Synergistic Therapeutic Effects of D-Mannitol-Cerium-Quercetin (Rutin) Coordination Polymer Nanoparticles on Acute Lung Injury.

Acute lung injury (ALI) remains a significant global health issue, necessitating novel therapeutic interventions. In our latest study, we pioneered the use of D-mannitol-cerium-quercetin/rutin coordination polymer nanoparticles (MCQ/R NPs) as a potential treatment for ALI. The MCQ/R NPs, which integrate rutin and quercetin for their therapeutic potential and D-mannitol for its pulmonary targeting, displayed exceptional efficacy. By utilizing cerium ions for optimal nanoparticle assembly, the MCQ/R NPs demonstrated an average size of less than 160 nm. Impressively, these nanoparticles outperformed conventional treatments in both antioxidative capabilities and biocompatibility. Moreover, our in vivo studies on LPS-induced ALI mice showed a significant reduction in lung tissue inflammation. This groundbreaking research presents MCQ/R NPs as a promising new approach in ALI therapeutics.

Harnessing cerium-based biomaterials for the treatment of bone diseases.

Bone, an actively metabolic organ, undergoes constant remodeling throughout life. Disturbances in the bone microenvironment can be responsible for pathologically bone diseases such as periodontitis, osteoarthritis, rheumatoid arthritis and osteoporosis. Conventional bone tissue biomaterials are not adequately adapted to complex bone microenvironment. Therefore, there is an urgent clinical need to find an effective strategy to improve the status quo. In recent years, nanotechnology has caused a revolution in biomedicine. Cerium(III, IV) oxide, as an important member of metal oxide nanomaterials, has dual redox properties through reversible binding with oxygen atoms, which continuously cycle between Ce(III) and Ce(IV). Due to its special physicochemical properties, cerium(III, IV) oxide has received widespread attention as a versatile nanomaterial, especially in bone diseases. This review describes the characteristics of bone microenvironment. The enzyme-like properties and biosafety of cerium(III, IV) oxide are also emphasized. Meanwhile, we summarizes controllable synthesis of cerium(III, IV) oxide with different nanostructural morphologies. Following resolution of synthetic principles of cerium(III, IV) oxide, a variety of tailored cerium-based biomaterials have been widely developed, including bioactive glasses, scaffolds, nanomembranes, coatings, and nanocomposites. Furthermore, we highlight the latest advances in cerium-based biomaterials for inflammatory and metabolic bone diseases and bone-related tumors. Tailored cerium-based biomaterials have already demonstrated their value in disease prevention, diagnosis (imaging and biosensors) and treatment. Therefore, it is important to assist in bone disease management by clarifying tailored properties of cerium(III, IV) oxide in order to promote the use of cerium-based biomaterials in the future clinical setting. STATEMENT OF SIGNIFICANCE: In this review, we focused on the promising of cerium-based biomaterials for bone diseases. We reviewed the key role of bone microenvironment in bone diseases and the main biological activities of cerium(III, IV) oxide. By setting different synthesis conditions, cerium(III, IV) oxide nanostructures with different morphologies can be controlled. Meanwhile, tailored cerium-based biomaterials can serve as a versatile toolbox (e.g., bioactive glasses, scaffolds, nanofibrous membranes, coatings, and nanocomposites). Then, the latest research advances based on cerium-based biomaterials for the treatment of bone diseases were also highlighted. Most importantly, we analyzed the perspectives and challenges of cerium-based biomaterials. In future perspectives, this insight has given rise to a cascade of cerium-based biomaterial strategies, including disease prevention, diagnosis (imaging and biosensors) and treatment.

The Effect of Cerium Oxide (CeO2) on Ischemia-Reperfusion Injury in Skeletal Muscle in Mice with Streptozocin-Induced Diabetes.

