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Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-γ (IFNγ) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNγ by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNγ in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-γ against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNγ mediated antitumor immunity that have implications for targeting a unique aspect of this disease., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Abnormal activation of the intestinal mucosal immune system, resulting from damage to the intestinal mucosal barrier and extensive invasion by pathogens, contributes to the pathogenesis of inflammatory bowel disease (IBD). Current first‐line treatments for IBD have limited efficacy and significant side effects. An innovative H2S‐releasing montmorillonite nanoformulation (DPs@MMT) capable of remodeling intestinal mucosal immune homeostasis, repairing the mucosal barrier, and modulating gut microbiota is developed by electrostatically adsorbing diallyl trisulfide‐loaded peptide dendrimer nanogels (DATS@PDNs, abbreviated as DPs) onto the montmorillonite (MMT) surface. Upon rectal administration, DPs@MMT specifically binds to and covers the damaged mucosa, promoting the accumulation and subsequent internalization of DPs by activated immune cells in the IBD site. DPs release H2S intracellularly in response to glutathione, initiating multiple therapeutic effects. In vitro and in vivo studies have shown that DPs@MMT effectively alleviates colitis by eliminating reactive oxygen species (ROS), inhibiting inflammation, repairing the mucosal barrier, and eradicating pathogens. RNA sequencing revealed that DPs@MMT exerts significant immunoregulatory and mucosal barrier repair effects, by activating pathways such as Nrf2/HO‐1, PI3K‐AKT, and RAS/MAPK/AP‐1, and inhibiting the p38/ERK MAPK, p65 NF‐κB, and JAK‐STAT3 pathways, as well as glycolysis. 16S rRNA sequencing demonstrated that DPs@MMT remodels the gut microbiota by eliminating pathogens and increasing probiotics. This study develops a promising nanoformulation for IBD management. [ABSTRACT FROM AUTHOR]

Colon mucosal overexpression of reactive oxygen and nitrogen species (RONS) accelerates the development of inflammatory bowel disease (IBD) and destroys the mucosa and its barrier. IBD can be alleviated by removing RONS from the inflamed colon. The preparation of strong and efficient nanoantioxidants remains a challenge despite the development of numerous nanoantioxidants. In this paper, Zn-TA nanoparticles with fine hollow microstructure (HZn-TA) were successfully prepared and could be effectively used to treat IBD. In the first step, ZIF-8 nanoparticles were synthesized by a one-pot method. On this basis, HZn-TA nanoparticles were etched by TA, and a multifunctional nanase was developed for the treatment of IBD. RONS, including reactive oxygen species (ROS) and nitric oxide (NO), can be eliminated to increase cell survival following Hydrogen peroxide (H 2 O 2) stimulation, including reactive oxygen species (ROS) and nitric oxide (NO with hydrogen peroxide (H 2 O 2). In a model for preventing and delaying acute colitis, clearance of RONS has been shown to reduce intestinal inflammation in mice by reducing colon damage, proinflammatory cytokine levels, the spleen index, and body weight. Intestinal mucosal healing can be promoted by HZn-TA nanoparticles, which can upregulate zonula occludens protein 1 (ZO-1) and claudin-1 expression. Based on the results of this study, HZn-TA nanoparticles were able to effectively treat IBD with minimal adverse effects by being biocompatible, multienzyme active, and capable of scavenging RONS. Therefore, we pioneered the application of HZn-TA nanoparticles for the treatment of IBD, which are capable of clearing RONS without significant adverse effects. ➢ HZn-TA nanoparticles were successfully prepared and could be effectively used to treat IBD. ➢ Intestinal mucosal healing can be promoted by HZn-TA nanoparticles, which can upregulate ZO-1 and claudin-1 expression. ➢ HZn-TA nanoparticles were able to effectively treat IBD with minimal adverse effects by being biocompatible, multienzyme active, and capable of scavenging RONS. [Display omitted] [ABSTRACT FROM AUTHOR]

