Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.

Pancreatic cancer is a highly fatal disease, and existing treatment methods are ineffective, so it is urgent to develop new effective treatment strategies. The high dependence of pancreatic cancer cells on glucose and glutamine suggests that disrupting this dependency could serve as an alternative strategy for pancreatic cancer therapy. We identified the vital genes glucose transporter 1 (GLUT1) and alanine-serine-cysteine transporter 2 (ASCT2) through bioinformatics analysis, which regulate glucose and glutamine metabolism in pancreatic cancer, respectively. Human serum albumin nanoparticles (HSA NPs) for delivery of GLUT1 and ASCT2 inhibitors, BAY-876/V-9302@HSA NPs, were prepared by a self-assembly process. This nanodrug inhibits glucose and glutamine uptake of pancreatic cancer cells through the released BAY-876 and V-9302, leading to nutrition deprivation and oxidative stress. The inhibition of glutamine leads to the inhibition of the synthesis of the glutathione, which further aggravates oxidative stress. Both of them lead to a significant increase in reactive oxygen species, activating caspase 1 and GSDMD and finally inducing pyroptosis. This study provides a new effective strategy for orthotopic pancreatic cancer treatment by dual starvation-induced pyroptosis. The study for screening metabolic targets using bioinformatics analysis followed by constructing nanodrugs loaded with inhibitors will inspire future targeted metabolic therapy for pancreatic cancer.

Terpinen-4-ol from tea tree oil prevents Aspergillus flavus growth in postharvest wheat grain.

Plant volatile organic compounds (PVOCs) have gained increasing attention for their role in preventing fungal spoilage and insect contamination in postharvest agro-products owing to their effectiveness and sustainability. In this study, the essential oil was extracted from fresh M. alternifolia (tea tree) leaves, and the fumigation vapor of tea tree oil (TTO) completely inhibited the growth of Aspergillus flavus on agar plates at a concentration of 1.714 µL/mL. Terpinen-4-ol was identified as the major component (40.76 %) of TTO volatiles analyzed using headspace gas chromatography-mass spectrometry. Terpinen-4-ol vapor completely inhibited the A. flavus growth on agar plates and 20 % moisture wheat grain at 0.556 and 1.579 µL/mL, respectively, indicating that terpinen-4-ol serves as the main antifungal constituent in TTO volatiles. The minimum inhibitory concentration of terpinen-4-ol in liquid-contact culture was 1.6 µL/mL. Terpinen-4-ol treatment caused depressed, wrinkled, and punctured mycelial morphology and destroyed the plasma membrane integrity of A. flavus. Metabolomics analysis identified significant alterations in 93 metabolites, with 79 upregulated and 14 downregulated in A. flavus mycelia exposed to 1.6 µL/mL terpinen-4-ol for 6 h, involved in multiple cellular processes including cell membrane permeability and integrity, the ABC transport system, pentose phosphate pathway, and the tricarboxylic acid cycle. Biochemical analysis and 2,7-dichlorofluorescein diacetate staining showed that terpinen-4-ol induced oxidative stress and mitochondrial dysfunction in A. flavus mycelia. This study provides new insights into the antifungal effects of the main TTO volatile compounds terpinen-4-ol on the growth of A. flavus.

Glutathione Induced In situ Synthesis of Cu Single-Atom Nanozymes with Anaerobic Glycolysis Metabolism Interference for Boosting Cuproptosis.