Objective: Lower extremity ischemia-reperfusion injury (IRI) may occur with trauma-related vascular injury and various vascular diseases, during the use of a tourniquet, in temporary clamping of the aorta in aortic surgery, or following acute or bilateral acute femoral artery occlusion. Mitochondrial dysfunction and increased basal oxidative stress in diabetes may cause an increase in the effects of increased reactive oxygen species (ROS) and mitochondrial dysfunction due to IRI. It is of great importance to examine therapeutic approaches that can minimize the effects of IRI, especially for patient groups under chronic oxidative stress such as DM. Cerium oxide (CeO2) nanoparticles mimic antioxidant enzymes and act as a catalyst that scavenges ROS. In this study, it was aimed to investigate whether CeO2 has protective effects on skeletal muscles in lower extremity IRI in mice with streptozocin-induced diabetes. Methods: A total of 38 Swiss albino mice were divided into six groups as follows: control group (group C, n = 6), diabetes group (group D, n = 8), diabetes-CeO2 (group DCO, n = 8), diabetes-ischemia/reperfusion (group DIR, n = 8), and diabetes-ischemia/reperfusion-CeO2 (group DIRCO, n = 8). The DCO and DIRCO groups were given doses of CeO2 of 0.5 mg/kg intraperitoneally 30 min before the IR procedure. A 120 min ischemia-120 min reperfusion period with 100% O2 was performed. At the end of the reperfusion period, muscle tissues were removed for histopathological and biochemical examinations. Results: Total antioxidant status (TAS) levels were found to be significantly lower in group DIR compared with group D (p = 0.047 and p = 0.022, respectively). In group DIRCO, total oxidant status (TOS) levels were found to be significantly higher than in group DIR (p < 0.001). The oxidative stress index (OSI) was found to be significantly lower in group DIR compared with group DCO (p < 0.001). Paraoxanase (PON) enzyme activity was found to be significantly increased in group DIR compared with group DCO (p < 0.001). The disorganization and degeneration score for muscle cells, inflammatory cell infiltration score, and total injury score in group DIRCO were found to be significantly lower than in group DIR (p = 0.002, p = 0.034, and p = 0.001, respectively). Conclusions: Our results confirm that CeO2, with its antioxidative properties, reduces skeletal muscle damage in lower extremity IRI in diabetic mice.

Cerium-Luteolin Nanocomplexes in Managing Inflammation-Related Diseases by Antioxidant and Immunoregulation.

Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and the antioxidant defense system, plays a pivotal role in inflammation-related diseases. Excessive ROS levels can induce cellular damage and impair normal physiological functions, triggering the release of inflammatory mediators and exacerbating the inflammatory response, ultimately leading to irreversible tissue damage. In this study, we synthesized cerium ion-luteolin nanocomplexes (CeLutNCs) by coordinating Ce ions with the natural product luteolin, aiming to develop a therapeutic agent with excellent antioxidant and immunoregulation properties for ROS-related inflammation treatment. In vitro experiments demonstrated that the prepared CeLutNCs effectively scavenged excess ROS, prevented cell apoptosis, down-regulated levels of important inflammatory cytokines, regulated the response of inflammatory macrophages, and suppressed the activation of the nuclear factor-κ-gene binding (NF-κB) pathway. In an acute kidney injury (AKI) animal model, CeLutNCs exhibited significant efficacy in improving kidney function, repairing damaged renal tissue, and reducing oxidative stress, inflammatory response, and cellular apoptosis. Moreover, the therapeutic potential of CeLutNCs in an acute lung injury (ALI) model was confirmed through the assessment of inflammatory responses and histopathological studies. This study emphasizes the effectiveness of these metal-natural product coordination nanocomplexes as a promising therapeutic approach for preventing AKI and other diseases associated with oxidative stress.

Effectiveness of Cerium Oxide Nanoparticles in Non-Alcoholic Fatty Liver Disease Evolution Using In Vivo and In Vitro Studies: A Systematic Review.

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of liver abnormalities, from benign steatosis to nonalcoholic steatohepatitis (NASH). Because of their antioxidant capabilities, CeNPs have sparked a lot of interest in biological applications. This review evaluated the effectiveness of CeNPs in NAFLD evolution through in vivo and in vitro studies. Databases such as MEDLINE, EMBASE, Scopus, and Web of Science were looked for studies published between 2012 and June 2023. Quality was evaluated using PRISMA guidelines. We looked at a total of nine primary studies in English carried out using healthy participants or HepG2 or LX2 cells. Quantitative data such as blood chemical markers, lipid peroxidation, and oxidative status were obtained from the studies. Our findings indicate that NPs are a possible option to make medications safer and more effective. In fact, CeNPs have been demonstrated to decrease total saturated fatty acids and foam cell production (steatosis), reactive oxygen species production and TNF-α (necrosis), and vacuolization in hepatic tissue when used to treat NAFLD. Thus, CeNP treatment may be considered promising for liver illnesses. However, limitations such as the variation in durations between studies and the utilization of diverse models to elucidate the etiology of NAFLD must be considered. Future studies must include standardized NAFLD models.