Abnormal activation of the gut mucosal immune system and a highly dysregulated gut microbiota play essential roles in the progression of inflammatory bowel disease (IBD). The clinical treatment of IBD remains highly challenging, with first‐line drugs showing limited efficacy and significant side effects. A reactive oxygen species (ROS)‐activated CO versatile nanomedicine (CMPs) capable of remodeling the gut immune‐microbiota microenvironment via potent anti‐oxidant, anti‐inflammatory, and antimicrobial effects is developed. CORM‐401‐loaded mannose‐modified peptide dendrimer nanogel: CMPs preferentially congregate on the surface of damaged colon mucosa after rectal administration and are subsequently internalized by activated immune cells. CORM‐401 can release numerous CO molecules in response to high ROS levels in cells and at the site of IBD, resulting in multiple therapeutic effects. In vitro and in vivo studies have demonstrated that CMPs scavenge ROS, suppress inflammatory responses, eliminate pathogens, and alleviate colitis in mouse models. RNA sequencing reveals that CMPs successfully remodel gut mucosal immune homeostasis by scavenging ROS, inhibiting NF‐κB/p38MAPK, activating PI3K‐Akt, and inhibiting HIF‐1‐induced glycolysis. 16S ribosomal RNA sequencing shows that CMPs can remodel the gut flora composition by restraining detrimental bacteria and augmenting beneficial bacteria. This study develops a promising and versatile nanomedicine for the management of IBD. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function, and is associated with a high risk of death. Many pathological changes happen in the process of AKI, including crucial alterations to oxidative stress levels. Numerous efforts have thus been made to develop effective medicines to scavenge excess reactive oxygen species (ROS). However, researchers have encountered several significant challenges, including unspecific biodistribution, high biotoxicity, and in vivo instability. To address these problems, engineered nanoparticles have been developed to target oxidative stress and treat AKI. This review thoroughly discusses the methods that empower nanodrugs to specifically target the glomerular filtration barrier and presents the latest achievements in engineering novel ROS‐scavenging nanodrugs in clustered sections. The analysis of each study's breakthroughs and imperfections visualizes the progress made in developing effective nanodrugs with specific biodistribution and oxidative stress‐targeting capabilities. This review fills the blank of a comprehensive outline over current progress in applying nanotechnology to treat AKI, providing potential insights for further research. [ABSTRACT FROM AUTHOR]

Cerebral ischemia-reperfusion injury (CIRI) is a complex pathological condition with high mortality. In particular, reperfusion can stimulate overproduction of reactive oxygen species (ROS) and activation of inflammation, causing severe secondary injuries to the brain. Despite tremendous efforts, it remains urgent to rationally design antioxidative agents with straightforward and efficient ROS scavenging capability. Herein, a potent antioxidative agent was explored based on iridium oxide nano-agglomerates (Tf-IrO 2 NAs) via the facile transferrin (Tf)-templated biomineralization approach, and innovatively applied to treat CIRI. Containing some small-size IrO 2 aggregates, these NAs possess intrinsic hydroxyl radicals (•OH)-scavenging ability and multifarious enzyme activities, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GP x). Moreover, they also showed improved blood-brain barrier (BBB) penetration and enhanced accumulation in the ischemic brain via Tf receptor-mediated transcytosis. Therefore, Tf-IrO 2 NAs achieved robust in vitro anti-inflammatory and cytoprotection effects against oxidative stress. Importantly, mice were effectively protected against CIRI by enhanced ROS scavenging activity in vivo , and the therapeutic mechanism was systematically verified. These findings broaden the idea of expanding Ir-based NAs as potent antioxidative agents to treat CIRI and other ROS-mediated diseases. (1) The ROS-scavenging activities of IrO 2 are demonstrated comprehensively, which enriched the family of nano-antioxidants. (2) The engineering Tf-IrO 2 nano-agglomerates present unique multifarious enzyme activities and simultaneous transferrin targeting and BBB crossing ability for cerebral ischemia-reperfusion injury therapy. (3) This work may open an avenue to enable the use of IrO 2 to alleviate ROS-mediated inflammatory and brain injury diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

