35 Based on natural photosynthesis, Wan et al. synthesized a nanoreactor consisting of chlorophyll a, Lascorbic acid, and gold nanoparticles encapsulated in a liposome (LIP) system (Figure 2e),36 which produced high levels of H2 via simulated photosynthesis and increased its local concentration to therapeutic levels. In addition, the LIP NIR system reduced oxidative stress both in vitro and in vivo (Figure 2f,g) and reduced the excessive production of proinflammatory cytokines such as IL-6 and IL-1β (Figure 2h). Zhang et al. constructed a photodriven nanofactory containing the reactants, intermediates, and byproducts by covalently loading liposomes with semiconducting polymer dots (Pdots) as catalysts (Figure 3a).37 H2 was produced continuously in situ under laser irradiation, which then penetrated the liposome bilayer and effectively lowered LPS-induced inflammation both in vitro (Figure 3b) and in vivo (Figure 3c).

SYNERGISTIC EFFECT OF HYDROGEN THERAPY H2 therapy can be synergized with cancer treatments such as surgical resection, chemotherapy, and radiation therapy, which often lead to systemic inflammation, in order to restore tissue function.10 Zhao et al. developed PdH0.2 nanocrystals with strong near-infrared (NIR) absorption, which generated heat by photothermal therapy (PTT) to release bioreductive H2 controllably for tumor-targeted delivery and hyperthermia (Figure 2a).32 Alone, PTT results in cell necrosis, which leads to inflammation that can stimulate tumor regeneration and hinder any follow-up treatment. As shown in Figure 2b,c, PdH0.2 markedly enhanced hydrogen release under NIR irradiation both in simulated body fluids and in HeLa cells. He et al. designed a hydrogenated Pd hydride−metal−organic framework (PdH-MOF) with high therapeutic H2 loading capacity, good biocompatibility, high photothermal effect, and excellent photoacoustic imaging (PAI) performance, which enabled PAI-guided hydrothermal therapy.33 In both of the above-mentioned two studies, hydrogen inhibited the inflammatory response caused by PTT in the tumor tissues and aided local tissue regeneration. Furthermore, the synergistic effect of hydrogen and PTT reduced the required intensity of the latter. The authors hypothesized that the effects of H2 on intratumoral levels of ROS and tumor metabolism were the cause of the therapeutic outcomes. Although the exact mechanism remains to be elucidated, the synergistic effect of H2 with conventional therapeutic modalities is highly promising for tumor treatment.

Nanomaterials can be used to design nanocarriers and hydrogen generators that release or produce H2 in response to exogenous or endogenous stimuli at the target site.

The synergistic effect of H2 with conventional therapeutic modalities is highly promising for tumor treatment.

The tumor microenvironment is characterized by low pH, high enzyme expression, and redox abnormalities caused by the Warburg effect, which can be exploited as endogenous stimuli for targeted H2 release. For instance, Yang et al. constructed mesoporous silica carriers that selectively released H2 at the acidic tumor site, which also reduced the toxicity of ammonia borane (Figure 3d).38 Because nanomaterials can passively accumulate at tumor sites via the EPR effect and the high specific surface area of mesoporous silica greatly increased H2 loading, these nanocarriers effectively inhibited tumor growth and increased survival of the tumor-bearing mice (Figure 3e,f). The authors attributed the anti-tumor effects to sustained H2 release in the tumor, which reduced the high levels of ROS in

HYDROGEN THERAPY USING NANOMATERIAL CARRIERS The amount of H2 released per unit volume is a major factor affecting the efficacy of H2 therapy. He et al. designed an ultrasound-visible H2 delivery system by loading H2 inside microbubbles,5 which not only improved its effective solubility and the therapeutic effect against myocardial ischemiareperfusion injury but also enabled real-time ultrasound imaging of gas release. Kong et al. constructed Mg@p-SiO2 nanoparticles with a core−shell structure that produced H2 via the reaction of Mg with water. The rate of H2 production D