Single-atom nanozyme (SAzyme) has sparked increasing interest for catalytic antitumor treatment due to their more tunable and diverse active sites than natural metalloenzymes in complex physiological conditions. However, it is usually a hard task to precisely conduct catalysis at tumor sites after intravenous injection of those SAzyme with high reactivity. Moreover, the explorations of SAzymes in the anticancer application are still in its infancy and need to be developed. Herein, an in situ synthesis strategy for Cu SAzyme was constructed to convert adsorbed copper ions into isolated atoms anchored by oxygen atoms (Cu-O2/Cu-O4) via GSH-responsive deformability of supports. Our results suggest that the in situ activation process could further facilitate the dissociation of copper ions and the consumption of glutathione, thereby leading to copper deposition in cytoplasm and triggering cuproptosis. Moreover, the in situ synthesis of Cu SAzyme with peroxidase-like activity enabled the intracellular reactive oxygen species production, resulting in specifically disturbance of copper metabolism pathway. Meanwhile, the in situ exposed glucose transporter (GLUT) inhibitor phloretin (Ph) can block the glycose uptake to boost cuproptosis efficacy. Overall, this in situ activation strategy effectively diminished the off-target effects of SACs-induced catalytic therapies and introduced a promising treatment paradigm for advancing cuproptosis-associated therapies.

Fabrication of Interface Engineered S-Scheme Heterojunction Nanocatalyst for Ultrasound-Triggered Sustainable Cancer Therapy.

In order to establish a set of perfect heterojunction designs and characterization schemes, step-scheme (S-scheme) BiOBr@Bi2S3 nanoheterojunctions that enable the charge separation and expand the scope of catalytic reactions, aiming to promote the development and improvement of heterojunction engineering is developed. In this kind of heterojunction system, the Fermi levels mediate the formation of the internal electric field at the interface and guide the recombination of the weak redox carriers, while the strong redox carriers are retained. Thus, these high-energy electrons and holes are able to catalyze a variety of substrates in the tumor microenvironment, such as the reduction of oxygen and carbon dioxide to superoxide radicals and carbon monoxide (CO), and the oxidation of H2O to hydroxyl radicals, thus achieving sonodynamic therapy and CO combined therapy. Mechanistically, the generated reactive oxygen species and CO damage DNA and inhibit cancer cell energy levels, respectively, to synergistically induce tumor cell apoptosis. This study provides new insights into the realization of high efficiency and low toxicity in catalytic therapy from a unique perspective of materials design. It is anticipated that this catalytic therapeutic method will garner significant interest in the sonocatalytic nanomedicine field.

Defect-Repaired g-C3N4 Nanosheets: Elevating the Efficacy of Sonodynamic Cancer Therapy Through Enhanced Charge Carrier Migration.

Sonodynamic therapy (SDT) has garnered growing interest owing to its high tissue penetration depth and minimal side effects. However, the lack of efficient sonosensitizers remains the primary limiting factor for the clinical application of this treatment method. Here, defect-repaired graphene phase carbon nitride (g-C3N4) nanosheets are prepared and utilized for enhanced SDT in anti-tumor treatment. After defect engineering optimization, the bulk defects of g-C3N4 are significantly reduced, resulting in higher crystallinity and exhibiting a polyheptazine imide (PHI) structure. Due to the more extended conjugated structure of PHI, facilitating faster charge transfer on the surface, it exhibits superior SDT performance for inducing apoptosis in tumor cells. This work focuses on introducing a novel carbon nitride nanomaterial as a sonosensitizer and a strategy for optimizing sonosensitizer performance by reducing bulk defects.

NADPH Oxidase-Like Nanozyme for High-Efficiency Tumor Therapy Through Increasing Glutathione Consumption and Blocking Glutathione Regeneration.

To counteract the high level of reactive oxygen species (ROS) caused by rapid growth, tumor cells resist oxidative stress by accelerating the production and regeneration of intracellular glutathione (GSH). Numerous studies focus on the consumption of GSH, but the regeneration of GSH will enhance the reduction level of tumor cells to resist oxidative stress. Therefore, inhibiting the regeneration of GSH; while, consuming GSH is of great significance for breaking the redox balance of tumor cells. Herein, a simple termed MnOx-coated Au (AMO) nanoflower, as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) nanoenzyme, is reported for efficient tumor therapy. Au nanoparticles exhibit the capability to catalyze the oxidation of NADPH, hindering GSH regeneration; while, concurrently functioning as a photothermal agent. During the process of eliminating intracellular GSH, MnOx releases Mn2+ that subsequently engages in Fenton-like reactions, ultimately facilitating the implementation of chemodynamic therapy (CDT). Overall, this NOX enzyme-based nanoplatform enhances ROS generation and disrupts the state of reduction equilibrium, inducing apoptosis and ferroptosis by blocking GSH regeneration and increasing GSH consumption, thereby achieving collaborative treatments involving photothermal therapy (PTT), CDT, and catalytic therapy. This research contributes to NADPH and GSH targeted tumor therapy and showcases the potential of nanozymes.

