Endogenous Peroxide Research Articles

Self‐Oxygenated Biomimetic Nanozyme for Tumor Catalytic Immunotherapy

AbstractThe treatment of solid tumors remains a significant challenge due to the complex, immunosuppressive tumor microenvironment (TME). This manuscript introduces the self‐oxygenated biomimetic nanozyme system, SS‐MSN@Au‐BOM, which innovatively combines catalytic therapy with immunotherapy to modulate the TME for enhanced therapeutic efficacy. Employing mesoporous silicon nanoparticles doped with disulfide bonds, the system integrates gold nanozymes that exhibit glucose oxidase (GOx)‐like and peroxidase (POD)‐like activities, along with a catalase (CAT) function derived from bacterial outer membrane (BOM) coatings. SS‐MSN@Au‐BOM significantly disrupted tumor growth by catalyzing endogenous hydrogen peroxide to generate cytotoxic ROS and essential oxygen, enhancing intratumoral ROS levels while alleviating hypoxia. This catalytic action facilitates immunogenic cell death, enhances dendritic cell maturation, and T‐cell activation. Notably, the system shows excellent biocompatibility, effective tumor targeting, and prolonged systemic circulation. SS‐MSN@Au‐BOM offers a dual‐functional approach that effectively disrupts the TME and promotes robust antitumor immunity. This study paves the way for further clinical investigation and the development of enzyme‐based therapeutics, potentially transforming the landscape of cancer treatment.

Multifunctional nanoplatform with near-infrared triggered nitric-oxide release for enhanced tumor ferroptosis

Ferroptosis has emerged as a promising strategy for cancer treatment. Nevertheless, the efficiency of ferroptosis-mediated therapy remains a challenge due to high glutathione (GSH) levels and insufficient endogenous hydrogen peroxide in the tumor microenvironment. Herein, we presented a nitric-oxide (NO) boost-GSH depletion strategy for enhanced ferroptosis therapy through a multifunctional nanoplatform with near-infrared (NIR) triggered NO release. The nanoplatform, IS@ATF, was designed that self-assembled by loading the NO donor L-arginine (L-Arg), ferroptosis inducer sorafenib (SRF), and indocyanine green (ICG) onto tannic acid (TA)-Fe3+‒metal-phenolic networks (MPNs) modified with hydroxyethyl starch. Inside the tumor, SRF could inhibit GSH biosynthesis, impair the activation of glutathione peroxidase 4, and disrupt the ferroptosis defensive system. In conjunction with TA-Fe3+‒MPNs, which has cascaded Fenton catalytic activity, it could navigate the lethal ferroptosis to cancer cells. Upon NIR laser irradiation, the ICG-generated ROS oxidated L-Arg to a substantial quantity of NO, which further depleted the intracellular GSH and caused LPO accumulation, enhancing cell ferroptosis. Moreover, ICG also serves as a photothermal agent that can produce hyperthermia when exposed to irradiation, further potentiating ferroptosis therapy. In addition, the nanoplatform showed significantly improved tumor therapeutic efficacy and anti-metastasis efficiency. This work thus demonstrated that utilizing NO boost-GSH depletion to enhance ferroptosis induction is a feasible and promising strategy for cancer treatment.Graphical abstract

Evidence for endogenous hydrogen peroxide production by E. coli fatty acyl-CoA dehydrogenase.