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Figure 3. (a) Schematic illustration of a liposomal nanofactory in situ photocatalytic H2 generation. (b) Confocal laser scanning microscopy images of lipopolysaccharide (LPS)-induced reactive oxygen species production in vitro (I, without LPS stimulation; II, liposomal nanoreactor-treated; III, laser irradiated; IV, liposomal nanoreactor + laser irradiation. Pdots: polymer dots. Scale bar = 50 μm). (c) Biooptical images of LPS-induced inflamed paws after the different treatments: I (left, LPS-induced; right, healthy), II (left, liposomal nanoreactor; right, laser irradiation), and III (left, without laser irradiation; right, with laser irradiation). Reprinted with permission from ref 37. Copyright 2019 Wiley-VCH. (d) Schematic illustration of the nanostructure of AB@MSN and the mechanism of acid-responsive decomposition and H2 release. (e) Tumor volume variation in the different groups. (f) Average tumor weight after treatment. Reprinted with permission from ref 38. Copyright 2018 Elsevier.

tion of H2 and X-ray therapy is highly promising, wherein H2 is not only the primary treatment agent but also a protective gas.

cancer cells. Although there have been reports that H2 can inhibit the growth of tumors, relatively few studies have focused on combinations of H2 and nanomaterials.

CONCLUSIONS AND OUTLOOK Although the past decade has witnessed rapid development in H2 therapy with several successful clinical trials, there remain many challenges regarding its efficacy and methods. Direct application of high concentrations of H2 has proven to be a feasible anticancer therapeutic strategy, although the complex mechanisms underlying the effects of H2 on tumor cells remain to be elucidated. H2 delivery via nanocarriers/generators has several advantages: (1) nanomaterials can achieve targeted and sustained release of H2 at the tumor site; (2) nanocarriers can be modified to increase their biocompatibility and half-life in circulation as well as target cell specificity, which further enhances passive or active targeted accumulation of H2 for optimum therapeutic outcome and minimum side effects;41 and (3) ultrasound-responsive materials can enable ultrasonic imaging to monitor H2 release and distribution in real time. Thus, nanomaterials can increase not only H2 loading but also its utilization and generation in vivo. Combining H2 therapy with other treatments has shown synergistic effects. For

HYDROGEN THERAPY AND HYDROGEN NANOGENERATORS Although several nanomaterials can be suitable H2 generators and display high H2 storage efficiency, biocompatibility and in vivo stability are essential criteria for therapeutic applications. H2 production can be achieved by nanoreactors through: (1) enzymatic catalysis, (2) chemical reactions, for example, active Mg and water, Zn and acid reactions, etc., (3) photocatalysis, and 4) in response to the tumor microenvironment. The noninvasiveness of light has prompted the development of new photocatalytic nanomaterials for H2 therapy. However, the penetration depth of light is insufficient for in vivo therapy, and photocatalysis in the NIR and second-infrared regions may obviate this limitation.39,40 Due to their high energy and penetration power, X-rays can be a suitable stimulus for H2 generation. Furthermore, reducing hydroxyl radicals can protect cells from radiation damage. Therefore, the combinaE

