Robust Reactive Oxygen Species Research Articles

Synchronously Sensitive Immunoassay and Efficient Inactivation of Living Zika Virus via DNAzyme Catalytic Amplification and In Situ Aggregation-Induced Emission Photosensitizer Generation.

Sensitive identification and effective inactivation of the virus are paramount for the early diagnosis and treatment of viral infections to prevent the risk of secondary transmission of viruses in the environment. Herein, we developed a novel two-step fluorescence immunoassay using antibody/streptavidin dual-labeled polystyrene nanobeads and biotin-labeled G-quadruplex/hemin DNAzymes with peroxidase-mimicking activity for sensitive quantitation and efficient inactivation of living Zika virus (ZIKV). The dual-labeled nanobeads can specifically bind ZIKV through E protein targeting and simultaneously accumulate DNAzymes, leading to the catalytic oxidation of Amplex Red indicators and generation of intensified aggregation-induced emission fluorescence signals, with a detection limit down to 66.3 PFU/mL and 100% accuracy. Furthermore, robust reactive oxygen species generated in situ by oxidized Amplex Red upon irradiation can completely kill the virus. This sensitive and efficient detection-inactivation integrated system will expand the viral diagnostic tools and reduce the risk of virus transmission in the environment.

Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation

BackgroundMesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated.MethodsIn the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs.ResultsBoth direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs.ConclusionIn conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

IRE1α regulates ROS and immune responses after UVB irradiation

UV irradiation of the skin induces photo damage and generates cytotoxic intracellular reactive oxygen species (ROS), activating the unfolded protein response (UPR) to adapt or reduce these UVB-mediated damages. We previously identified a role for the key UPR mediator inositol requiring enzyme 1 (IRE1α) in the UV-DNA damage response. Here, we show that in the absence of IRE1α, PERK activity and protein levels are significantly compromised following UVB irradiation. Additionally, the loss of IRE1α suppressed phosphorylation of the PERK target, nuclear factor erythroid-2-related factor 2 (NRF2), and NRF2-dependent antioxidant gene expression after UVB irradiation. Interestingly, IRE1α-deficient keratinocytes exhibit elevated basal ROS levels, while a robust ROS induction upon UVB exposure is abolished. Because UVB-induced ROS plays an essential role in regulating skin inflammation, we analyzed recruited immune cell populations and the expression of pro-inflammatory cytokines, Il-6 and Tnfα in mice with epidermally-targeted deletion of Ire1α. Following UVB irradiation, there was significantly less recruitment of neutrophils and leukocytes and reduced expression of pro-inflammatory cytokine genes in the skin of mice lacking IRE1α. Furthermore, keratinocyte proliferation was also significantly reduced after chronic UVB exposure in the skin of these mice. Collectively, our findings indicate that IRE1α is essential for basal and UVB-induced oxidative stress response, UV-induced skin immune responses, and keratinocyte proliferation. These findings shed new light on the protective function of IRE1α in the response to UV.

Smart Nanoassembly Enabling Activatable NIR Fluorescence and ROS Generation with Enhanced Tumor Penetration for Imaging-Guided Photodynamic Therapy.

Fluorescence imaging-guided photodynamic therapy (FIG-PDT) holds promise for cancer treatment, yet challenges persist in poor imaging quality, phototoxicity, and insufficient anti-tumor effect. Herein, a novel nanoplatform, LipoHPM, designed to address these challenges, is reported. This approach employs an acid-sensitive amine linker to connect a biotin-modified hydrophilic polymer (BiotinPEG) with a new hydrophobic photosensitizer (MBA), forming OFF-state BiotinPEG-MBA (PM) micelles via an aggregation-caused quenching (ACQ) effect. These micelles are then co-loaded with the tumor penetration enhancer hydralazine (HDZ) into pH-sensitive liposomes (LipoHPM). Leveraging the ACQ effect, LipoHPM is silent in both fluorescence and reactive oxygen species (ROS) generation during blood circulation but restores both properties upon disassembly. Following intravenous injection in tumor-bearing mice, LipoHPM actively targets tumor cells overexpressing biotin-receptors, contributing to enhanced tumor accumulation. Upon cellular internalization, LipoHPM disassembles within lysosomes, releasing HDZ to enhance tumor penetration and inhibit tumor metastasis. Concurrently, the micelles activate fluorescence for tumor imaging and boost the production of both type-I and type-II ROS for tumor eradication. Therefore, the smart LipoHPM synergistically integrates near-infrared emission, activatable tumor imaging, robust ROS generation, efficient anti-tumor and anti-metastasis activity, successfully overcoming limitations of conventional photosensitizers and establishing itself as a promising nanoplatform for potent FIG-PDT applications.