Antifungal effects of carvacrol, the main volatile compound in Origanum vulgare L. essential oil, against Aspergillus flavus in postharvest wheat.

Plant volatile organic compounds (VOCs) with antimicrobial activity could potentially be extremely useful fumigants to prevent and control the fungal decay of agricultural products postharvest. In this study, antifungal effects of volatile compounds in essential oils extracted from Origanum vulgare L. against Aspergillus flavus growth were investigated using transcriptomic and biochemical analyses. Carvacrol was identified as the major volatile constituent of the Origanum vulgare L. essential oil, accounting for 66.01 % of the total content. The minimum inhibitory concentrations of carvacrol were 0.071 and 0.18 µL/mL in gas-phase fumigation and liquid contact, respectively. Fumigation with 0.60 µL/mL of carvacrol could completely inhibit A. flavus proliferation in wheat grains with 20 % moisture, showing its potential as a biofumigant. Scanning electron microscopy revealed that carvacrol treatment caused morphological deformation of A. flavus mycelia, and the resulting increased electrolyte leakage indicates damage to the plasma membrane. Confocal laser scanning microscopy confirmed that the carvacrol treatment caused a decrease in mitochondrial membrane potential, reactive oxygen species accumulation, and DNA damage. Transcriptome analysis revealed that differentially expressed genes were mainly associated with fatty acid degradation, autophagy, peroxisomes, the tricarboxylic acid cycle, oxidative phosphorylation, and DNA replication in A. flavus mycelia exposed to carvacrol. Biochemical analyses of hydrogen peroxide and superoxide anion content, and catalase, superoxide dismutase, and glutathione S-transferase activities showed that carvacrol induced oxidative stress in A. flavus, which agreed with the transcriptome results. In summary, this study provides an experimental basis for the use of carvacrol as a promising biofumigant for the prevention of A. flavus contamination during postharvest grain storage.

Effects of Skeleton Structure of Mesoporous Silica Nanoadjuvants on Cancer Immunotherapy.

Mesoporous silica nanoparticles (MSNs) have been widely praised as nanoadjuvants in vaccine/tumor immunotherapy thanks to their excellent biocompatibility, easy-to-modify surface, adjustable particle size, and remarkable immuno-enhancing activity. However, the application of MSNs is still greatly limited by some severe challenges including the unclear and complicated relationships of structure and immune effect. Herein, three commonly used MSNs with different skeletons including MSN with tetrasulfide bonds (TMSN), MSN containing ethoxy framework (EMSN), and pure -Si-O-Si- framework of MSN (MSN) are comprehensively compared to study the impact of chemical construction on immune effect. The results fully demonstrate that the three MSNs have great promise in improving cellular immunity for tumor immunotherapy. Moreover, the TMSN performs better than the other two MSNs in antigen loading, cellular uptake, reactive oxygen species (ROS) generation, lymph node targeting, immune activation, and therapeutic efficiency. The findings provide a new paradigm for revealing the structure-function relationship of mesoporous silica nanoadjuvants, paving the way for their future clinical application.

NIR-Activatable Heterostructured Nanoadjuvant CoP/NiCoP Executing Lactate Metabolism Interventions for Boosted Photocatalytic Hydrogen Therapy and Photoimmunotherapy.