To effectively treat diabetic wounds, the development of versatile medical dressings that can long-term regulate blood glucose and highly effective anti-oxidative stress, antibacterial and anti-inflammatory are critical. Here, an all-in-one CO gas-therapy-based versatile hydrogel dressing (ICOQF) was developed via the dynamic Schiff base reaction between the amino groups on quaternized chitosan (QCS) and the aldehyde groups on benzaldehyde-terminated F108 (F108-CHO) micelles. CORM-401 (an oxidant-sensitive CO-releasing molecules) was encapsulated in the hydrophobic core of F108-CHO micelles and insulin was loaded in the three-dimensional network structure of ICOQF. The dynamic Schiff base bonds not only endowed ICOQF with good tissue adhesion, injectability and self-healing, but also gave it sustained and controllable insulin release ability. In addition, ICOQF could quickly generate CO in inflamed wound tissue by consuming reactive oxygen species. The generated CO could effectively anti-oxidative stress by activating the expression of heme oxygenase; antibacterial by inducing the rupture of bacterial cell membranes and mitochondrial dysfunction and inhibiting the synthesis of adenosine triphosphate; and anti-inflammatory by inhibiting the proliferation of activated macrophages and promoting the polarization of the M1 phenotype to the M2 phenotype. Due to these outstanding properties, ICOQF significantly promoted the healing of STZ-induced MRSA -infected diabetic wounds accompanied by good biocompatibility. This study clearly shows that ICOQF is a versatile hydrogel dressing with great application potential for the management of diabetic wounds. The development of some versatile hydrogel dressings that can not only provide a prolonged and controlled insulin release property but also utilize a non-antibiotic treatment modality for highly effective antibacterial, anti-inflammatory, and anti-oxidative stress effects is vital for the successful treatment of diabetic wounds. Herein, we developed an all-in-one CO gas-therapy-based versatile hydrogel dressing (ICOQF) with sustained and controllable insulin release abilities. Moreover, ICOQF could not only quickly release CO in the inflamed wound tissue by consumption of reactive oxygen species but also utilize the generated CO to highly effectively anti-oxidative stress, antibacterial, and anti-inflammatory. ICOQF therapy substantially promoted the healing of STZ-induced MRSA -infected diabetic wounds. Overall, this work provides a multifunctional hydrogel dressing for the management of diabetic wounds. [Display omitted] [ABSTRACT FROM AUTHOR]

Magnetic micro/nanorobots (MagRobots) with unparalleled advantages, including remote mobility, high reconfigurability and programmability, lack of fuel requirement, and versatility, can be manipulated under a magnetic field, which has attracted considerable research attention in the biomedicine. Magnetic materials, as the key components of MagRobots, generate reactive oxygen species (ROS) in vivo to induce tissue/organ damage through Fenton/Fenton‐like reactions, which may hinder the clinical application of MagRobots. Here, the biologically active Prussian blue is generated on the surfaces of MagRobots via an in situ reaction to obtain magnetically actuated ROS‐scavenging nano‐robots (ROSrobots). The generated Prussian blue blocks ROS production and endows the MagRobots with additional functionalities, markedly expanding their potential medical applications. Under the action of a magnetic field, the reconfigurable ROSrobots realize multimode transformation, locomotion, and manipulation in complex environments. Importantly, a simple control method is proposed to achieve movement in 3D geometries to allow the completion of tasks in a complex environment. Furthermore, the osteoarthritis (OA) rat model was employed for proof of concept. Notably, under the guidance of ultrasound imaging, ROSrobots can be accurately injected into the articular cavity to actively target the treatment of OA. This research may further promote the clinical application of MagRobots. [ABSTRACT FROM AUTHOR]

Oxidative stress and excessive inflammatory responses are the two critical mechanisms of hepatic ischemia-reperfusion injury (HIRI) encountered in many clinical settings, including following hepatectomy and liver transplantation. Effective anti-inflammatory and anti-oxidative pharmacological interventions are urgently needed to counter HIRI. The present study showed that a biocompatible Prussian blue (PB) scavenger with reactive oxygen species (ROS) scavenging and anti-inflammatory properties might be used a promising treatment for HIRI. Following intravenous administration, PB scavenger was mainly distributed in the liver, where it showed excellent ability to alleviate apoptosis, tissue injury and organ dysfunction after HIRI. PB scavenger was found to protect liver tissue by scavenging ROS, reducing neutrophil infiltration and promoting macrophage M2 polarization. In addition, PB scavenger significantly reduced oxidative stress in primary hepatocytes, restoring cell viability under oxidative stress condition. PB scavenger effectively reduced lipopolysaccharide-stimulated inflammation in RAW 264.7 cells. These findings indicate that PB scavenger may be a potential therapeutic agent for the treatment of HIRI, providing an alternative treatment for ROS-associated and inflammatory liver diseases. [ABSTRACT FROM AUTHOR]

Backgrounds: Sonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor strategy is challenged by the rapid depletion of oxygen, as well as the hypoxic tumor microenvironment. Instead of the presently available coping strategies that amplify the endogenous O2 level, we have proposed a biodegradable O2 economizer to reduce expenditure for augmenting SDT efficacy in the present study. Results: We successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) via conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (hematoporphyrin monomethyl ether; HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia conditions. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induced excessive activation of autophagy for promoting the therapeutic efficacy. As a result, when accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP could achieve the remarkable antitumor activity, which was systematically validated both in vivo and in vitro assays. Conclusions: This work not only provides a reduce expenditure means for enduring SDT, but also represents an inquisitive strategy for tumor treatments by inducing pro-death autophagy. [ABSTRACT FROM AUTHOR]