Quasi-MOF-Engineered MnOx /CeBTC Multinanozyme as a Robust Self-Cascade ROS Generator toward Antibacterial Face Mask.

It is of great importance to endow personal protective equipments with bactericidal property combating against infected pathogens. Nanozyme that can generate reactive oxygen species (ROS) in an enzyme-catalytic manner is regarded as a novel and promising nanobactericide. But until now, very rare of them is designed specifically for personal protective equipments. In this study, a multinanozyme of manganese oxide supported on Ce-containing MOF (CeBTC) is constructed with post-engineering via a quasi-metal-organic framework (MOF) strategy (denoted as MnOx /q-CeBTC). The strategy enables a full exposure of the metal cluster nodes, introduction of new active Mn─O─Ce bonds and strengthens interaction between the metal nodes and the guest oxide. As an advanced multinanozyme, the MnOx /q-CeBTC exhibits excellent multiple enzymatic activities at low temperature, and enables abundant and self-cascade ROS generation without H2 O2 addition. This empowers it with high efficiency in bacteria killing, which is also reflected when incorporated into face mask to combat against pathogen invasion even at low temperature. The results achieved in this work provide guidance for rational design of effective bactericide based on nanozyme and broaden their application in personal protective equipment and other fields.

MRI-Guided Tumor Therapy Based on Synergy of Ferroptosis, Immunosuppression Reversal and Disulfidptosis.

Triple negative breast cancer (TNBC) cells have a high demand for oxygen and glucose to fuel their growth and spread, shaping the tumor microenvironment (TME) that can lead to a weakened immune system by hypoxia and increased risk of metastasis. To disrupt this vicious circle and improve cancer therapeutic efficacy, a strategy is proposed with the synergy of ferroptosis, immunosuppression reversal and disulfidptosis. An intelligent nanomedicine GOx-IA@HMON@IO is successfully developed to realize this strategy. The Fe release behaviors indicate the glutathione (GSH)-responsive degradation of HMON. The results of titanium sulfate assay, electron spin resonance (ESR) spectra, 5,5'-Dithiobis-(2-nitrobenzoicacid (DTNB) assay and T1 -weighted magnetic resonance imaging (MRI) demonstrate the mechanism of the intelligent iron atom (IA)-based cascade reactions for GOx-IA@HMON@IO, generating robust reactive oxygen species (ROS). The results on cells and mice reinforce the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis triggered by the GOx-IA@HMON@IO with the following steps: 1) GSH peroxidase 4 (GPX4) depletion by disulfidptosis; 2) IA-based cascade reactions; 3) tumor hypoxia reversal; 4) immunosuppression reversal; 5) GPX4 depletion by immunotherapy. Based on the synergistic mechanisms of ferroptosis, immunosuppression reversal and disulfidptosis, the intelligent nanomedicine GOx-IA@HMON@IO can be used for MRI-guided tumor therapy with excellent biocompatibility and safety.

A novel barrier membrane with long-term ROS scavenging function for complete prevention of postoperative adhesion

Local oxidative stress induced by surgical trauma has been recognized as one of pathogenesis for postsurgical adhesion tissue formation. Herein, tannic acid (TA) based metal-phenolic networks (MPNs) was assembled via chelating with Fe3+, and acted as a novel bio-filler for nanofibrous polycaprolactone (PCL) barrier membrane to endow it with reactive oxygen species (ROS) scavenging capacity. By chelating with Fe3+, the release of TA could last for more than 20 days, rendering the membrane with continuous ROS scavenging capacity. The modified membrane could effectively inhibit fibroblasts adhesion and proliferation, as well as immune cells recruitment, infiltration, and expression of pro-inflammatory cytokines. Consequently, a complete prevention of peritoneal adhesion formation was obtained in a rat model of sidewall defect-cecum abrasion, far better than commercial Poly lactic acid (PLA) membrane. Systematic biological mechanism investigations revealed that the enhanced anti-adhesion function was mainly ascribed to its robust ROS scavenging capacity, through which the PI3K-Akt signaling pathway was blocked, leading to repress of downstream NF-κB-TGFβ1-SMAD signaling pathway, finally inhibiting the bioactivity of fibroblasts and immune cells. This work provided a new strategy for the design of advanced barrier membrane, demonstrated its efficacy and mechanism on preventing postoperative adhesion, holding great promise for future clinical application.