Near-infrared (NIR) laser-induced photoimmunotherapy has aroused great interest due to its intrinsic noninvasiveness and spatiotemporal precision, while immune evasion evoked by lactic acid (LA) accumulation severely limits its clinical outcomes. Although several metabolic interventions have been devoted to ameliorate immunosuppression, intracellular residual LA still remains a potential energy source for oncocyte proliferation. Herein, an immunomodulatory nanoadjuvant based on a yolk-shell CoP/NiCoP (CNCP) heterostructure loaded with the monocarboxylate transporter 4 inhibitor fluvastatin sodium (Flu) is constructed to concurrently relieve immunosuppression and elicit robust antitumor immunity. Under NIR irradiation, CNCP heterojunctions exhibit superior photothermal performance and photocatalytic production of reactive oxygen species and hydrogen. The continuous heat then facilitates Flu release to restrain LA exudation from tumor cells, whereas cumulative LA can be depleted as a hole scavenger to improve photocatalytic efficiency. Subsequently, potentiated photocatalytic therapy can not only initiate systematic immunoreaction, but also provoke severe mitochondrial dysfunction and disrupt the energy supply for heat shock protein synthesis, in turn realizing mild photothermal therapy. Consequently, LA metabolic remodeling endows an intensive cascade treatment with an optimal safety profile to effectually suppress tumor proliferation and metastasis, which offers a new paradigm for the development of metabolism-regulated immunotherapy.

π Bridge Engineering-Boosted Dual Enhancement of Type-I Photodynamic and Photothermal Performance for Mitochondria-Targeting Multimodal Phototheranostics of Tumor.

Designing mitochondria-targeting phototheranostic agents (PTAs), which can simultaneously possess exceptional and balanced type-I photodynamic therapy (PDT) and photothermal therapy (PTT) performance, still remains challenging. Herein, benzene, furan, and thiophene were utilized as π bridges to develop multifunctional PTAs. STB with thiophene as a π bridge, in particular, benefiting from stronger donor-accepter (D-A) interactions, reduced the singlet-triplet energy gap (ΔES1-T1), allowed more free intramolecular rotation, and exhibited outstanding near-infrared (NIR) emission, effective type-I reactive oxygen species (ROS) generation, and relatively high photothermal conversion efficiency (PCE) of 51.9%. In vitro and in vivo experiments demonstrated that positive-charged STB not only can actively target the mitochondria of tumor cells but also displayed strong antitumor effects and excellent in vivo imaging ability. This work subtly established a win-win strategy by π bridge engineering, breaking the barrier of making a balance between ROS generation and photothermal conversion, boosting a dual enhancement of PDT and PTT performance, and stimulating the development of multimodal imaging-guided precise cancer phototherapy.

Sodium Citrate Nanoparticles Induce Dual-Path Pyroptosis for Enhanced Antitumor Immunotherapy through Synergistic Ion Overload and Metabolic Disturbance.

Metabolic reprogramming, as one of the characteristics of cancer, is associated with tumorigenesis, growth, or migration, and the modulation of metabolic pathways has emerged as a novel approach for cancer therapy. However, the conventional metabolism-mediated apoptosis process in tumor cells exhibits limited immunogenicity and inadequate activation of antitumor immunity. Herein, phospholipid-coated sodium citrate nanoparticles (PSCT NPs) are successfully prepared, which dissolve in tumor cells and then release significant amounts of citrate ions and Na+ ions. Massive quantities of ions lead to increased intracellular osmotic pressure, which activates the caspase-1/gasdermin D (GSDMD) mediated pyroptosis pathway. Simultaneously, citrate induces activation of the caspase-8/gasdermin C (GSDMC) pathway. The combined action of these two pathways synergistically causes intense pyroptosis, exhibiting remarkable antitumor immune responses and tumor growth inhibition. This discovery provides new insight into the potential of nanomaterials in modulating metabolism and altering cell death patterns to enhance antitumor immunotherapy.

Tumor Microenvironment-Activated Nanocomposite for Self-Amplifying Chemodynamic/Starvation Therapy Enhanced IDO-Blockade Tumor Immunotherapy.