Aerobic organisms continuously generate internal superoxide and hydrogen peroxide, which can damage enzymes and impair growth. To avoid this problem cells maintain high levels of superoxide dismutases, catalases, and peroxidases. Surprisingly, we do not know the primary sources of these reactive oxygen species (ROS) in living cells. However, in vitro studies have shown that flavoenzymes can inadvertently transfer electrons to oxygen. Therefore, it seems plausible that substantial ROS may be generated when large metabolic fluxes flow through flavoproteins. Such a situation may arise during the catabolism of fatty acids. Acyl-CoA dehydrogenase (FadE) is a flavoprotein involved in each turn of the beta-oxidation cycle. In the present study the catabolism of dodecanoic acid specifically impaired the growth of strains that lack enzymes to scavenge hydrogen peroxide. The defect was absent from fadE mutants. Direct measurements confirmed that the beta-oxidation pathway amplified the rate of intracellular hydrogen peroxide formation. Scavenging-proficient cells did not display the FadE-dependent growth defect. Those cells also did not induce the peroxide stress response during dodecanoate catabolism, indicating that the basal defenses are sufficient to cope with moderately elevated peroxide formation. In vitro work still is needed to test whether the ROS evolve specifically from the FadE flavin site and to determine whether superoxide as well as peroxide is released. At present such experiments are challenging because the natural redox partner of FadE has not been identified. This study supports the hypothesis that the degree of internal ROS production can depend upon the type of active metabolism inside cells.

The Metallothionein System in Tetrahymena thermophila Is Iron-Inducible.

Metallothioneins are multifunctional proteins implicated in various cellular processes. They have been used as biomarkers of heavy metal exposure and contamination due to their intrinsic ability to bind heavy metals and their transcriptional response to both physiological and noxious metal ions such as cadmium (Cd) and mercury (Hg). In this study, we aimed to clarify the role of iron and reactive oxygen species (ROSs) in the induction of the metallothionein system (Mtt) in the ciliate protozoan Tetrahymena thermophila. We investigated the relative mRNA abundances of the metallothionein genes Mtt1, Mtt2/4, and Mtt5, revealing for the first time their responsiveness to iron exposure. Furthermore, by using inhibitors of superoxide dismutase (SOD) and catalase (CAT), alone or in combination with iron, we highlighted the roles of superoxide ion and endogenous hydrogen peroxide, as well as the complex interplay between the metal and ROSs. These results enhance our understanding of the metallothionein system in ciliates and suggest that ROSs may be a primary evolutionary driver for the selection of these proteins in nature.

Shortening the early diagnostic window of Hg2+-induced liver injury with a H2O2-activated fluorescence/afterglow imaging assay

Mercury ions (Hg2+) and mercury derivatives are a serious threat to ecosystems and human health due to their toxicity, and their toxicological effects are associated with a burst of reactive oxygen species (ROS) due to the oxidative stress. Endogenous hydrogen peroxide (H2O2), a featured ROS in vivo, plays an irreplaceable role in a significant number of pathological processes. However, the exact bioeffect role that H2O2 plays in Hg2+-induced oxidative stress in a specific disease has not been well answered. In particular, optical imaging probes for H2O2 endowed with afterglow emission properties are very rare. Here, the first fluorescence/afterglow probe (FA-H2O2) for accurate and specific detection of H2O2 in cells, zebrafish, and mice under Hg2+-induced oxidative stress is reported. Moreover, FA-H2O2 in its afterglow emission enables efficient monitoring of endogenous H2O2 with a higher signal-to-noise ratio (SNR) in comparison to its fluorescence signals. More importantly, by virtue of the merits of afterglow emission that can eliminate autofluorescence, thus for the first time, shortening the diagnostic window of Hg2+-induced liver injury with FA-H2O2 via noninvasive afterglow emission tracking of H2O2 is achieved, which definitely provides a new opportunity and promising tool for early diagnosis of Hg2+-induced liver injury.

Endogenous hydrogen peroxide positively regulates secretion of a gut-derived peptide in neuroendocrine potentiation of the oxidative stress response in C. elegans.