Dye-augmented bandgap engineering of a degradable cascade nanoreactor for tumor immune microenvironment-enhanced dynamic phototherapy of breast cancer

Non-invasive precision tumor dynamic phototherapy has broad application prospects. Traditional semiconductor materials have low photocatalytic activity and low reactive oxygen species (ROS) production rate due to their wide band gap, resulting in unsatisfactory phototherapy efficacy for tumor treatment. Employing the dye-sensitization mechanism can significantly enhance the catalytic activity of the materials. We develop a multifunctional nanoplatform (BZP) by leveraging the benefits of bismuth-based semiconductor nanomaterials. BZP possesses robust ROS generation and remarkable near-infrared photothermal conversion capabilities for improving tumor immune microenvironment and achieving superior phototherapy sensitization. BZP produces highly cytotoxic ROS species via the photocatalytic process and cascade reaction, amplifying the photocatalytic therapy effect. Moreover, the simultaneous photothermal effect during the photocatalytic process facilitates the improvement of therapeutic efficacy. Additionally, BZP-mediated phototherapy can trigger the programmed death of tumor cells, stimulate dendritic cell maturation and T cell activation, modulate the tumor immune microenvironment, and augment the therapeutic effect. Hence, this study demonstrates a promising research paradigm for tumor immune microenvironment-improved phototherapy. Statement of significanceThrough the utilization of dye sensitization and rare earth doping techniques, we have successfully developed a biodegradable bismuth-based semiconductor nanocatalyst (BZP). Upon optical excitation, the near-infrared dye incorporated within BZP promptly generates free electrons, which, under the influence of the Fermi energy level, undergo transfer to BiF3 within BZP, thereby facilitating the effective separation of electron–hole pairs and augmenting the catalytic capability for reactive oxygen species (ROS) generation. Furthermore, a cascade reaction mechanism generates highly cytotoxic ROS, which synergistically depletes intracellular glutathione, thereby intensifying oxidative stress. Ultimately, this dual activation strategy, combining oxidative and thermal damage, holds significant potential for tumor immunotherapy.

Integration of O2-economised tumour-targeted photosensitive magnetic nanomaterials in the diagnosis and therapy of gastric cancer.

Hypoxia in the tumour microenvironment is a major limiting factor in photodynamic therapy. The present study employed a novel O2-economised photosensitizer, ACSN, to effectively curtail oxygen consumption by impeding the aerobic respiration of tumour cells, thereby increasing the reactive oxygen species (ROS) production in photodynamic therapy. To enhance the efficacy of photodynamic therapy, the active targeting peptide iRGD was employed to facilitate drug accumulation in the tumour tissue. Therefore, we constructed a targeted drug platform, ACSN/Fe3O4@MSNs-iRGD, that integrates diagnosis and treatment. The drug exhibited excellent active targeting ability towards gastric cancer MGC-803 cells and can efficiently penetrate the mitochondria upon cellular internalisation. The photosensitizer ACSN, released from the drug, effectively suppressed mitochondrial aerobic respiration to conserve oxygen and exhibited robust ROS production upon laser excitation. The core-shell structure comprises Fe3O4, which offers excellent T2 dark contrast for real-time tumour monitoring through MRI imaging. By incorporating excellent photodynamic therapy and MRI imaging capabilities, this drug can serve as an effective platform for the integration of tumour diagnosis and treatment, thus addressing the limitations associated with conventional tumour therapies. It is anticipated that this approach will soon be clinically translated.