Disrupting intracellular redox homeostasis combined with immune checkpoint blockade therapy is considered as an effective way to accelerate tumor cell death. However, suppressed tumor immune microenvironment and lower cargo delivery restrict the efficiency of tumor therapy. In this study, a multifunctional tumor microenvironment (TME)-responsive nanocomposite is constructed using manganese tetroxide (Mn3 O4 )-decorated disulfide-bond-incorporated dendritic mesoporous organosilica nanoparticles (DMONs) to co-deliver indoleamine 2,3-dioxygenase (IDO) inhibitor Epacadostat (IDOi) and glucose oxidase (GOx) following modification with polyethylene glycol. Owing to the responsiveness of Mn3 O4 -decorated DMONs to the mildly acidic and glutathione (GSH) overexpressed TME, the nanocomposite can rapidly decompose and release inner contents, thus substantially improving the cargo release ability. Mn3 O4 can effectively catalyze hydrogen peroxide (H2 O2 ) decomposition to generate oxygen, enhance the ability of GOx to consume glucose to produce H2 O2 , and further promote the generation of hydroxyl radicals (•OH) by Mn2+ . Furthermore, Mn2+ -mediated GSH depletion and the production of •OH can disrupt intracellular redox homeostasis, contributing to immunogenic cell death. Simultaneously, IDOi can inhibit IDO to reverse inhibited immune response. The results show that self-amplifying chemodynamic/starvation therapy combined IDO-blockade immunotherapy synergistically inhibits tumor growth and metastasis in vivo.

Transcriptomic and biochemical analyses revealed antifungal mechanism of trans-anethole on Aspergillus flavus growth.

Plant volatile compounds have great potential for preventing and controlling fungal spoilage in post-harvest grains. Recently, we have reported the antifungal effects of trans-anethole, the main volatile constituent of the Illicium verum fruit, on Aspergillus flavus. In this study, the inhibitory mechanisms of trans-anethole against the growth of A. flavus mycelia were investigated using transcriptomic and biochemical analyses. Biochemical and transcriptomic changes in A. flavus mycelia were evaluated after exposure to 0.2 µL/mL trans-anethole. Scanning electron microscopy showed that trans-anethole treatment resulted in the surface wrinkling of A. flavus mycelia, and calcofluor white staining confirmed that trans-anethole treatment disrupted the mycelial cell wall structure. Annexin V-fluorescein isothiocyanate/propidium iodide double staining suggested that trans-anethole induced apoptosis in A. flavus mycelia. Reduced mitochondrial membrane potential and DNA damage were observed in trans-anethole-treated A. flavus mycelia using 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine and 4',6-diamidino-2-phenylindole staining, respectively. 2',7'- Dichloro-dihydro-fluorescein diacetate staining and biochemical assays demonstrated that trans-anethole treatment cause the accumulation of reactive oxygen species in the A. flavus mycelia. Transcriptome results showed that 1673 genes were differentially expressed in A. flavus mycelia exposed to trans-anethole, which were mainly associated with multidrug transport, oxidative phosphorylation, citric acid cycle, ribosomes, and cyclic adenosine monophosphate signaling. We propose that trans-anethole can inhibit the growth of A. flavus mycelia by disrupting the cell wall structure, blocking the multidrug transport process, disturbing the citric acid cycle, and inducing apoptosis. This study provides new insights into the inhibitory mechanism of trans-anethole on A. flavus mycelia and will be helpful for the development of natural fungicides. KEY POINTS: • Biochemical analyses of A. flavus mycelia exposed to trans-anethole were performed • Transcriptomic changes in trans-anethole-treated A. flavus mycelia were analyzed • An inhibitory mechanism of trans-anethole on the growth of A. flavus mycelia was proposed.

Sodium Bicarbonate Nanoparticles for Amplified Cancer Immunotherapy by Inducing Pyroptosis and Regulating Lactic Acid Metabolism.