Cerium oxide nanoparticles in diabetic foot ulcer management: Advances, limitations, and future directions.

Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes, potentially resulting in wound infection and amputation under severe circumstances. Oxidative stress and dysbiosis are the primary factors that delay wound healing, posing challenges to effective treatment. Unfortunately, conventional approaches in these aspects have proven satisfactory in achieving curative outcomes. Recent research has increasingly focused on using nanoparticles, leveraging their potential in wound dressing and medication delivery. Their unique physical properties further enhance their therapeutic effectiveness. Among these nanoparticles, cerium oxide nanoparticles (CONPs) have garnered attention due to their notable beneficial effects on oxidative stress and microbial abundance, thus representing a promising therapeutic avenue for DFU. This review comprehensively assesses recent studies on CONPs in treating DFU. Furthermore, we elaborate on the wound healing process, ceria synthesis, and incorporating CONPs with other materials. Crucially, a thorough evaluation of CONPs' toxicity as a novel metallic nanomaterial for therapeutic use must precede their formal clinical application. Additionally, we identify the current challenges CONPs encounter and propose future directions for their development.

Biomimetic Epigallocatechin Gallate-Cerium Assemblies for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease that is so far incurable with long-term health risks. The high doses and frequent administration for the available RA drug always lead to adverse side effects. Aiming at the obstacles to achieving effective RA treatment, we prepared macrophage cell membrane-camouflaged nanoparticles (M-EC), which were assembled from epigallocatechin gallate (EGCG) and cerium(IV) ions. Due to its geometrical similarity to the active metal sites of a natural antioxidant enzyme, the EC possessed a high scavenge efficiency to various types of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The macrophage cell membrane assisted M-EC in escaping from the immune system, being uptaken by inflammatory cells, and specifically binding IL-1ß. After tail vein injection to the collagen-induced arthritis (CIA) mouse model, the M-EC accumulated at inflamed joints and effectively repaired the bone erosion and cartilage damage of rheumatoid arthritis by relieving synovial inflammation and cartilage erosion. It is expected that the M-EC can not only pave a new way for designing metal-phenolic networks with better biological activity but also provide a more biocompatible therapeutic strategy for effective treatment of RA.

Nanoceria: an innovative strategy for cancer treatment.

Nanoceria or cerium oxide nanoparticles characterised by the co-existing of Ce3+ and Ce4+ that allows self-regenerative, redox-responsive dual-catalytic activities, have attracted interest as an innovative approach to treating cancer. Depending on surface characteristics and immediate environment, nanoceria exerts either anti- or pro-oxidative effects which regulate reactive oxygen species (ROS) levels in biological systems. Nanoceria mimics ROS-related enzymes that protect normal cells at physiological pH from oxidative stress and induce ROS production in the slightly acidic tumour microenvironment to trigger cancer cell death. Nanoceria as nanozymes also generates molecular oxygen that relieves tumour hypoxia, leading to tumour cell sensitisation to improve therapeutic outcomes of photodynamic (PDT), photothermal (PTT) and radiation (RT), targeted and chemotherapies. Nanoceria has been engineered as a nanocarrier to improve drug delivery or in combination with other drugs to produce synergistic anti-cancer effects. Despite reported preclinical successes, there are still knowledge gaps arising from the inadequate number of studies reporting findings based on physiologically relevant disease models that accurately represent the complexities of cancer. This review discusses the dual-catalytic activities of nanoceria responding to pH and oxygen tension gradient in tumour microenvironment, highlights the recent nanoceria-based platforms reported to be feasible direct and indirect anti-cancer agents with protective effects on healthy tissues, and finally addresses the challenges in clinical translation of nanoceria based therapeutics.

State-of-the-art cerium nanoparticles as promising agents against human viral infections.

The world is faces a significant global health challenge in the form of viral infections, particularly the emergence of viral strains that are resistant to effective antiviral therapies. This underscores the urgent need for the development of effective and safe antiviral agents. Nanoscale materials are now being used as novel antiviral agents. Cerium nanoparticles have unique chemical and physical properties that make them particularly promising for viral infections. These particles reduce inflammation and the autoimmune response. Cerium nanoparticles, in addition to their antiviral properties, have many other advantages that are highly sought after for various aspects of biomedical applications. This review focuses on the various properties of cerium nanoparticles as a novel agent against viral infections.

