A biomimetic spore nanoplatform for boosting chemodynamic therapy and bacteria-mediated antitumor immunity for synergistic cancer treatment

Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer.However,the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations.Furthermore,monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors.In this study,based on our discovery that spore shell(SS)of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity,we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy,chemodynamic therapy and antitumor immunity for synergistic cancer treatment.In detail,SS is separated from probiotic spores and then attached to the surface of liposome(Lipo)that was loaded with hemoglobin(Hb),glucose oxidase(GOx)and JQ1to construct SS@Lipo/Hb/GOx/JQ1.In tumor tissue,highly toxic hydroxyl radicals(·OH)are generated via sequential catalytic reactions:GOx catalyzing glucose into H_(2)O_(2)and Fe^(2+)in Hb decomposing H_(2)O_(2)into·OH.The combination of·OH and SS adjuvant can improve tumor immunogenicity and activate immune system.Meanwhile,JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response.In this manner,SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis.To summarize,the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

Light/pH dual controlled drug release"nanocontainer"alleviates tumor hypoxia for synergistic enhanced chemotherapy,photodynamic therapy and chemodynamic therapy

Photodynamic therapy(PDT)has significant advantages in treating primary tumors.However,the hypoxic tumor microenvironment hinders the generation of sufficient reactive oxygen species during PDT to effectively kill tumor cells,further greatly limiting the applications of PDT in cancer treatment.Herein,we reported a temperature/pH dual controlled drug delivery system LPC@PCN@PDA/Fe^(3+)-AS1411 based on a porous coordination network(PCN(Mn))coated with polydopamine(PDA)and modified with an aptamer AS1411.β-lapachone(LPC)was loaded inside the PCN(Mn)framework,and Fe^(3+)was attached to the surface of the PDA coating.These nanoparticles(NPs)exhibited excellent multimodal cancer therapeutic effects and tumor targeting ability with their photo-and chemodynamic properties.The therapeutic effect can be enhanced by the production of sufficient oxygen by the internal hydrogen peroxide,which improves the photodynamic effect of the photosensitizer PCN(Mn)and the chemotherapy effect ofβ-lapachone.Notably,the conversion of Fe^(2+)to Fe^(3+)in the tumor cells exerts the Fenton effect,which generates hydroxyl radicals that cause lipid peroxidation in tumor cells and induce apoptosis,thus enhancing the chemodynamic therapeutic effect.In vitro and in vivo experiments revealed that the NPs demonstrated specific tumor targeting,excellent inhibition effect on tumor growth,and biocompatibility.Together,our findings can help develop an intelligent multifunctional therapeutic nanoplatform for cancer therapy.

Boosting Chemodynamic Therapy by the Synergistic Effect of Co‑Catalyze and Photothermal Effect Triggered by the Second Near‑Infrared Light

In spite of the tumor microenvironments responsive cancer therapy based on Fenton reaction(i.e.,chemodynamic therapy,CDT)has been attracted more attentions in recent years,the limited Fenton reaction efficiency is the important obstacle to further application in clinic.Herein,we synthesized novel FeO/MoS2 nanocomposites modified by bovine serum albumin(FeO/MoS2-BSA)with boosted Fenton reaction efficiency by the synergistic effect of co-catalyze and photothermal effect of MoS2 nanosheets triggered by the second near-infrared(NIR II)light.In the tumor microenvironments,the MoS2 nanosheets not only can accelerate the conversion of Fe3+ions to Fe2+ions by Mo4+ions on their surface to improve Fenton reaction efficiency,but also endow FeO/MoS2-BSA with good photothermal performances for photothermal-enhanced CDT and photothermal therapy(PTT).Consequently,benefiting from the synergetic-enhanced CDT/PTT,the tumors are eradicated completely in vivo.This work provides innovative synergistic strategy for constructing nanocomposites for highly efficient CDT.