Although immunotherapy has a broad clinical application prospect, it is still hindered by low immune responses and immunosuppressive tumor microenvironment. Herein, a simple and drug-free inorganic nanomaterial, alkalescent sodium bicarbonate nanoparticles (NaHCO3 NPs), is prepared via a fast microemulsion method for amplified cancer immunotherapy. The obtained alkalescent NaHCO3 regulates lactic acid metabolism through acid-base neutralization so as to reverse the mildly acidic immunosuppressive tumor environment. Additionally, it can further release high amounts of Na+ ions inside tumor cells and induce a surge in intracellular osmolarity, and thus activate the pyroptosis pathway and immunogenic cell death (ICD), release damage-associated molecular patterns (DAMPs) and inflammatory factors, and improve immune responses. Collectively, NaHCO3 NPs observably inhibit primary/distal tumor growth and tumor metastasis through acid neutralization remitted immunosuppression and pyroptosis induced immune activation, showing an enhanced antitumor immunity efficiency. This work provides a new paradigm for lactic acid metabolism and pyroptosis mediated tumor treatment, which has a potential for application in clinical tumor immunotherapy.

Defect Engineering in Biomedical Sciences.

With the promotion of nanochemistry research, large numbers of nanomaterials have been applied in vivo to produce desirable cytotoxic substances in response to endogenous or exogenous stimuli for achieving disease-specific therapy. However, the performance of nanomaterials is a critical issue that is difficult to improve and optimize under biological conditions. Defect-engineered nanoparticles have become the most researched hot materials in biomedical applications recently due to their excellent physicochemical properties, such as optical properties and redox reaction capabilities. Importantly, the properties of nanomaterials can be easily adjusted by regulating the type and concentration of defects in the nanoparticles without requiring other complex designs. Therefore, this tutorial review focuses on biomedical defect engineering and briefly discusses defect classification, introduction strategies, and characterization techniques. Several representative defective nanomaterials are especially discussed in order to reveal the relationship between defects and properties. A series of disease treatment strategies based on defective engineered nanomaterials are summarized. By summarizing the design and application of defective engineered nanomaterials, a simple but effective methodology is provided for researchers to design and improve the therapeutic effects of nanomaterial-based therapeutic platforms from a materials science perspective.

Iron oxide-EDTA nanoparticles for chelation-enhanced chemodynamic therapy and ion interference therapy.

As an emerging anti-tumor strategy, chemodynamic therapy (CDT) utilizes a Fenton/Fenton-like reaction to generate highly toxic hydroxyl radicals to kill tumor cells. However, the efficiency of CDT is still hindered by the low Fenton/Fenton-like reaction rate. Herein, we report the combination of ion interference therapy (IIT) and chemodynamic therapy (CDT) via an amorphous iron oxide (AIO) nanomedicine with encapsulated EDTA-2Na (EDTA). Iron ions and EDTA are released from the nanomedicine in acidic tumors and chelate to form iron ion-EDTA, which improves the efficiency of CDT and promotes the generation of reactive oxygen species (ROS). In addition, EDTA can disrupt the homeostasis of Ca2+ in tumor cells by chelating with Ca2+ ions, which induces the separation of tumor cells and affects normal physiological activities. Both in vitro and in vivo experiments show that the nano chelating drugs exhibit significant improvement in Fenton reaction performance and excellent anti-tumor activity. This study based on chelation provides a new idea for designing efficient catalysts to enhance the Fenton reaction and provides more revelations on future research on CDT.

Assembling AgAuSe Quantum Dots with Peptidoglycan and Neutrophils to Realize Enhanced Tumor Targeting, NIR (II) Imaging, and Sonodynamic Therapy.

