Mitochondria-specific near-infrared photoactivation of peroxynitrite upconversion luminescent nanogenerator for precision cancer gas therapy

Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatiotemporal release precision,associated with gas therapy.In this study,we developed a series of photoactivatable nitric oxide(NO)donors NRh-R-NO(R=Me,Et,Bn,iPr,and Ph)based on an N-nitrosated upconversion luminescent rhodamine scaffold.Under the irradiation of 808 nm light,only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion luminescence(FUCL)signal at 740 nm,ascribed to lower N-N bond dissociation energy.We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy,including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation,the superoxide anion O_(2)^(⋅−)produced by the photodynamic therapy(PDT)effect of NRh-Ph,and highly toxic peroxynitrite anion(ONOO‒)generated from the co-existence of NO and O_(2)^(⋅−).After mild nano-modification,the nanogenerator(NRh-Ph-NO NPs)empowered with superior biocompatibility could target mitochondria.Under an 808 nm laser irradiation,NRh-Ph-NO NPs could induce NO/ROS to generate RNS,causing a decrease in the mitochondrial membrane potential and initiating apoptosis by caspase-3 activation,which further induced tumor immunogenic cell death(ICD).In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy,demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging.Collectively,this versatile strategy defines the targeted RNS-mediated cancer therapy.

Antibacterial gas therapy: Strategies, advances, and prospects

One of the challenges posed by current antibacterial therapy is that the expanded and massive use of antibiotics endows bacteria with the ability to resist almost all kinds of antibiotics.Therefore,developing alternative strategies for efficient antibacterial treatment is urgently needed.Antibacterial gas therapy has attracted much attention in the past decade.Nitric oxide(NO),carbon monoxide(CO),sulfur dioxide(SO2),hydrogen sulfide(H_(2)S),and hydrogen(H_(2))are not only known as endogenous signaling molecules,but also play critical roles in many pathological processes.These gases are considered as attractive bactericidal agents because they are able to kill bacteria,disperse biofilms,and promote bacteria-infected wound healing while avoiding resistance.In this review,we discuss the bactericidal properties of these gases,as well as the recent advances of gas-involving systems in antibacterial,antibiofilm,and wound treatment applications.Moreover,we summarize various gas donors utilized in antibacterial treatment.We hope this review will shed new light on the future design and applications of advanced antibacterial gas therapy.

2D graphene oxide-L-arginine-soybean lecithin nanogenerator for synergistic photothermal and NO gas therapy

Nitric oxide(NO) gas therapy has been regarded as a promising strategy for cancer treatment. However,its therapeutic efficiency is still unsatisfying due to the limitations of monotherapy. Previous preclinical and clinical studies have shown that combination therapy could significantly enhance therapeutic efficiency. Herein, a graphene oxide(GO)-L-arginine(L-Arg, a natural NO donor) hybrid nanogenerator is developed followed by surface functionalization of soybean lecithin(SL) for synergistic enhancement of cancer treatment through photothermal and gas therapy. The resultant GO-Arg-SL nanogenerator not only exhibited good biocompatibility and excellent endocytosis ability, but also exhibited excellent photothermal conversion capability and high sensitivity to release NO within tumor microenvironment via inducible NO synthase(i NOS) catalyzation. Moreover, the produced hyperthermia and intracellular NO could synergistically kill cancer cells both in vitro and in vivo. More importantly, this nanogenerator can efficiently eliminate tumor while inhibiting the tumor recurrence because of the immunogenic cell death(ICD) elicited by NIR laser-triggered hyperthermia and the immune response activation by massive NO generation. We envision that the GO-Arg-SL nanogenerator could provide a potential strategy for synergistic photothermal and gas therapy.