Fe3+ mediated shikonin and PPA coloaded liposomes induce robust immunogenic cell death by integrating ROS enhancement and GSH depletion

Reactive oxygen species (ROS) can not only induce cellular oxidative stress, but also trigger antitumor immune response. However, single ROS generated therapy is usually not enough to induce efficient antitumor immune response. Furthermore, the adaptive antioxidant mechanisms coupled with overexpressed ROS can also decrease the antitumor capacity of ROS therapy. To circumvent this problem, we designed a synergistic strategy for inducing robust ROS based ICD effect by constructing a coloaded liposomes (PPA, Pyropheophorbide-alpha and SHK, shikonin) with Fe3+ gradient to simultaneously enhance ROS mediated oxidative stress and glutathione depletion. Interestingly, the coloaded liposome possesses an acid/GSH dual triggered release profile. More importantly, with the help of depleting GSH, LipoPS (coloaded liposome of SHK and PPA) can excite robust ROS and demonstrate synergistic antitumor efficacy with amplified ICD effect. Summarized, the established coloaded liposome LipoPS exhibits good therapeutic security and synergistic antitumor effect with strong antitumor immune activation, providing potential for further development.

Mitochondria-targeted SkQ1 nanoparticles for dry eye disease: Inhibiting NLRP3 inflammasome activation by preventing mitochondrial DNA oxidation

Dry eye disease (DED) is a multifactorial ocular surface disorder mutually promoted by reactive oxygen species (ROS) and ocular surface inflammation. NLRP3 is the key regulator for inducing ocular surface inflammation in DED. However, the mechanism by which ROS influences the bio-effects of NLRP3, and the consequent development of DED, largely remains elusive. In the present study, we uncovered that robust ROS can oxidate mitochondrial DNA (ox-mtDNA) along with loss of mitochondria compaction causing the cytosolic release of ox-mtDNA and subsequent co-localization with cytosolic NLRP3, which can promote the activation of NLRP3 inflammasome and stimulate NLRP3-mediated inflammation. Visomitin (also known as SkQ1), a mitochondria-targeted anti-oxidant, could reverse such a process by in situ scavenging of mitochondrial ROS. To effectively deliver SkQ1, we further developed a novel mitochondria-targeted SkQ1 nanoparticle (SkQ1 NP) using a charge-driven self-assembly strategy. Compared with free SkQ1, SkQ1 NPs exhibited significantly higher cytosolic- and mitochondrial-ROS scavenging activity (1.7 and 1.9 times compared to levels of the free SkQ1 group), thus exerting a better in vitro protective effect against H2O2-induced cell death in human corneal epithelial cells (HCECs). After topical administration, SkQ1 NPs significantly reduced in vivo mtDNA oxidation, while suppressing the expressions of NLRP3, Caspase-1, and IL-1β, which consequently resulted in better therapeutic effects against DED. Results suggested that by efficiently scavenging mitochondrial ROS, SkQ1 NPs could in situ inhibit DED-induced mtDNA oxidation, thus blocking the interaction of ox-mtDNA and NLRP3; this, in turn, suppressed NLRP3 inflammasome activation and NLRP3-mediated inflammatory signaling. Results suggested that SkQ1 NPs have great potential as a new treatment for DED.

Robust reactive oxygen species production in interfacial reaction between organic acids and biochar: The combined effect of electron acceptance and electron conduction

Interfacial electron transport and reactive oxygen species (ROS) generation in the redox action between biochar (BC) and low-molecular-weight organic acids (LMWOAs) have been overlooked during the utilization of BC in soil amelioration/remediation. Herein, BC and N-doped BC (NBC) with various physicochemical properties were prepared at pyrolysis temperatures of 350, 550 and 750 °C (namely BC/NBC350, 550 and 750) and their interactions with LMWOAs were systematically investigated. Results of ROS quenching and electrochemical cell experiments revealed that BC/NBC could strongly interact with LMWOAs, especially ascorbic acid (AA), and acted as an electron shuttle to mediate one electron transfer from AA to oxygen to generate O2•−, followed by the robust generation of H2O2 and •OH. Interestingly, the generation rates of •OH and H2O2 in the NBC-AA system were significantly higher than that in the BC-AA system, of which the NBC550-AA system exhibited the best performance, enabling its superior ability in bisphenol A degradation. Different from conventional wisdom, the electron shuttle capacity depended on a combined aromatization degree and electron-accepting capacity of BC/NBC. These findings complement the interfacial electron transfer mechanism during the natural BC-LMWOAs interaction and provide new inspiration for the development of green and efficient organic pollutant removal technologies.