The long‐term prognosis of vascular restenosis after endovascular interventional treatment is a critical challenge in a clinical setting. Over‐production of reactive oxygen species (ROS) is a major factor to aggravate vascular restenosis. Current clinical pharmacological interventions for vascular restenosis are still unsatisfactory. Based on the intrinsic ROS scavenging properties, nanozymes have been widely applied in the treatment of inflammatory‐related diseases. However, the vascular endothelial cell barrier hinder the delivery efficiency of intravenously injected nanomaterials in most diseases. Herein, an effective therapeutic strategy for vascular restenosis is developed based on endothelial cells exfoliation by endovascular interventional treatment through vascular balloon injury, which provides an opportunity to enhance nanozyme passive permeation into the vascular intima and uptake by macrophages to alleviate long‐term vascular restenosis in vivo. Moreover, the macrophages polarization modulation mechanism of vascular restenosis prevention is further investigated. This interesting discovery that endothelial cells exfoliation enhanced nanoparticle vascular permeation by endovascular interventional treatment may provide applicative perspectives in the treatment of other disease by nanomaterials. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a prevalent chronic neurodegenerative disease. However, to date, none of the developed drug candidates targeting at a single therapeutic target of AD have achieved success in clinical trials. Herein, we proposed a hypothesis of hollow manganese Prussian white nanocapsules (HMPWCs)-mediated attenuation of Tau-related pathology and alleviation of cognitive decline via simultaneously alleviating neuroinflammation, scavenging reactive oxygen species, and reducing hyperphosphorylated Tau proteins. The HMPWCs self-assemblied with manganese Prussian white analogue and bovine serum albumin via a novel biomimetic mineralization present good biocompatibility, variable valence states, and low oxidation-reduction potential. They own the outstanding capabilities of relieving oxidative stress, inhibiting Tau neuropathology, and counteracting neuroinflammation, which could be used to treat Tau-related AD-like neurodegeneration. Importantly, they can also attenuate the cognitive impairments of Tau-related AD-like rats without significant side effects. This research takes the advantages of catalytic chemistry, nanomedicine and specific neurodegenerative microenvironment together, providing an alternative efficient treatment strategy for Tau-related neurodegeneration diseases, such as AD, Pick's disease, frontotemporal dementia, Creutzfeldt-Jakob Disease and progressive supranuclear palsy. Image 1 [ABSTRACT FROM AUTHOR]

[Display omitted] • A concept of "natural product-induced and lactate depletion-enhanced ferroptosis" strategy is proposed for promoting the occurrence of ferroptosis. • The engineered lactic acid responsive natural product delivery system presents unique cascade enzymatic/Fenton catalytic performance for distinctive ferroptosis-based anticancer therapy. • The strategy integrating natural product and tumor-specific GPX4 deactivation presents an effective ferroptosis inducing strategy. • This work might provide new insight for realizing effective ferroptosis-based tumor treatment. Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H 2 O 2) into hydroxyl radicals (•OH) by Ir3+-mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H 2 O 2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H 2 O 2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy. [ABSTRACT FROM AUTHOR]