Ultrasound-propelled Janus Au NR-mSiO_(2) nanomotor for NIR-II photoacoustic imaging guided sonodynamic-gas therapy of large tumors

Varieties of contrast agents have been developed for photoacoustic(PA)and ultrasound(US)imaging of cancers in vivo.However,access of traditional contrast agents into the sites of tumors has been principally through passive infiltration without any external force,preventing their deep penetration into the tissues of the tumors,and hindering the use of PA and US for deep tumor imaging.The concept of micro/nanomotors has been the focus of increasing attention as active theranostic agents due to their active movement in particular fluids,thereby conducting assigned tasks.Herein,US-propelled Janus mesoporous SiO_(2)partially coated gold nanorods(Au NR-mSiO_(2))were fabricated for deep tumor NIR-II PA imaging and synergistic sonodynamic-gas therapy.Following US irradiation,2,2-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride(AIPH)loaded in mSiO_(2)(Au NR-mSiO_(2)/AIPH)generated N_(2)microbubbles with high efficiency to achieve nanomotor drive.Due to the deep penetration of US,the nanomotors exhibited a capability to travel deep within sites of tumors,providing enhanced PA/US imaging inside the tumors.Furthermore,the nanomotor based cancer therapy was demonstrated through synergistic N_(2)gas and sonodynamic therapy.The US-propelled nanomotors demonstrated a novel strategy for the simultaneous PA/US dual imaging deep within tumor tissues and precise therapy of large tumors.

Ultrasound-driven self-decomposition porphyrins as metal-free CO precursors for gas and sonodynamic synergistic therapy

Carbon monoxide(CO) is an endogenous therapeutic gas with an anti-tumor effect. The precise delivery and controlled release of CO in tumor tissues play crucial roles in anti-cancer treatment. However, efficient in situ generation of CO from metal-free COreleasing molecules(CORMs) remains a formidable challenge. Herein, we develop ultrasound(US)-driven self-decomposition porphyrin as organic and metal-free US-CORMs, which can spatiotemporally control the CO release(347 mmol CO/mol porphyrin) efficiently under physiologically harmless US conditions(1.0 MHz, 1.5 W/cm^(2), 50% duty cycle, 50 min). Moreover,porphyrin as a sonosensitizer can also generate reactive oxygen species(ROS) under US treatment to achieve sonodynamic therapy(SDT). Advanced functions of such porphyrin-based CORMs in CO gas-sonodynamic synergistic treatment have been demonstrated by evaluating the in vitro and in vivo anti-tumor effects.

A multi-parameter-induced activation of gas therapeutic platform to remarkably amplify photodynamic therapy efficacy

Gas therapy(GT)combined with photodynamic therapy(PDT)is an effective strategy to compensate for the PDT limitation caused by the hypoxic tumor microenvironment,which can greatly improve PDT efficacy.The uncontrolled leakage of gas molecules during delivery seriously hinders its practical biological application.Herein,we report a multifunction nanomedicine that enables precise gas therapy(including carbon monoxide(CO)release and H_(2)S depletion)using a multi-parameter-induced activation gas release strategy,enlarging the PDT efficacy.This nanomedicine uses a disulfide bond to covalently link a photosensitizer with the CO donor 3-hydroxyflavone(3-HF).The disulfide bond can be specifically consumed in H_(2)S-rich tumor areas,releasing the CO donor(3-HF),and also depleting H_(2)S.More importantly,the photo-controlled production of^(1)O_(2)can induce 3-HF precise release of CO in the tumor location.Such H_(2)S,light,and^(1)O_(2)multi-parameter-induced activation of gas release strategy ensures the accuracy of GT to amplify PDT efficiency.As expected,in vitro and in vivo investigations show that GT makes up for the PDT limitation,exhibiting the highest tumor therapeutic effect.This multi-parameter-activated design strategy provides a new way to improve the precision and efficacy of multimodal synergistic therapy of tumors.

Biomineralized CO gas-releasing nanoprodrug for endoplasmic reticulum stress mediated cancer therapy

The anti-tumor effect of therapeutic carbon monoxide(CO)has been considered concerning the electron transport chain on the inner mitochondrial membrane.Herein,a tumor microenvironment and photo-responsive CO nanoplatform Ca-Flav nanoparticles(NPs)were constructed through biomineralizing acryloyl-modified flavonol,which could release CO both in normoxia and hypoxia conditions upon irradiation at tumor lesion.The in vitro experiments demonstrated that the endoplasmic reticulum stress-related signal pathways could be activated through oxidative stress caused by CO mediated mitochondrial biogenesis and calcium ion turbulence induced by Ca_(3)(PO_(4))_(2)acidolysis,resulting in mitochondrial dysfunction and cell apoptosis.In addition,the Ca-Flav NPs exhibited excellent biocompatibility and tumor inhibition effect in vivo.This work provides new insight into the potential characteristics of CO,paving a new way to engineer more efficient treatment based on CO.