Integrating machine learning algorithms to systematically assess reactive oxygen species levels to aid prognosis and novel treatments for triple -negative breast cancer patients.

Breast cancer has become one of the top health concerns for women, and triple-negative breast cancer (TNBC) leads to treatment resistance and poor prognosis due to its high degree of heterogeneity and malignancy. Reactive oxygen species (ROS) have been found to play a dual role in tumors, and modulating ROS levels may provide new insights into prognosis and tumor treatment. This study attempted to establish a robust and valid ROS signature (ROSig) to aid in assessing ROS levels. The driver ROS prognostic indicators were searched based on univariate Cox regression. A well-established pipeline integrating 9 machine learning algorithms was used to generate the ROSig. Subsequently, the heterogeneity of different ROSig levels was resolved in terms of cellular communication crosstalk, biological pathways, immune microenvironment, genomic variation, and response to chemotherapy and immunotherapy. In addition, the effect of the core ROS regulator HSF1 on TNBC cell proliferation was detected by cell counting kit-8 and transwell assays. A total of 24 prognostic ROS indicators were detected. A combination of the Coxboost+ Survival Support Vector Machine (survival-SVM) algorithm was chosen to generate ROSig. ROSig proved to be the superior risk predictor for TNBC. Cellular assays show that knockdown of HSF1 can reduce the proliferation and invasion of TNBC cells. The individual risk stratification based on ROSig showed good predictive accuracy. High ROSig was identified to be associated with higher cell replication activity, stronger tumor heterogeneity, and an immunosuppressive microenvironment. In contrast, low ROSig indicated a more abundant cellular matrix and more active immune signaling. Low ROSig has a higher tumor mutation load and copy number load. Finally, we found that low ROSig patients were more sensitive to doxorubicin and immunotherapy. In this study, we developed a robust and effective ROSig model that can be used as a reliable indicator for prognosis and treatment decisions in TNBC patients. This ROSig also allows a simple assessment of TNBC heterogeneity in terms of biological function, immune microenvironment, and genomic variation.

Phage-Ce6-Manganese Dioxide Nanocomposite-Mediated Photodynamic, Photothermal, and Chemodynamic Therapies to Eliminate Biofilms and Improve Wound Healing

Biofilms have become one of the fundamental issues for chronic infections, while traditional therapies are often ineffective in removing quiescent (persister) cells from biofilms, resulting in a variety of implant-related or nosocomial infections. Recently, bacteriophage (phage) therapy has reflourished in research and clinical trials. However, phage therapy alone manifested many intrinsic defects, including poor biofilm penetration, incomplete clearance of quiescent cells, etc. In this study, a phage-Chlorin e6 (Ce6)-manganese dioxide nanocomposite (PCM) was constructed by mild biomineralization. The results demonstrated that PCM contained both the vigorous activities of host bacterial targeting and efficient delivery of Ce6 to penetrate the biofilm. Assisted with NIR irradiation, robust reactive oxygen species (ROS) was triggered within the biofilm. In the weak acidic and GSH-rich infection niche, PCM was degraded into ultra-small nanosheets, endowing PCM with moderate photothermal therapy (PTT) effects and considerable Mn2+ release, thus exerting strong chemodynamic therapy (CDT) effects in situ. In vivo application demonstrated that the combination of PCM application and NIR irradiation strikingly reduced the pathogen loading, activated innate and adaptive immunity, promoted neocollagen rearrangement, and attenuated cicatricial tissue formation. Our research may pave a new way for bacterial treatment, biofilm-related infections, and other diseases caused by bacteria.