Diabetic bone regeneration with nanoceria-tailored scaffolds by recapitulating cellular microenvironment: Activating integrin/TGF-ß co-signaling of MSCs while relieving oxidative stress.

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-ß co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.

Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

The Use of Cerium Compounds as Antimicrobials for Biomedical Applications.

Cerium and its derivatives have been used as remedies for wounds since the early 20th century. Cerium nitrate has attracted most attention in the treatment of deep burns, followed later by reports of its antimicrobial properties. Its ability to mimic and replace calcium is presumed to be a major mechanism of its beneficial action. However, despite some encouraging results, the overall data are somewhat confusing with seemingly the same compounds yielding opposing results. Despite this, cerium nitrate is currently used in wound treatment in combination with silver sulfadiazine as Flammacérium. Cerium oxide, especially in nanoparticle form (Nanoceria), has lately captured much interest due to its antibacterial properties mediated via oxidative stress, leading to an increase of published reports. The properties of Nanoceria depend on the synthesis method, their shape and size. Recently, the green synthesis route has gained a lot of interest as an alternative environmentally friendly method, resulting in production of effective antimicrobial and antifungal nanoparticles. Unfortunately, as is the case with antibiotics, emerging bacterial resistance against cerium-derived nanoparticles is a growing concern, especially in the case of bacterial biofilm. However, diverse strategies resulting from better understanding of the biology of cerium are promising. The aim of this paper is to present the progress to date in the use of cerium compounds as antimicrobials in clinical applications (in particular wound healing) and to provide an overview of the mechanisms of action of cerium at both the cellular and molecular level.

Cytokine Regulation and Fast Inflammation Resolution in Early Rheumatoid Arthritis by Cerium-Modified Gold Nanoclusters.

Rheumatoid arthritis (RA) is an incurable chronic disorder that may induce autoinflammation and serious pain in the joints. Early diagnosis and treatment are important for RA prognosis. However, there is a lack of effective and objective diagnostic approaches. Levels of several immunity cytokines were found to change for patients with early RA, including IL-6, TNF-α, and IL-17 in serum. We assumed a combined change of these cytokines could predict early RA, and a total of 37 outpatients were found. After these patients with early symptoms had been followed for more than one year, 32 clinical cases of RA were diagnosed. The accuracy rate of the current method is >86%. We assumed the symptom relief could be achieved by regulating these cytokines and serum lipid-associated indicators. Thereafter, (R)-dihydrolipoic acid (R-DHLA)-stabilized gold nanoclusters (AuNCs) without (R-DHLA-AuNCs) and with cerium modification (R-DHLA-AuNCs-Ce) were employed for treatment of the RA rat model in vitro and in vivo. R-DHLA-AuNCs-Ce exhibited extraordinary reactive oxygen species-scavenging and anti-inflammation effects by regulating macrophage polarization, which was found to be more effective than methotrexate. The inflammation response of the joint microenvironment was also reduced with an exciting efficiency. By complex analysis of the pro-inflammatory cytokines and activity period indicators in vivo and in vitro, we concluded that macrophage-mediated inflammation exacerbated autoimmunity, which fully relieved the symptoms after administration of R-DHLA-AuNCs-Ce to RA rats.

Cerium Nitrate Treatment in the Management of Burns.

Significance: The standard of care for deep burn wounds is eschar excision and autologous skin grafting within the first postburn days. However, when this is not practical due to medical reasons, unavailable surgical facilities, or lack of donor sites or other coverage, surgeons have used topical cerium nitrate (CN) in a cream with silver sulfadiazine (SSD) for over four decades to convert the eschar into a pliable and protective crust that facilitates the postponement or staging of eschar excision and grafting. CN+SSD treatment is reported to reduce dressing changes, improve patient comfort, and reduce bacterial burden, with unaffected epithelialization and few complications. Recent Advances: CN aqueous solutions applied topically alone or together with solid silver dressings in animal models have mitigated wound injury progression, wound microbial burden, and systemic immune dysfunction. Critical Issues: CN+SSD cream is not approved by U.S. Food and Drug Administration (FDA) and its efficacy in clinical trials has been challenging to demonstrate. One reason is that CN changes the eschar visibly, introducing unavoidable bias. Also, the market and patient population is small and burn wound presentation is highly variable. Future Directions: For use in settings wherein the once- or twice-daily CN+SSD cream dressing changes are least feasible (low-income, military, and mass casualty settings), it may be possible to develop a solid dressing containing cerium and silver that requires infrequent dressing changes. For future clinical studies, the trial design most suited to comparing silver-containing dressings with and without cerium may be paired difference of matched intrapatient wounds.