Significant progress is made in drug delivery systems, but they still face problems such as poor stability in vivo, off-target drugs, and difficulty in crossing biological barriers. It is urgent to realize efficient targeted delivery and precisely controlled sustained release of drugs by using the integrated nanoplatform. Theranostic nanoplatform is a new biomedical technology that combines diagnosis or monitoring of diseases with treatment. Here, an integrated strategy of diagnosis and treatment is reported for delivering NIR-II imaged and therapeutic AgAuSe quantum dots (QDs) carried by peptidoglycan multilayer networks of bacteria to hitchhike circulating neutrophils for targeting the tumor. The assembled nanomaterials have good stability, which can not only initiate endogenous cells for drug delivery and achieve efficient targeting, but also guide drug imaging with excellent fluorescence property. Meanwhile, the elimination of established solid tumor is achieved with the administration of sonodynamic therapy without recurrence. This drug system expands the application of endogenous cell to participate in drug delivery system. Thus, the assembly strategy demonstrates the potential of endogenous neutrophils in functioning as natural drug vehicles and the application of NIR-II fluorescent QDs in biomedical engineering.

Construction of Multiform Hollow-Structured Covalent Organic Frameworks via a Facile and Universal Strategy for Enhanced Sonodynamic Cancer Therapy.

The special structural morphology of hollow covalent organic frameworks (HCOFs) has an important influence on their applications. However, the rapid and precise control of morphology for HCOFs still remains largely challenging. Herein, we present a facile and universal two-step strategy based on solvent evaporation and oxidation of imine bond for the controllable synthesis of HCOFs. The strategy enables to prepare HCOFs in a greatly shortened reaction time and seven kinds of HCOFs are fabricated by the oxidation of imine bond via hydroxyl radicals (⋅OH) generated from Fenton reaction. Importantly, a fascinating library of HCOFs with diverse nanostructures, including bowl-like, yolk-shell, capsule-like and flower-like morphologies, has been ingeniously constructed. Owing to the large cavities, the obtained HCOFs are ideal candidates for drug delivery, which are employed to load five small molecule drugs, achieving the enhanced sonodynamic cancer therapy in vivo.

Heterostructural Nanoadjuvant CuSe/CoSe2 for Potentiating Ferroptosis and Photoimmunotherapy through Intratumoral Blocked Lactate Efflux.

The desirable curative effect in clinical immunotherapy has been challenging due to the immunosuppressive tumor microenvironment (TME) with high lactic acid (LA) metabolism in solid tumors. Although targeting metabolic reprogramming of tumor cells can restore the survival and function of immune cells in the TME, it is also plagued by insufficient immunogenicity. Herein, an activatable immunomodulatory nanoadjuvant CuSe/CoSe2@syrosingopine (CSC@Syro) is constructed for simultaneously relieving immunosuppressive TME and boosting tumor immune response. Specifically, CuSe/CoSe2 (CSC) exhibits TME-activated glutathione (GSH) depletion and hydroxyl radical (•OH) generation for potential ferroptosis. Meanwhile, the remarkable photothermal conversion efficiency and elevated photocatalytic ROS level both promote CSC heterostructures to induce robust immunogenic cell death (ICD). Besides, the loaded syrosingopine inhibitor achieves LA metabolism blockade in cancer cells by downregulating the expression of monocarboxylate transporter 4 (MCT4), which could sensitize ferroptosis by intracellular milieu acidification and neutralize the acidic TME to alleviate immunosuppression. Hence, advanced metabolic modulation confers the potentiated immune infiltration of ICD-stimulated T lymphocytes and further reinforces antitumor therapy. In brief, CSC@Syro-mediated synergistic therapy could elicit potent immunogenicity and suppress tumor proliferation and metastasis effectually by integrating the tumor metabolic regulation and ferroptosis with immunotherapy.

Fe(III)-Naphthazarin Metal-Phenolic Networks for Glutathione-Depleting Enhanced Ferroptosis-Apoptosis Combined Cancer Therapy.

Nowadays, Fenton chemistry-based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H2 O2 into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one-step strategy for the construction of Fe3+ -naphthazarin metal-phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH2 -PEG-NH2 , is developed. The carrier-free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe3+ , which is further reduced to Fe2+ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)-triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe2+ as a T1 -weighted contrast agent endows the FNP MPNs with magnetic resonance imaging (MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.