The precise delivery and controllable release of carbon monoxide (CO) to tumor tissues is an emerging anticancer therapy because CO in a high dose can be detrimental to cell survival and tumor growth. However, CO gas therapy is limited by the gaseous nature of CO that hinders its enrichment and controllable release to tumor tissues. Here, a novel photodynamic therapy (PDT)‐driven CO controllable release system (CORM@G3DSP‐Ce6) that integrates the photosensitizer chlorin e6 (Ce6) and H2O2‐sensitive CO releasing molecule CORM‐401 into peptide dendrimer‐based nanogels (G3DSP) is described. Upon excitation with near‐infrared light, Ce6‐mediated photochemical effect not only promotes the efficient cellular internalization of CORM@G3DSP‐Ce6, but also triggers the rapid intracellular CO release from CORM‐401 by depleting the H2O2 produced during PDT. Importantly, the PDT‐driven CO release does not impair the generation capability of singlet oxygen (1O2). As a result, accompanied with the simultaneous generation of large amounts of 1O2 and CO in cells, the combination of PDT and CO gas therapy offers significant synergistic anticancer effects and superior therapeutic safety both in vitro and in vivo. A photodynamic therapy (PDT)‐driven carbon monoxide (CO) controllable release system is developed for PDT+CO synergistic anticancer therapy. With near‐infrared light excitation, this system not only exhibits efficient cellular internalization but also triggers rapid intracellular CO release by depleting H2O2 produced during PDT, without impairing singlet oxygen generation. Significant synergistic anticancer effects with superior biosafety are achieved both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Insufficient concentrations of intracellular substrates such as hypoxia and H 2 O 2 considerably reduce the effectiveness of reactive oxygen species (ROS)-associated cancer therapy. Modulating the tumor microenvironment (TME) for augmenting efficacy has become a promising strategy. Herein, a phase-change cascaded nanomedicine (Lap-IrO x @PCM) was constructed via co-encapsulation of iridium oxide nanozyme (IrO x) and β-lapachone (Lap) by using thermal-responsive phase-change materials (PCMs). After photothermal activation, the protective PCM layer was melted, causing the rapid release of IrO x and Lap. Simultaneously, the peroxidase-like nanozyme IrO x reacted with endogenous H 2 O 2 to liberate highly toxic hydroxyl radicals (•OH) for inducing tumor cell death. Meanwhile, IrO x as another glutathione peroxidase nanozyme also consumed glutathione (GSH) to protect ROS from scavenging. Importantly, the released Lap efficiently generated H 2 O 2 for facilitating the catalytic efficacy of IrO x and provoke the cleavage of heat shock protein 90 (Hsp90) for overcoming tumor heat tolerance in photothermal therapy (PTT). As systematically demonstrated both in vitro and in vivo , this well-defined system achieved a superior antitumor effect via mild photothermal-enhanced nanocatalytic therapy. Our findings have provided the proof of concept of the phase change-mediated, in vivo catalytic activity of nanozymes that can be customized for intensive, TME-mediated, self-enhanced nanocatalytic cancer therapy. We report a domino-like nanomedicine (Lap-IrO x @PCM) that possesses both H 2 O 2 self-supply and GSH-elimination properties for achieving highly cascaded catalytic-therapeutic outcomes by integrating a peroxidase-like moiety of the IrO x nanozyme and β-Lapachone within a thermal-responsive phase-change material (PCM). This work presents a universal idea of a phase-change nanomedicine design for intensive, mild PTT-enhanced nanocatalytic therapy. [Display omitted] • A concept of "phase change nanomedicine-mediated H 2 O 2 self-supplying" strategy is proposed. • β-Lapachone is exploited as a H 2 O 2 productor and heat shock protein inhibitor to fabricate cascade nanocatalyst. • The engineered Lap-IrO x @PCM presents an idea of a phase-change nanomedicine design for intensive nanocatalytic therapy. • This work provides the first example of a nanozyme-type phase-change nanomedicine. [ABSTRACT FROM AUTHOR]

• Electromagnetically actuated magneto-nanozyme synergetic therapy was proposed. • Fe 0.73 O nanoparticles produces •OH, 1O 2 , and •O 2 – in the presence of H 2 O 2. • Magnetic hyperthermia promotes the production of •OH, 1O 2 , and •O 2 –. • Fe 0.73 O nanoparticles remove biofilms through physical and chemical effects. The emergence of bacterial resistance and rapid reconstruction of biofilm pose great challenges to biofilm-associated infections. Magnetically actuated micro-/nanorobots have shown great prospects in various medical applications. In this work, an electromagnetically actuated magneto-nanozyme mediated synergistic therapy (EMST) was proposed and proved to have powerful potential to eradicate biofilm. The developed mesoporous iron oxide nanoparticles (MNPs) with polyvalent iron (0, +2, and +3) simultaneously produce three kinds of reactive oxygen species (ROS, including hydroxyl radical, singlet oxygen, and superoxide anion) in the presence of H 2 O 2 , for catalytic bactericidal and degradation of extracellular polymeric substance (EPS) of biofilm. Driven by electromagnetic actuation system, the MNPs were assembled into microswarm to generate shear force and physically destroy biofilm like "sweeping robot". In addition, the MNP microswarm generates magnetic hyperthermia under alternating magnetic field to promotes the production of ROS, which further improves the bactericidal effect. The excellent anti-infection effects of this EMST were also confirmed in mouse model of skin infection. Overall, this study provides an effective method for the elimination of biofilm infection by combining physical and chemical bactericidal effects. [ABSTRACT FROM AUTHOR]