The gut-brain axis mediates bidirectional signaling between the intestine and the nervous system and is critical for organism-wide homeostasis. Here we report the identification of a peptidergic endocrine circuit in which bidirectional signaling between neurons and the intestine potentiates the activation of the antioxidant response in C. elegans in the intestine. We identify a FMRF-amide-like peptide, FLP-2, whose release from the intestine is necessary and sufficient to activate the intestinal oxidative stress response by promoting the release of the antioxidant FLP-1 neuropeptide from neurons. FLP-2 secretion from the intestine is positively regulated by endogenous hydrogen peroxide (H2O2) produced in the mitochondrial matrix by sod-3/superoxide dismutase, and is negatively regulated by prdx-2/peroxiredoxin, which depletes H2O2 in both the mitochondria and cytosol. H2O2 promotes FLP-2 secretion through the DAG and calciumdependent protein kinase C family member pkc-2 and by the SNAP25 family member aex-4 in the intestine. Together, our data demonstrate a role for intestinal H2O2 in promoting inter-tissue antioxidant signaling through regulated neuropeptide-like protein exocytosis in a gut-brain axis to activate the oxidative stress response.

A BODIPY-Ferrocene Conjugate for the Combined Photodynamic Therapy and Chemodynamic Therapy with Improved Antitumor Efficiency.

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (⋅OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and ⋅OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.

Defect engineering synergistically boosts the catalytic activity of Fe-MoOv for highly efficient breast mesh antitumor therapy

The demand for breast mesh with antitumor properties is critical in post-mastectomy breast reconstruction to prevent local tumor recurrence. Molybdenum-based oxide (MoOx) exhibits enzyme-like activities by catalyzing endogenous hydrogen peroxide to produce reactive oxygen species for inducing tumor cell apoptosis. However, its catalytic activity is limited by insufficient active sites. Herein, a defect engineering strategy is proposed to create redox nanozymes with multiple enzymatic activities by incorporating Fe into MoOx (Fe-MoOv). Fe-MoOv is subsequently integrated into polycaprolactone (PCL) to fabricate breast meshes for establishing an enzyme-catalyzed antitumor platform. The doping of Fe into MoOx formed numerous defect sites, including oxygen vacancies (OV) and Fe substitution sites, synergistically boosting the binding capacity and catalytic activity of Fe-MoOv. Density functional theory calculations demonstrated that the outstanding peroxidase-like catalytic activity of Fe-MoOv resulted from the synergy between OV and Fe sites. Additionally, OV contributes to the localized surface plasmon resonance effect, enhancing the photothermal capability of the PCL/Fe-MoOv mesh. Upon near-infrared laser exposure, the catalytic activity of the PCL/Fe-MoOv mesh is further improved, leading to increased generation of reactive oxygen species and enhanced antitumor efficacy, achieving 86.7% tumor cell mortality, a 264% enhancement compared to the PCL/MoOx mesh.

Ultrasmall iridium-encapsulated porphyrin metal-organic frameworks for enhanced photodynamic/catalytic therapy by producing reactive oxygen species storm

Transition metal-coordinated porphyrin metal-organic frameworks (MOFs) were perspective in photodynamic therapy (PDT) and catalytic therapy. However, the tumor hypoxia and the insufficient endogenous hydrogen peroxide (H2O2) seriously limited their efficacies. Herein, by encapsulating ultrasmall iridium (Ir) and modifying glucose oxidase (GOx), an iron-coordinated porphyrin MOF (Fe-MOF) nanoplatform (Fe-MOF@Ir/GOx) was designed to strengthen PDT/catalytic therapy by producing reactive oxygen species (ROS) storm. In this nanoplatform, Fe-MOF showed glutathione (GSH)-responsive degradation, by which porphyrin, GOx and ultrasmall Ir were released. Moreover, ultrasmall Ir possessed dual-activities of catalase (CAT)-like and peroxidase (POD)-like, which provided sufficient oxygen (O2) to enhance PDT efficacy, and hydroxyl radical (·OH) production was also improved by combining Fenton reaction of Fe2+. Further, GOx catalyzed endogenous glucose produced H2O2, also reduced pH value, which accelerated Fenton reaction and resulted in generation of ROS storm. Therefore, the developed Fe-MOF@Ir/GOx nanoplatform demonstrated enhanced PDT/catalytic therapy by producing ROS storm, and also provided a promising strategy to promote degradation/metabolism of inorganic nanoplatforms.