Construction of a Mesoporous Ceria Hollow Sphere/Enzyme Nanoreactor for Enhanced Cascade Catalytic Antibacterial Therapy.

Nanozyme has been regarded as one of the antibacterial agents to kill bacteria via a Fenton-like reaction in the presence of H2O2. However, it still suffers drawbacks such as insufficient catalytic activity in near-neutral conditions and the requirement of high H2O2 levels, which would minimize the side effects to healthy tissues. Herein, a mesoporous ceria hollow sphere/enzyme nanoreactor is constructed by loading glucose oxidase in the mesoporous ceria hollow sphere nanozyme. Due to the mesoporous framework, large internal voids, and high specific surface area, the obtained nanoreactor can effectively convert the nontoxic glucose into highly toxic hydroxyl radicals via a cascade catalytic reaction. Moreover, the generated glucose acid can decrease the localized pH value, further boosting the peroxidase-like catalytic performance of mesoporous ceria. The generated hydroxyl radicals could damage severely the cell structure of the bacteria and prevent biofilm formation. Moreover, the in vivo experiments demonstrate that the nanoreactor can efficiently eliminate 99.9% of bacteria in the wound tissues and prevent persistent inflammation without damage to normal tissues in mice. This work provides a rational design of a nanoreactor with enhanced catalytic activity, which can covert glucose to hydroxyl radicals and exhibits potential applications in antibacterial therapy.

Preparation of cerium-curcumin and cerium-quercetin complexes and their LEDs irradiation assisted anticancer effects on MDA-MB-231 and A375 cancer cell lines.

Cancer remains common and often is difficult to eradicate. In particular resistant forms like triple negative breast cancer and melanoma generally allow for very short survival. Curcumin and quercetin as two important polyphenols from plants which have different biological roles, potentially including anti-cancer effect. But their clinical application is limited due to poor solubility in aqueous medium. Photodynamic therapy (PDT) is a cancer treatment using select chemical compounds as photosensitizers, which when activated by light create toxic singlet oxygen. Studies done on plant based photosensitizers such as curcumin and quercetin have shown the ability to ablate tumors. Here we discuss using them as improved PS by making their complex with cerium ions as a delivery system for MDA-MB-231 and A375 cancer cell lines treatment. For this purpose, the MDA-MB-231 human breast cancer cell line exposed to red light irradiation (as pretreatment) then treated with curcumin and quercetin alone and also their complex with cerium. In another study the cells treated with curcumin-cerium and quercetin-cerium complex and then irradiated with blue light (photodynamic treatment). Cell survival and apoptosis were determined using MTT and fluorescence microscopy. The result showed that curcumin and quercetin in complex with cerium ions have better toxic effect against both breast and melanoma cancer cells as compared to each compound alone. The finding revealed that curcumin and quercetin in cerium complex could be considered as a new approach in the photodynamic treatment of breast and melanoma cancer cells.

Yb3+, Er3+ Codoped Cerium Oxide Upconversion Nanoparticles Enhanced the Enzymelike Catalytic Activity and Antioxidative Activity for Parkinson's Disease Treatment.

Oxidative stress plays an important role in Parkinson's disease (PD) and is considered a therapeutic target for PD. However, most therapeutic antioxidants show limitations due to their low reactive oxygen species (ROS) catalytic properties and low crossing of blood-brain barrier. Herein, the antioxidative activity of Yb3+ and Er3+ double-doped CeO2-x (Yb/Er/CeO2-x) upconversion nanoparticles (UCNPs) is obtained for PD treatment. Doping of Yb3+ and Er3+ ions increases oxygen vacancies, which leads to higher enzymelike catalytic activities compared to CeO2-x nanoparticles alone. Tyrosine hydroxylase protein and glial fibrillary acidic protein expression in substantia nigra and striatum as well as the open-field activity test indicates that Yb/Er/CeO2-x is effective for treatment of PD. The activities of glutathione peroxidase and total antioxidant capacity increase and the production of ROS decreases with Yb/Er/CeO2-x UCNP treatment compared with MPTP-induced injury. This indicates that the mechanism of PD treatment is to catalyze ROS products. There have been no reports to date on the usage of Yb/Er/CeO2-x as an antioxidant for PD treatment. Yb/Er/CeO2-x UCNPs cross the blood-brain barrier and exhibit biocompatibility and antioxidant catalytic properties, which decrease the ROS and effectively help in treating PD.