Specifically inhibiting the proliferation of activated macrophages and clearing the high levels of reactive oxygen species (ROS) secreted by macrophages is crucial for osteoarthritis (OA) treatment. Moreover, if the clearance of these high levels of ROS can be simultaneously used to induce oxidation-responsive release of anti-inflammatory drugs, the therapeutic effect of OA may be further improved. Here, a multifunctional anti-inflammatory drug (CPHs) based on a peptide dendrimer nanogel was constructed by physically encapsulating CORM-401 and wrapping its surface with folic acid (FA)-modified hyaluronic acid (HA). CPHs is capable of efficiently entering activated macrophages via FA- and HA-mediated specific targeting effects and then rapidly release large amounts of CO by massive consumption of H 2 O 2. The generated CO effectively suppresses the secretion of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by inhibiting cell proliferation; inducing the activation of heme oxygenase (HO-1), and downregulating the expression of p38 MAPK, NF-kB (p50/p65) and TLR-2. In vivo experiments further confirmed that CPHs can massively deplete ROS in OA joints and effectively suppress the degradation of articular cartilage and their extracellular matrix. More importantly, CPHs is non-toxic to normal macrophages, and the high levels of CO generated in the joints do not result in notable changes in the HbCO levels in blood. Together, these results show that CPHs is an effective and safe anti-inflammatory drug and has essential application prospects in OA treatment. Image 1 [ABSTRACT FROM AUTHOR]

• Magnetic nanoplatform was developed to overcome tumor hypoxia. • The enhanced SDT plays a great role in the alleviation of thermotolerance. • The synergistic effect between SDT/MHT was revealed via modulating ROS and HSPs. As a promising treatment modality with spatial and temporal control, alternating magnetic field (AMF) triggered magnetic hyperthermal therapy (MHT) shows broad and promising applications to overcome the drawbacks of traditional focal therapies in combating cancer. However, the MHT efficacy is still not satisfactory with the presence of heat shock proteins (HSPs). In addition, sustained tumor hypoxia haunts practical implications for the treatment of solid tumors. Herein, a novel magnetic nanosystem composed of hollow iron oxide nanoparticles (HIONs), Fe 3 O 4 , and sonosensitizers, hematoporphyrin (HP) was rationally designed and successfully synthesized. The hollow HIONs show a large inner cavity for loading sonosensitizer molecules and possess nanozyme activity for catalyzing decomposition of endogenous overexpressed hydrogen peroxide (H 2 O 2) to produce molecular oxygen (O 2) that can overcome tumor hypoxia, thus augmenting the sonodynamic therapy (SDT)-induced highly toxic reactive oxygen species (ROS) production for efficient cancer cell apoptosis. Importantly, the generated ROS can also activates the cleavage of HSPs that further eliminate themotolerance and facilitates MHT efficacy. The synergistic catalysis-enhanced SDT efficiency and MHT effect realized most potent tumor suppression efficacy. This work develops a versatile nanoplatform for a multifunctional strategy and broadens the biological applications by rationally designing their structure. [ABSTRACT FROM AUTHOR]

• An intelligent "on/off" switching strategy of site-specific co-loading MnO x and Ce6 into HMSNs. • MRI-guided efficient PDT with reduced side-effects. • Based on different solubility of surfactant (e.g., C 18 TMS) in different solvents. • General strategy of confined nanoparticle growth within hollow mesoporous nanoreactors. Mesoporous silica nanoparticles (MSNs) have been extensively applied as a promising carrier in biomedical application due to their excellent structure with tunable function. Based on the fact that the surfactant trimethoxyoctadecylsilane (C 18 TMS) could present different on/off states in different solvents, herein, an intelligent "on/off" switching strategy of site-specific co-loading MnO x and Ce6 into MSNs was proposed for the first time. The multifunctional theranostic nanoplatform, i.e., Ce6/MnO x @HMSNs-PEG (CMHP), shows a sensitive longitudinal relaxation signal to the over-expressed hydrogen peroxide (H 2 O 2) and weak acidic pH in the tumor microenvironment (TME). Furthermore, MnO x component could react with H 2 O 2 in TME to generate O 2 , which enable to relieve tumorous hypoxia and afterwards accelerate the generation of singlet oxygen (1O 2) upon laser irradiation when combined with Ce6. Both in vitro and in vivo results confirm that this constructed nanosystem can be applied to MRI-guided sufficient photodynamic therapy (PDT) with reduced side-effects. [ABSTRACT FROM AUTHOR]