Probing trace of intracellularly-originated hydrogen peroxide based Pt–Cd bimetallic nanozyme on an enzyme-free electrochemical sensor

BackgroundMeasurement of endogenous cellular hydrogen peroxide (H2O2) can provide information on cellular status, and help to understand cellular metabolism and signaling processes, thus contributing to elucidation of disease mechanisms and new diagnostics/therapeutic approaches. ResultsIn this work, Pt–Cd bimetallic nanozyme was successfully prepared via the solvothermal synthetic method for sensitive detection of H2O2. The synthesized Pt–Cd bimetallic nanozyme could exhibited good electrochemical activity. Then, the materials were analyzed for the electrochemical properties and catalytic properties of H2O2 by cyclic voltammetry and chronoamperometry, respectively. Results indicated that the synthesized nanozyme had superior sensitivity (295 μA⸳mM−1⸳cm−2) and selectivity toward H2O2 with a detection limit of 0.21 μM. Further, the Pt–Cd bimetallic nanozyme displayed good electrochemical properties compared to platinum catalysts alone. The application was extended to determine the produced H2O2 from human hepatocellular carcinoma cells (HepG2) and normal hepatocyte (LO2) samples after ascorbic acid stimulation, thus enabling the early warning of cellular carcinogenesis. SignificanceThis strategy promises simple, rapid, inexpensive and effective electrochemical sensing and provides a new pathway for the synthesis of bimetallic nanozymes to construct an electrochemical sensor for the sensitive detection of H2O2.

A Self-Catalytic NO/O2 Gas-Releasing Nanozyme for Radiotherapy Sensitization through Vascular Normalization and Hypoxia Relief.

Radiotherapy (RT), essential for treating various cancers, faces challenges from tumor hypoxia, which induces radioresistance. A tumor-targeted "prosthetic-Arginine" coassembled nanozyme system, engineered to catalytically generate nitric oxide (NO) and oxygen (O2) in the tumor microenvironment (TME), overcoming hypoxia and enhancing radiosensitivity is presented. This system integrates the prosthetic heme of nitric oxide synthase (NOS) and catalase (CAT) with NO-donating Fmoc-protected Arginine and Ru3+ ions, creating HRRu nanozymes that merge NOS and CAT functionalities. Surface modification with human heavy chain ferritin (HFn) improves the targeting ability of nanozymes (HRRu-HFn) to tumor tissues. In the TME, strategic arginine incorporation within the nanozyme allows autonomous O2 and NO release, triggered by endogenous hydrogen peroxide, elevating NO and O2 levels to normalize vasculature and improve blood perfusion, thus mitigating hypoxia. Employing the intrinsic O2-transporting ability of heme, HRRu-HFn nanozymes also deliver O2 directly to the tumor site. Utilizing esophageal squamous cell carcinoma as a tumor model, the studies reveal that the synergistic functions of NO and O2 production, alongside targeted delivery, enable the HRRu-HFn nanozymes to combat tumor hypoxia and potentiate radiotherapy. This HRRu-HFn nanozyme based approach holds the potential to reduce the radiation dose required and minimize side effects associated with conventional radiotherapy.

Dual-enzyme inhibiting nanomedicines for enhanced cancer chemodynamic therapy by inducing intratumoral acidosis

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Tumor-targeted delivery of hyaluronic acid/polydopamine-coated Fe2+-doped nano-scaled metal–organic frameworks with doxorubicin payload for glutathione depletion-amplified chemodynamic-chemo cancer therapy