NIR-switchable local hydrogen generation by tandem bimetallic MOFs nanocomposites for enhanced chemodynamic therapy

The inadequate quantity of hydrogen peroxide(H_(2)O_(2))in cancer cells promptly results in the constrained success of chemodynamic therapy(CDT).Significant efforts made throughout the years;nevertheless,researchers are still facing the great challenge of designing a CDT agent and securing H_(2)O_(2) supply within the tumor cell.In this study,taking advantage of H_(2)O_(2) level maintenance mechanism in cancer cells,a nanozyme-based bimetallic metal-organic frameworks(MOFs)tandem reactor is fabricated to elevate intracellular H_(2)O_(2) levels,thereby enhancing CDT.In addition,under nearinfrared excitation,the upconversion nanoparticles(UCNPs)loaded into the MOFs can perform photocatalysis and generate hydrogen,which increases cellular susceptibility to radicals induced from H_(2)O_(2),inhibits cancer cell energy,causes DNA damages and induces tumor cell apoptosis,thus improving CDT therapeutic efficacy synergistically.The proposed nanozyme-based bimetallic MOFs-mediated CDT and UCNPs-mediated hydrogen therapy act as combined therapy with high efficacy and low toxicity.

Newly developed gas-assisted sonodynamic therapy in cancer treatment

Sonodynamic therapy(SDT) is an emerging noninvasive treatment modality that utilizes lowfrequency and low-intensity ultrasound(US) to trigger sensitizers to kill tumor cells with reactive oxygen species(ROS).Although SDT has attracted much attention for its properties including high tumor specificity and deep tissue penetration,its anticancer efficacy is still far from satisfactory.As a result,new strategies such as gas-assisted therapy have been proposed to further promote the effectiveness of SDT.In this review,the mechanisms of SDT and gas-assisted SDT are first summarized.Then,the applications of gas-assisted SDT for cancer therapy are introduced and categorized by gas types.Next,therapeutic systems for SDT that can realize real-time imaging are further presented.Finally,the challenges and perspectives of gas-assisted SDT for future clinical applications are discussed.

Ultrasound-active ReCORM-AIEgen for gas and sonodynamic therapy of mycobacterium biofilms

Bacterial infection is the leading cause of many severe inflammation diseases. The development of novel and effective therapeutic approaches to counter bacterial infections, especially for drug-resistant bacteria, is essential. Herein, we have successfully developed an ultrasound-active tricarbonyl rhenium(Ⅰ) complex with tetraphenylethylene(TPE) modification(RePyTPE) for CO gas therapy and sonodynamic therapy of bacterial infections. RePy-TPE produced reactive oxygen species and released CO under ultrasound irradiation. In addition, RePy-TPE showed aggregation-induced emission in water due to the introduction of TPE, which enhanced the yield of ^(1)O_(2) generation in a biological aqueous solution. The produced ^(1)O_(2) and released CO killed mycobacterium smegmatis(M. smegmatis) and Escherichia coli(E. coli), as shown by bacterial membrane damage and biofilm elimination. Furthermore, ultrasound-active RePy-TPE perturbed the purine metabolism of the bacteria, which disturbed the biosynthesis of DNA and energy metabolism, eventually reducing the vitality of bacteria. This article provides a novel strategy for the development of ultrasound-active metal-based antibiotics.