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(7) Dole, M.; Wilson, F. R.; Fife, W. P. Hyperbaric Hydrogen Therapy: A Possible Treatment for Cancer. Science 1975, 190, 152− 154. (8) Ichihara, M.; Sobue, S.; Ito, M.; Ito, M.; Hirayama, M.; Ohno, K. Beneficial Biological Effects and the Underlying Mechanisms of Molecular Hydrogen - Comprehensive Review of 321 Original Articles. Med. Gas Res. 2015, 5, 12. (9) Kurioka, T.; Matsunobu, T.; Satoh, Y.; Niwa, K.; Shiotani, A. Inhaled Hydrogen Gas Therapy for Prevention of Noise-Induced Hearing Loss through Reducing Reactive Oxygen Species. Neurosci. Res. 2014, 89, 69−74. (10) Gharib, B.; Hanna, S.; Abdallahi, O. M.; Lepidi, H.; Gardette, B.; De Reggi, M. Anti-Inflammatory Properties of Molecular Hydrogen: Investigation on Parasite-Induced Liver Inflammation. C. R. Acad. Sci., Ser. III 2001, 324, 719−724. (11) Xin, H. G.; Zhang, B. B.; Wu, Z. Q.; Hang, X. F.; Xu, W. S.; Ni, W.; Zhang, R. Q.; Miao, X. H. Consumption of Hydrogen-Rich Water Alleviates Renal Injury in Spontaneous Hypertensive Rats. Mol. Cell. Biochem. 2014, 392, 117−124. (12) Li, J.; Dong, Y.; Chen, H.; Han, H.; Yu, Y.; Wang, G.; Zeng, Y.; Xie, K. Protective Effects of Hydrogen-Rich Saline in a Rat Model of Permanent Focal Cerebral Ischemia via Reducing Oxidative Stress and Inflammatory Cytokines. Brain Res. 2012, 1486, 103−111. (13) Sobue, S.; Yamai, K.; Ito, M.; Ohno, K.; Ito, M.; Iwamoto, T.; Qiao, S.; Ohkuwa, T.; Ichihara, M. Simultaneous Oral and Inhalational Intake of Molecular Hydrogen Additively Suppresses Signaling Pathways in Rodents. Mol. Cell. Biochem. 2015, 403, 231− 241. (14) Wang, R.; Wu, J.; Chen, Z.; Xia, F.; Sun, Q.; Liu, L. Postconditioning with Inhaled Hydrogen Promotes Survival of Retinal Ganglion Cells in a Rat Model of Retinal Ischemia/Reperfusion Injury. Brain Res. 2016, 1632, 82−90. (15) Zhou, Y.; Zheng, H.; Ruan, F.; Chen, X.; Zheng, G.; Kang, M.; Zhang, Q.; Sun, X. Hydrogen-Rich Saline Alleviates Experimental Noise-Induced Hearing Loss in Guinea Pigs. Neuroscience 2012, 209, 47−53. (16) Yu, S.; Zhao, C.; Che, N.; Jing, L.; Ge, R. Hydrogen-Rich Saline Attenuates Eosinophil Activation in a Guinea Pig Model of Allergic Rhinitis via Reducing Oxidative Stress. J. Inflammation 2017, 14, 1. (17) Zhang, J. Y.; Song, S. D.; Pang, Q.; Zhang, R. Y.; Wan, Y.; Yuan, D. W.; Wu, Q. F.; Liu, C. Hydrogen-Rich Water Protects Against Acetaminophen-Induced Hepatotoxicity in Mice. World J. Gastroenterol. 2015, 21, 4195−4209. (18) Han, B.; Zhou, H.; Jia, G.; Wang, Y.; Song, Z.; Wang, G.; Pan, S.; Bai, X.; Lv, J.; Sun, B. MAPKs and Hsc70 are Critical to the Protective Effect of Molecular Hydrogen During the Early Phase of Acute Pancreatitis. FEBS J. 2016, 283, 738−756. (19) Xie, K.; Liu, L.; Yu, Y.; Wang, G. Hydrogen Gas Presents a Promising Therapeutic Strategy for Sepsis. BioMed Res. Int. 2014, 2014, 807635. (20) Fu, Y.; Ito, M.; Fujita, Y.; Ito, M.; Ichihara, M.; Masuda, A.; Suzuki, Y.; Maesawa, S.; Kajita, Y.; Hirayama, M.; Ohsawa, I.; Ohta, S.; Ohno, K. Molecular Hydrogen is Protective Against 6Hydroxydopamine-Induced Nigrostriatal Degeneration in a Rat Model of Parkinson’s Disease. Neurosci. Lett. 2009, 453, 81−85. (21) Sobue, S.; Inoue, C.; Hori, F.; Qiao, S.; Murate, T.; Ichihara, M. Molecular Hydrogen Modulates Gene Expression via Histone Modification and Induces the Mitochondrial Unfolded Protein Response. Biochem. Biophys. Res. Commun. 2017, 493, 318−324. (22) Li, H. M.; Shen, L.; Ge, J. W.; Zhang, R. F. The Transfer of Hydrogen from Inert Gas to Therapeutic Gas. Med. Gas Res. 2017, 7, 265−272. (23) Guo, S. X.; Fang, Q.; You, C. G.; Jin, Y. Y.; Wang, X. G.; Hu, X. L.; Han, C. M. Effects of Hydrogen-Rich Saline on Early Acute Kidney Injury in Severely Burned Rats by Suppressing Oxidative Stress Induced Apoptosis and Inflammation. J. Transl. Med. 2015, 13, 183. (24) Kawamura, T.; Wakabayashi, N.; Shigemura, N.; Huang, C. S.; Masutani, K.; Tanaka, Y.; Noda, K.; Peng, X.; Takahashi, T.; Billiar, T.