Chemodynamic therapy (CDT), an emerging cancer treatment modality, uses multivalent metal elements to convert endogenous hydrogen peroxide (H2O2) to toxic hydroxyl radicals (•OH) via a Fenton or Fenton-like reaction, thus eliciting oxidative damage of cancer cells. However, the antitumor potency of CDT is largely limited by the high glutathione (GSH) concentration and low catalytic efficiency in the tumor sites. The combination of CDT with chemotherapy provides a promising strategy to overcome these limitations. In this work, to enhance antitumor potency by tumor-targeted and GSH depletion-amplified chemodynamic-chemo therapy, the hyaluronic acid (HA)/polydopamine (PDA)-decorated Fe2+-doped ZIF-8 nano-scaled metal–organic frameworks (FZ NMs) were fabricated and utilized to load doxorubicin (DOX), a chemotherapy drug, via hydrophobic, π-π stacking and charge interactions. The attained HA/PDA-covered DOX-carrying FZ NMs (HPDFZ NMs) promoted DOX and Fe2+ release in weakly acidic and GSH-rich milieu and exhibited acidity-activated •OH generation. Through efficient CD44-mediated endocytosis, the HPDFZ NMs internalized by CT26 cells not only prominently enhanced •OH accumulation by consuming GSH via PDA-mediated Michael addition combined with Fe2+/Fe3+ redox couple to cause mitochondria damage and lipid peroxidation, but also achieved intracellular DOX release, thus eliciting apoptosis and ferroptosis. Importantly, the HPDFZ NMs potently inhibited CT26 tumor growth in vivo at a low DOX dose and had good biosafety, thereby showing promising potential in tumor-specific treatment.

H2O2 Self‐Supplied Chemodynamic Nanosystem Enhanced by Ca2+ Interference and Starvation Strategy for Targeted Cancer Therapy

AbstractChemodynamic therapy (CDT) has received increasing attention in recent years due to its effectiveness and specificity. However, the limited endogenous hydrogen peroxide (H2O2) concentration and resistance to reactive oxygen species in cancer cells hinder the further application of CDT. Here, an H2O2 self‐supplied nanosystem FCaO2@ZIF‐67‐2‐DG‐FA (FZDF) is synthesized to achieve efficient CDT improvement by Ca2+ overload and starvation therapy. Under folic acid‐mediated tumor targeting and endocytosis, the ZIF‐67 layer of FZDF is cleaved in the mildly acidic environment, releasing Co2+ and 2‐deoxy‐D‐glucose (2‐DG). The decomposition of exposed FCaO2 generates sufficient H2O2, which further produces abundant •OH via the Fenton‐like reaction of Co2+. Simultaneously, Ca2+ overload‐triggered mitochondrial dysfunction couples with glycolysis inhibition via 2‐DG‐induced starvation, which disrupts intracellular adenosine triphosphate (ATP) synthesis and amplifies the efficacy of CDT. Silicon nanoparticles released from FCaO2 are applied as in vitro fluorescent probes to image tumor cells overexpressing folate receptors. The results have presented that FZDF can actively accumulate in tumor cells, causing the mitochondrial membrane potential abnormality and a decrease in intracellular ATP content, thereby enhancing the self‐supplied CDT with less effect on normal cells and tissues. This work provides a novel strategy for constructing effective CDT nanosystems by hindering intracellular energy supply.

Iron(III) Binding Properties of PF1140, a Fungal N-Hydroxypyridone, and Activity against Mycoplasma genitalium.

Mycoplasma genitalium is a sexually transmitted bacterium associated with urogenital disease syndromes in the US and worldwide. The global rise in drug resistance in M. genitalium necessitates the development of novel drugs to treat this pathogen. To address this need, we have screened extracts from a library of fungal isolates assembled through the University of Oklahoma Citizen Science Soil Collection Program. Analysis of one of the bioactive extracts using bioassay-guided fractionation led to the purification of the compound PF1140 (1) along with a new and several other known pyridones. The N-hydroxy pyridones are generally regarded as siderophores with high binding affinity for iron(III) under physiological conditions. Results from UV-vis absorption spectroscopy-based titration experiments revealed that 1 complexes with Fe3+. As M. genitalium does not utilize iron, we propose that the PF1140-iron complex induces cytotoxicity by facilitating the cellular uptake of iron, which reacts with endogenous hydrogen peroxide to produce toxic hydroxyl radicals.