H_(2)S-releasing adhesive hydrogel as oral radioprotectant for gastrointestinal tract radioprotection

Radiation damage can cause a series of gastrointestinal(GI)tract diseases.The development of safe and effective GI tract radioprotectants still remains a great challenge clinically.Here,we firstly report an oral radioprotectant Gel@GYY that integrates a porous gelatin-based(Gel)hydrogel and a pH-responsive hydrogen sulfide(H2S)donor GYY4137(morpholin-4-ium 4 methoxyphenyl(morpholino)phosphinodithioate).Gel@GYY has a remarkable adhesion ability and long retention time,which not only enables responsive release of low-dose H2S in stomach and subsequently sustained release of H2S in the whole intestinal tract especially in the colon,but also ensures a close contact between H2S and GI tract.The released H2S can effectively scavenge free radicals induced by X-ray radiation,reduce lipid peroxidation level,repair DNA damage and recover vital superoxide dismutase and glutathione peroxidase activities.Meanwhile,the released H2S inhibits radiation-induced activation of nuclear factorκB(NF-κB),thus reducing inflammatory cytokines levels in GI tract.After treatment,Gel@GYY displays efficient excretion from mice body due to its biodegradability.This work provides a new insight for therapeutic application of intelligent H2S-releasing oral delivery system and potential alternative to clinical GI physical damage protectant.

Recent deveolpment of multifunctional responsive gas-releasing nanoplatforms for tumor therapeutic application

Gas therapy(GT)exhibits great potential for clinical application due to its high therapeutic efficiency,low systemic side effects,and biosafety,thereinto,a multifunctional nanoplatform is generally needed for controllable gas release and precise delivery to tumor tissue.In this review,the recent development of multifunctional nanoplatforms for efficient tumor delivery of stimuliresponsive gas-releasing molecules(GRMs),which could be triggered by either exogenous physical or endogenous tumor microenvironment(TME)is summarized.The reported therapeutic gas molecules,including oxygen(O_(2)),hydrogen sulfide(H_(2)S),nitric oxide(NO),hydrogen(H_(2)),and carbon monoxide(CO),etc.,could directly influence or change the pathological status.Additionally,abundant nanocarriers have been employed for gas delivery into cancer region,such as mesoporous silica nanoparticles(MSNs),metal-organic frameworks(MOFs),two-dimensional(2D)nanomaterials,and liposomes,as well as nonnanocarriers including inorganic and organic nanoparticles.In the end,the outlooks of current challenges of GT and GRMs delivery nanoplatforms as well as the prospects of future clinical applications are proposed.

Near-infrared light switching nitric oxide nanogenerator with“linkage mechanism”for tumor targeting multimodal synergistic therapy

Gaseous therapy based on nitric oxide(NO),as a potential anti-tumor treatment strategy,has attracted great attention,but the targeted and controlled gas release in the tumor site still remains a challenge.In addressing these difficulties,a near-infrared(NIR)light-triggered NO release nanogenerator with a“linkage mechanism”was designed on the basis of sodium nitroprussidedoped mesoporous Prussian blue nanoparticles,in which the outer structure was modified with p H-sensitive gatekeeper chitosan and tumor-targeting agent folic acid.The“linkage mechanism”can achieve precise release of NO under the control of photothermal effect at tumor site,which can couple photothermal therapy and gas therapy to address the premature release of gas during transportation.Meanwhile,the amount of released gas can be controlled by adjusting the irradiation time and laser intensity.Furthermore,as-fabricated nanocomposites hold high photothermal conversion efficiency under NIR laser irradiation,resulting in the on-demand release of NO and chemotherapy drugs.The released NO can inhibit the expression of hypoxiainducible factorα(HIF-1α)and alleviate the hypoxic tumor microenvironment,thereby enhancing the efficacy of chemotherapy.Moreover,in vitro and in vivo experiments exhibited remarkable antitumor efficiency,and the synergistic gas/chemo/photothermal therapy of deep tumors was achieved.These findings indicate an effective strategy to stimulate further the development of deep tumor therapy,which may provide new insights into other NO-related medical applications.