In Vivo Regenerable Cerium Oxide Nanozyme-Loaded pH/H2O2-Responsive Nanovesicle for Tumor-Targeted Photothermal and Photodynamic Therapies.

Photodynamic therapy (PDT) and photothermal therapies (PTTs) are both promising strategies for effective tumor therapy. However, the absence of O2 at tumor sites hinders the sustained response of photosensitizers. Here, we develop a recycled cerium oxide (CeO2) catalase nanozyme-loaded hyaluronic acid nanovesicle to address the hypoxic tumor microenvironments and targeted delivery of the photosensitizers [indocyanine green (ICG)] to tumors. A polysaccharide complex effectively modifies the surface of a polyethylenimine phenylboronic acid nanostructure to achieve the CeO2 nanozyme-loading nanovesicles that exhibit both tumor-targeted enhancement and an improved hypoxic microenvironment. Also, the hydrogen peroxide responsiveness and acid-sensitive cleavage of phenylboronic acid specifically disintegrate the ICG/nanozyme coloaded nanovesicles in the tumor microenvironment. The in vitro synergistic tests and tumor suppression rate tests indicated that the cerium oxide nanozyme significantly improves the outcomes of PDT via cerium-element valence state recycling and hypoxia improvement, thus enhancing the tumor suppression efficiency. This pH/H2O2-responsive nanozyme/ICG codelivery system provides a good carrier model for improving the tumor microenvironment and increasing the efficiency of tumor-targeted PTT and PDT therapies.

Ceria Nanozymes with Preferential Renal Uptake for Acute Kidney Injury Alleviation.

Rhabdomyolysis-induced acute kidney injury (AKI) is closely related to abundant reactive oxygen species (ROS). Owing to the multi-enzymatic activity and broad-spectrum ROS scavenging capacity of ceria nanoparticles (ceria NPs), herein, we report ultrasmall citric acid modified ceria nanozymes (3-4 nm) as antioxidants to alleviate rhabdomyolysis-induced AKI through removing excessive ROS. The as-prepared ceria NPs exhibited multi-enzymatic properties such as peroxidase, catalase, and superoxide dismutase, offering efficient protection of renal cells against H2O2 stimulation in vitro. Moreover, due to their ultrasmall size, ceria NPs could efficiently accumulate in the kidneys, thus protecting renal cells against ROS in vivo. Our results present ultrasmall ceria nanozymes as antioxidants for rhabdomyolysis-induced AKI alleviation, which shows great potential in clinic.

Dual-path modulation of hydrogen peroxide to ameliorate hypoxia for enhancing photodynamic/starvation synergistic therapy.

The common existence of hypoxia within the tumor microenvironment severely restricts the efficacy of photodynamic therapy (PDT), which is attributed to the fact that the PDT process is strongly oxygen (O2) dependent. Here, a multifunctional composite (named CPCG), which combines polyethylene glycol (PEG) functionalized cerium oxide nanoparticles (CeO2) with photosensitizer chlorin e6 (Ce6) and glucose oxidase (GOx), is reported for generating O2 within the tumor microenvironment by the dual-path hydrogen peroxide (H2O2)-modulated ways to ameliorate hypoxia, thereby enhancing the PDT efficiency. This process is realized based on the dual enzyme-like activity of CeO2. The first modulated way is to transform the superoxide anion (O2˙-) into H2O2 by the superoxide dismutase-like activity of CeO2. The second modulated way is to decompose glucose into H2O2 through the catalysis of GOx. Subsequently, H2O2 generated from the above dual modulated ways can further produce O2via the catalase-like activity of CeO2. Additionally, the depletion of glucose could impede the nutrient supply to obtain starvation therapy. Both in vitro and in vivo experiments indicate that the CPCG composite could enhance the efficacy of photodynamic/starvation synergistic therapy. Therefore, this strategy offers great potential to modulate the O2 level in the tumor microenvironment for better therapeutic outcomes, and can act as a promising candidate in photodynamic/starvation synergistic therapy.