NIR activated upconversion based nanocatalysts for CT/PA imaging-guided triple synergistic PTT/PDT/CDT cancer treatment

Photodynamic therapy (PDT), as a non-invasive treatment, is expected to be widely used in clinical cancer treatment. In this paper, a near-infrared (NIR) light responsive Lu2O3:Yb/Er/Li-Ce6@MIL-101/GOx-PDA (LCMGP) nanodiagnostic platform was prepared for CT/PA imaging-guided multimodality synergistic therapy. Under 808 nm laser irradiation, Lu2O3:Yb/Er/Li-Ce6 (LC) NPs in the nano-diagnostic platform are activated and sensitized by NIR light, resulting in the generation of more single-linear oxygen (1O2) for efficient PDT. Glucose oxidase (GOx) and MIL-101 (Fe) nanozymes can utilize their excellent enzyme cascade catalytic properties and peroxidase-like catalytic properties to undergo glycolysis reactions and catalyze the decomposition of endogenous hydrogen peroxide (H2O2), producing a large amount of hydroxyl radicals (•OH), achieving efficient chemodynamic therapy (CDT). The functionalized modification of polydopamine (PDA) endows the LCMGP nanoparticles with higher photothermal conversion efficiency, which can prompt high local temperature at the tumor site under the irradiation of NIR light to achieve efficient photothermal therapy (PTT). In addition, hyperthermia accelerates the catalytic efficiency of the nanozymatic cascade of LCMGP nanoparticles to enhance ROS production while increasing cellular uptake, resulting in PTT-induced PDT/CDT synergistic effect (96%). Based on the excellent photothermal conversion effect of PDA and the high X-ray attenuation effect of Lu/Fe, the LCMGP nanotherapeutic system demonstrates good CT/PA imaging function, providing new insights and ideas for imaging-mediated multimodal synergistic therapy.

A novel AIE fluorescent probe for the detection and imaging of hydrogen peroxide in living tumor cells and in vivo

Hydrogen peroxide (H2O2), a key reactive oxygen species (ROS), plays crucial roles in redox signaling pathways and immune responses associated with cell proliferation, differentiation, migration, and disease progression. The selective monitoring of overproduced H2O2 is important for understanding the diagnosis and pathogenesis of diseases such as cardiovascular disease, cancers, diabetes, Parkinson’s disease, Alzheimer’s disease, and inflammation. In this paper, an AIE fluorescent probe BQM-H2O2 was developed by connecting phenyl borate with the fluorophore BQM-PNH for selective detection of H2O2. In the presence of H2O2 at fw = 99% (pH = 7.4, 1% DMSO), the probe BQM-H2O2 could generate strong fluorescent signals due to the oxidation of the borate ester. The probe exhibited high selectivity and a low detection limit toward H2O2 with the calculated LOD of 112.6 nM. Importantly, it was employed in the detection of exogenous and endogenous hydrogen peroxide in 4T1 cells with low cytotoxicity. This probe has also been successfully applied to imaging of H2O2 in Blab/c mice bearing 4T1 graft tumors.

Manganese (III) phthalocyanine complex nanoassembly: Oxygen-Independent generation of superoxide radicals and singlet oxygen for ultrasound-augmented chemodynamic therapy

Singlet oxygen (1O2), an excellent reactive oxygen species (ROS) for tumor therapy, has garnered significant attention recently. However, its production is hindered by the low oxygen content in solid tumors characterized by hypoxia. Consequently, it is urgent to develop an O2-independent generator. In this study, we present a novel nano-assembly composed of manganese (Ⅲ) phthalocyanine complex (MnClPc) encapsulated by human serum albumin (MnClPc@HSA). MnClPc@HSA serves as a conventional sonosensitizer, facilitating the conversion of O2 to 1O2 under ultrasonic stimulation (US). Moreover, MnClPc@HSA enables the conversion of endogenous hydrogen peroxide (H2O2) within tumor to superoxide radical (·O2–) and 1O2 and further enhanced by US. This O2-independent generation of multiple ROS by MnClPc@HSA overcomes the limitations imposed by tumor hypoxia, while inducing immunogenic cell death (ICD) and enhancing the infiltration of T cells as well. When combined with conventional PD-L1 immunotherapy, this approach effectively inhibits the proliferation of distal and lung-metastatic tumors, while concurrently eliminating primary tumors in the bilateral-tumor model of 4 T1 tumor-bearing mice.