Manganese-doped mesoporous polydopamine nanoagent for T1-T2 magnetic resonance imaging and tumor therapy

Theranostic nanodrugs combining magnetic resonance imaging(MRI)and cancer therapy have attracted extensive interest in cancer diagnosis and treatment.Herein,a manganese(Mn)-doped mesoporous polydopamine(Mn-MPDA)nanodrug incorporating the nitric oxide(NO)prodrug BNN6 and immune agonist R848 was developed.The nanodrug responded to the H^(+)and glutathione being enriched in tumor microenvironment to release R848 and Mn^(2+).The abundant Mn^(2+)produced through a Fenton-like reaction enabled a highly sensitive T1-T2 dual-mode MRI for monitoring the tumor accumulation process of the nanodrug,based on which an MRI-guided laser irradiation was achieved to trigger the NO gas therapy.Meanwhile,R848 induced the re-polarization of tumor-promoting M2-like macrophage to a tumoricidal M1 phenotype.Consequently,a potent synergistic antitumor effect was realized in mice bearing subcutaneous 4T1 breast cancer,which manifested the great promise of this multifunctional nanoplatform in cancer treatment.

Redox-responsive micelles integrating catalytic nanomedicine and selective chemotherapy for effective tumor treatment

Chemotherapy is one of the most conventional modalities for cancer therapy.However,the high multidrug resistance of tumor cells still limited the clinical application of current chemotherapy.Considering the ability of nitric oxide(NO) to modulate potent P-glycoprotein to inhibit multi-drug resistance,a synergistic methodology combining chemotherapy and sustained NO generation is an ideal way to further promote the chemotherapy.Herein,a multi-functional micelle with tumor-selective chemotherapy driven by redox-triggered doxorubicin(DOX) release and drug resistance inhibition based on intracellular NO generation was fabricated for effective tumor treatment.The micelle consists of DOX as core,arginine/glucose oxidase(Arg/GOx) as shell and redox-responsive disulfide bond as a linker,which is denoted as micelle-DOX-Arg-GOx.The Arg serves as the biological precursor of nitric oxide for inhibition of multi-drug resistance to promote chemotherapy and GOx catalyzes glucose to produce hydrogen peroxide(H_(2) O_(2)) for increasing the generation of NO.Moreover,the glucose supply could be simultaneously blocked by the catalytic process,which further enhanced therapeutic efficiency.This micelle requests a tumor-specific microenvironment(a considerable amount of GSH) to perform synergistic therapeutics including chemotherapy,starvation therapy(catalytic medicine),and gas therapy for tumor treatment,which resulted in significant cytotoxicity to tumor tissue.

Promising gas therapies for severe COVID-19

The novel coronavirus disease 2019(COVID-19)pandemic is a worldwide catastrophe,thoroughly challenging the healthcare systems.A growing number of victims suffer from a remarkable acute respiratory distress syndrome(ARDS)that necessitates admission to the intensive care unit(ICU),but there are no satisfactory treatments.Various gas therapies including nitric oxide,ozone,hyperbaric oxygen,hydrogen,and heliox have been employed in the fight against the pandemic and have improved clinical outcomes.However,the potential roles of these gases in COVID-19 treatment need to be verified in well-designed randomized controlled trials.This paper reviews advances in gaseous therapy of COVID-19.

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications

Hydrogen sulfide(H_(2)S)plays an important role in regulating various pathological processes such as protecting mammalian cell from harmful injuries,promoting tissue regeneration,and regulating the process of various diseases caused by physiological disorders.Studies have revealed that the physiological effects of H_(2)S are highly associated with its concentrations.At relatively low concentration,H_(2)S shows beneficial functions.However,long-time and high-dose donation of H_(2)S would inhibit regular biological process,resulting in cell dysfunction and apoptosis.To regulate the dosage of H_(2)S delivery for precision medicine,H_(2)S delivery systems with intelligent characteristics were developed and a variety of biocompatibility polymers have been utilized to establish intelligent polymeric H_(2)S delivery systems,with the abilities to specifically target the lesions,smartly respond to pathological microenvironments,as well as real-timely monitor H_(2)S delivery and lesion conditions by incorporating imaging-capable moieties.In this review,we focus on the design,preparation,and therapeutic applications of intelligent polymeric H_(2)S delivery systems in cardiovascular therapy,inflammatory therapy,tissue regenerative therapy,cancer therapy and bacteria-associated therapy.Strategies for precise H_(2)S therapies especially imaging-guided H_(2)S theranostics are highlighted.Since H_(2)S donors with stimuli-responsive characters are vital components for establishing intelligent H_(2)S delivery systems,the development of H_(2)S donors is also briefly introduced.