Sono-promoted drug penetration and extracellular matrix modulation potentiate sonodynamic therapy of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) exhibits difficult penetration of most drugs, leading to a very poor therapeutic outcome with a quite low five-year survival rate. The foremost reason is the highly-dense extracellular matrix (ECM) with abundant collagen and fibronectin secreted by the activated pancreatic stellate cells (PSCs). Here, we constructed a sono-responsive polymeric perfluorohexane (PFH) nanodroplet to elicit a deep drug penetration in PDAC via the combination of exogenous ultrasonic (US) exposure and endogenous ECM modulation for potent sonodynamic therapy (SDT) of PDAC. Under US exposure, the rapid drug release and deep penetration in PDAC tissues were realized. The released and well penetrated all-trans retinoic acid (ATRA) as an inhibitor of activated PSCs successfully reduced the secretion of ECM components to form a non-dense matrix conducive to drug diffusion. Meanwhile, the sonosensitizer, manganese porphyrin (MnPpIX), was triggered to produce robust reactive oxygen species (ROS) to exert the SDT effect under US exposure. Furthermore, oxygen (O2) delivered by PFH nanodroplets alleviated tumor hypoxia and enhanced the eradication of cancer cells. Overall, the sono-responsive polymeric PFH nanodroplets were successfully developed as an efficient strategy for PDAC therapy. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a representative refractory cancer with a highly dense extracellular matrix (ECM), making it difficult for most drugs to penetrate the nearly impenetrable desmoplastic stroma. Seeking methods for deep drug penetration is an extremely pressing matter for the treatment of PDAC and many other solid tumors. Herein, we designed a fluoroalkane-modified polymer to prepare a sono-responsive polymeric perfluorohexane (PFH) nanodroplet for loading sonosensitizers, and inhibitors of activated PSCs and O2. Under ultrasonic exposure, the nanodroplet elicited deep drug penetration in PDAC via ultrasonic disturbance and stromal remodeling, inducing potent sonodynamic therapy (SDT) of PDAC. By combining exogenous ultrasonic exposure and endogenous ECM modulation, this work successfully alleviated the severe physiological barrier of PDAC and achieved a favourable treatment effect.

Cartilage-targeting and inflammatory-responsive nanocarriers for effective osteoarthritis treatment via reactive oxygen species scavenging and anti-angiogenesis

Osteoarthritis (OA), a common disabling joint disease, is highly associated with microenvironmental changes in the cartilage and subchondral bone. Elevated reactive oxygen species (ROS) in the cartilage and subchondral bone angiogenesis accelerate articular cartilage erosion. New cartilage-targeting drug delivery systems that are aimed at preventing ROS production and angiogenesis may be of clinical significance for OA treatment. Herein, an ROS scavenger and an inflammatory-responsive nanocarrier are designed by immobilizing the natural polyphenol (curcumin) in chitosan-catechol nanoformulations (Cur-CS-C NPs) via boronate ester. The robust cartilage-targeting effects and ROS scavenging capacities of Cur-CS-C NPs were respectively determined in cartilage explants and chondrocytes. Intra-articular injection of Cur-CS-C NPs in OA rat models efficiently suppressed angiogenesis and cartilage degradation partially via the ROS-mediated NF-κB/PI3K-Akt signaling pathway. The developed curcumin-functionalized nanocarriers can significantly delay OA progression and provide a promising therapeutic strategy for other inflammatory diseases that are characterized by oxidative stress and angiogenesis.

Multifunctional IL-Based Hydrogel Modulator for the Synergistic Acceleration of Wound Healing: Optimizing Drug Solubility, Antioxidant, and Anti-Inflammatory Effects

Inflammatory infection can cause the chronic nonhealing of wounds, posing considerable challenges to skin tissue reconstruction. Thus, an injectable wound dressing hydrogel with multiple functions such as remodelability, self-healing, and enhanced bioavailability has been developed to promote defect tissue regeneration, thereby offering great biomedical value for clinical application. In this study, the etodolac (ETC)-based ionic liquid (IL), LCE, was utilized for the first time as a drug template to enhance the bioavailability of the reference drug (ETC). Silk sericin (SS)/poly(vinyl alcohol) (PVA) hydrogel substrates were used to prepare a novel LCE-loaded hydrogel modulator, Gel-LCE. Additionally, LCE as a main functional group, which exhibited excellent antioxidant activity and high water solubility, was immobilized on the SS/PVA hydrogel via the formation of stable hydrogen bonds, and the fabricated Gel-LCE exhibited excellent biocompatibility and drug utilization, as well as synergistic anti-inflammatory behaviors. Furthermore, this versatile hydrogel (Gel-LCE) could completely fit the irregular wound shape geometry during drug injection, thereby preventing secondary infections. More strikingly, the hydrogel facilitated excellent wound recovery in an experiment involving an animal wound model, reflecting its ability to significantly accelerate wound healing, as further demonstrated by its robust reactive oxygen species (ROS) scavenging capacity, as well as comparable levels of control over inflammatory cytokines (TNF-α and PGE-2). Therefore, this IL-based hydrogel, Gel-LCE, can become a very attractive and popular multifunctional wound dressing material, which can optimize the solubility of the drug to further exert stronger biomedical value.