A transformable and self-oxygenated smart probe for enhanced tumor sonodynamic therapy

Sonodynamic therapy (SDT) is emerging as a promising modality for cancer treatment. However, improving the tumor bioavailability and anti-hypoxia capability of sonosensitizers faces a big challenge. In this work, we present a tumor microenvironment (TME)-mediated nanomorphology transformation and oxygen (O2) self-production strategy to enhance the sonodynamic therapeutic efficacy of tumors. A smart probe Ce6-Leu@Mn2+ that consists of a glutathione (GSH) and leucine amino peptidase (LAP) dual-responsive unit, a 2-cyanobenzothiazole (CBT) group, and a Mn2+-chelated Ce6 as sonosensitizer for tumor SDT was synthesized, and its SDT potential for liver tumor HepG2 in living mice was systematically studied. It was found that the probes could self-assemble into large nanoparticles in physiological condition and spontaneously transformed into small particles under the dual stimulation of GSH and LAP in TME resulting in enhanced tumor accumulation and deep penetration. More notably, Ce6-Leu@Mn2+ could convert endogenous hydrogen peroxide to O2, thereby alleviating the hypoxia and achieving effective SDT against hypoxic tumors under the excitation of ultrasound. We thus believe this smart TME-responsive probe may provide a noninvasive and efficient means for malignant tumor treatment. Statement of significanceSonodynamic therapy (SDT) is emerging as a promising therapeutic modality for cancer treatment. However, how to improve the tumor bioavailability and anti-hypoxia capability of sonosensitizers remains a huge challenge. Herein, we rationally developed a theranostic probe Ce6-Leu@Mn2+ that can transform into small-size nanoparticles from initial large particles under the dual stimulation of LAP and GSH in tumor microenvironment (TME) resulting in enhanced tumor accumulation, deep tissue penetration as well as remarkable O2 self-production for enhanced sonodynamic therapy of human liver HepG2 tumor in living mice. This smart TME-responsive probe may provide a noninvasive and efficient means for hypoxic tumor treatment.

MnO2-coated nanodiamond-driven photodynamic therapy for enhanced antitumor effect by addressing hypoxia and glutathione depletion

The generation of reactive oxygen species (ROS) at the tumor site to induce destruction is emerging as a novel strategy for cancer treatment, which involves photodynamic therapy (PDT). Nevertheless, tumors typically create a hypoxic environment and are equipped with an endogenous antioxidant defense system that could potentially impede the efficiency of the therapeutic approach. To overcome these drawbacks, herein, a tumor microenvironment-responsive the ND-PAA-CD-Ce6@MnO2 (NPCC@M) delivery system was fabricated by disulfide bond coupling chlorin e6 (Ce6) to nanodiamond (ND) and further wrapped by MnO2 nanosheets to facilitate PDT. The use of disulfide bond not only stabilizes Ce6 in the blood circulation to prevent premature leakage, but also destroys the antioxidant barrier of overexpressed glutathione (GSH) in tumor cells. Moreover, the outer MnO2 was rapidly degraded by the endogenous hydrogen peroxide (H2O2) in the acidic pH and GSH within the tumor cells, which leads to an abundance of O2 and while increases the level of 1O2 under laser irradiation. The results eventually broke the redox homeostasis and attenuate hypoxia, thereby inducing apoptosis and necrosis of tumor cells. Detailed in vitro and in vivo biological effect has revealed a good biosafety profile and a high tumor suppression effect. Such a novel ND-based system with tumor microenvironment-modulating capability to elevate oxygen content and promote GSH consumption in tumor cells opens new opportunities for enhanced ROS treatment paradigms.