instance, H2 can sensitize drug-resistant cells and may induce an immunological response28 against distal tumors. Therefore, the combination of H2 therapy and immunotherapy is a promising strategy to explore.

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Jibin Song: 0000-0003-4771-5006 Xiaoyuan Chen: 0000-0002-9622-0870 Huanghao Yang: 0000-0001-5894-0909 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS We gratefully acknowledge support by the National Natural Science Foundation of China (nos. U1505221 and 21874024), the Program for Changjiang Scholars and the Innovative Research Team in University (no. IRT15R11), and the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIH). ABBREVIATIONS CAT, catalase; CLSM, confocal laser scanning microscopy; HCA, hydrogen-containing air; HMGB-1, high-mobility group box 1; HRS, hydrogen-rich physiological solution; HRW, hydrogen-rich water; LIP, liposome; Nrf2, nuclear factorerythroid 2p45-related factor 2; NF-κB, nuclear factor κ B; PAI, photoacoustic imaging; Pdots, polymer dots; PTT, photothermal therapy; ROS, reactive oxygen species; SOD, superoxide dismutase; TLR4, Toll-like receptor 4; TNF-α, tumor necrosis factor α REFERENCES (1) Zhang, K.; Xu, H.; Jia, X.; Chen, Y.; Ma, M.; Sun, L.; Chen, H. Ultrasound-Triggered Nitric Oxide Release Platform Based on Energy Transformation for Targeted Inhibition of Pancreatic Tumor. ACS Nano 2016, 10, 10816−10828. (2) Fan, W.; Lu, N.; Huang, P.; Liu, Y.; Yang, Z.; Wang, S.; Yu, G.; Liu, Y.; Hu, J.; He, Q.; Qu, J.; Wang, T.; Chen, X. GlucoseResponsive Sequential Generation of Hydrogen Peroxide and Nitric Oxide for Synergistic Cancer Starving-Like/Gas Therapy. Angew. Chem., Int. Ed. 2017, 56, 1229−1233. (3) Zheng, D. W.; Li, B.; Li, C. X.; Xu, L.; Fan, J. X.; Lei, Q.; Zhang, X. Z. Photocatalyzing CO2 to CO for Enhanced Cancer Therapy. Adv. Mater. 2017, 29, 1703822. (4) Li, S.; Liu, R.; Jiang, X.; Qiu, Y.; Song, X.; Huang, G.; Fu, N.; Lin, L.; Song, J.; Chen, X.; Yang, H. Near-Infrared Light Triggered Sulfur Dioxide Gas Therapy of Cancer. ACS Nano 2019, 13, 2103− 2113. (5) He, Y.; Zhang, B.; Chen, Y.; Jin, Q.; Wu, J.; Yan, F.; Zheng, H. Image-Guided Hydrogen Gas Delivery for Protection from Myocardial Ischemia-Reperfusion Injury via Microbubbles. ACS Appl. Mater. Interfaces 2017, 9, 21190−21199. (6) Ohsawa, I.; Ishikawa, M.; Takahashi, K.; Watanabe, M.; Nishimaki, K.; Yamagata, K.; Katsura, K.; Katayama, Y.; Asoh, S.; Ohta, S. Hydrogen Acts as a Therapeutic Antioxidant by Selectively Reducing Cytotoxic Oxygen Radicals. Nat. Med. 2007, 13, 688−694. F

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DOI: 10.1021/acsnano.9b05124 ACS Nano XXXX, XXX, XXX−XXX