Flower-like Nanozyme with Highly Porous Carbon Matrix Induces Robust Oxidative Storm against Drug-Resistant Cancer.

Reactive oxygen species (ROS) generators are sparking breakthroughs in sensitization and treatment of therapy-resistant tumors, yet the efficacy is drastically compromised by limited substrate concentrations, short lifetimes of free radicals, and restricted oxidative damage. Herein, a flower-like nanozyme with highly permeable leaflets accommodating catalytic metal sites was developed to address the challenges by boosting substrate and product accessibility. In the formation of a zeolite imidazole framework, cobalt ions promoted catalytic polymerization and deposition of polydopamine. The polymers acted as a stiffener for preventing framework collapse and maneuvering pore reopening during carbonization. The cobalt single-atom/cluster sites in the highly porous matrix generated peroxidase/oxidase-like activities with high catalytic efficiency (Kcat/Km) up to 6 orders of magnitude greater than that of conventional nano-/biozymes. Thereby, a robust ROS storm induced by selective catalysis led to rapid accumulation of oxidative damage and failure of antioxidant and antiapoptotic defense synchronization in drug-resistant cancer cells. By synergy of a redox homeostasis disrupter co-delivered, a significantly high antitumor efficiency was realized in vivo. This work offers a route to kinetically favorable ROS generators for advancing the treatment of therapy-resistant tumors.

A Strategy of Fenton Reaction Cycloacceleration for High-Performance Ferroptosis Therapy Initiated by Tumor Microenvironment Remodeling.

The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H2 O2 , and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)-guided high-performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)-positive tumors based on the CAIX-mediated active targeting, and increased acidification via the inhibition of CAIX by 4-(2-aminoethyl) benzene sulfonamide (ABS) (remodeling TME). This accumulated H+ and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex to release the loaded cuprous oxide nanodots (CON), β-lapachon (LAP), Fe3+ , and gallic acid-ferric ions coordination networks (GF). The Fenton and Fenton-like reactions are cycloaccelerated via the catalytic loop of Fe-Cu, and the LAP-triggered and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1-mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI-guided high-performance ferroptosis therapy of tumors.

Oxygen-vacancy-rich molybdenum carbide MXene nanonetworks for ultrasound-triggered and capturing-enhanced sonocatalytic bacteria eradication

Incurable bacterial infection and intractable multidrug resistance remain critical challenges in public health. A prevalent approach against bacterial infection is phototherapy including photothermal and photodynamic therapy, which is unfortunately limited by low penetration depth of light accompanied with inevitable hyperthermia and phototoxicity damaging healthy tissues. Thus, eco-friendly strategy with biocompatibility and high antimicrobial efficacy against bacteria is urgently desired. Herein, we propose and develop an oxygen-vacancy-rich MoOxin situ on fluorine-free Mo2C MXene with unique neural-network-like structure, namely MoOx@Mo2C nanonetworks, in which their desirable antibacterial effectiveness originates from bacteria-capturing ability and robust reactive oxygen species (ROS) generation under precise ultrasound (US) irradiation. The high-performance, broad-spectrum microbicidal activity of MoOx@Mo2C nanonetworks without damaging normal tissues is validated based on systematic in vitro and in vivo assessments. Additionally, RNA sequencing analysis illuminates that the underlying bactericidal mechanism is attributed to the chaotic homeostasis and disruptive peptide metabolisms on bacteria instigated by MoOx@Mo2C nanonetworks under US stimulation. Considering antibacterial efficiency and a high degree of biosafety, we envision that the MoOx@Mo2C nanonetworks can serve as a distinct antimicrobial nanosystem to fight against diverse pathogenic bacteria, especially eradicating multidrug-resistant bacteria-induced deep tissue infection.