Self-Assembly Protein Superstructures as a Powerful Chemodynamic Therapy Nanoagent for Glioblastoma Treatment

Glioblastoma(GBM) remains a formidable challenge in oncology.Chemodynamic therapy(CDT) that triggers tumor cell death by reactive oxygen species(ROS) could open up a new door for GBM treatment.Herein,we report a novel CDT nanoagent.Hemoglobin(Hb)and glucose oxidase(GOx) were employed as powerful CDT catalysts.Instead of encapsulating the proteins in drug delivery nanocarriers,we formulate multimeric superstructures as self-delivery entities by crosslinking techniques.Red blood cell(RBC) membranes are camouflaged on the protein superstructures to promote the delivery across blood-brain barrier.The as-prepared RBC@Hb@GOx nanoparticles(NPs) offer superior biocompatibility,simplified structure,and high accumulation at the tumor site.We successfully demonstrated that the NPs could efficiently produce toxic ROS to kill U87 MG cancer cells in vitro and inhibit the growth of GBM tumor in vivo,suggesting that the new CDT nanoagent holds great promise for treating GBM.

Cytochrome-c aptamer functionalized Pt nanoclusters for enhanced chemodynamic therapy

Catalysis-based chemodynamic therapy(CDT)is an emerging cancer treatment strategy which uses a Fenton-like reaction to kill tumor cells by catalyzing endogenous hydrogen peroxide(H_(2)O_(2))into a toxic hydroxyl radical(·OH).The performance of CDT is greatly dependent on PDT agent.Herein,mitochondria-targeting Pt nanoclusters were synthesized using cytochrome c aptamer(CytcApt)as template.The obtained CytcApt-PtNCs can produce.OH by H_(2)O_(2)under the acidic conditions.Moreover,CytcApt-PtNCs could kill 4T1 tumor cells in a pH-dependent manner,but had no side effect on normal 293T cells.Therefore,CytcApt-PtNCs possess excellent therapeutic effect and good biosafety,indicating their great potential for CDT.

Valence-tailored copper-based nanoparticles for enhanced chemodynamic therapy through prolonged ROS generation and potentiated GSH depletion

Chemodynamic therapy(CDT),an inventive approach to cancer treatment,exploits innate chemical processes to trigger cell death through the generation of reactive oxygen species(ROS).While offering advantages over conventional treatments,the optimization of CDT efficacy presents challenges stemming from suboptimal catalytic efficiency and the counteractive ROS scavenging effect of intracellular glutathione(GSH).In this study,we aim to address this dual challenge by delving into the role of copper valence states in CDT.Leveraging the unique attributes of copper-based nanoparticles,especially zero-valent copper nanoparticles(CuPd NPs),we aim to enhance the therapeutic potential of CDT.Our experiments reveal that zero-valent CuPd NPs outperform divalent copper nanoparticles(Ox-CuPd NPs)by displaying superior catalytic performance and sustaining ROS generation through a dual approach integrating peroxidase-like(POD-like)activity and Cu+release.Notably,zero-valent NPs exhibit enhanced GSH depletion compared to their divalent counterparts,thereby intensifying CDT and inducing ferroptosis,ultimately resulting in high-efficiency tumor growth inhibition.These findings reveal the impact of valences on CDT,providing novel insights for the optimization and design of CDT agents.

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.

Fe(Ⅲ)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy

Chemodynamic therapy(CDT)relying on the transformation of endogenous hydrogen peroxide(H_(2)O_(2))into cytotoxic hydroxyl radicals(·OH)based on the catalysis of Fenton/Fenton-type reactions exhibits great potentiality for cancer treatment.However,the inadequate H_(2)O_(2)supply and intricate redox homeostasis in tumor microenvironment(TME)severely impair the efficacy of CDT.Herein,we design selfassembled 1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated polyethylene glycol(DSPE-PEG)-modified Fe(Ⅲ)-juglone nanoscale coordination polymers(FJP NCPs)as redox homeostasis disruptors for juglone-enhanced CDT.Responding to glutathione(GSH)-rich and acidic TME,the Fe^(2+)/Fe^(3+)-guided CDT and GSH consumption by Fe^(3+)are activated,resulting in·OH downstream and up-regulation of lipid peroxidation(LPO).In addition,the released juglone not only depletes GSH through Michael addition,but also elevates intracellular H_(2)O_(2)level for achieving·OH further bursting.With the impressive efficiency of GSH exhaustion and reactive oxygen species(ROS)storm generation,ferroptosis and apoptosis are significantly enhanced by FJP NCPs in vivo.In brief,this facile and efficient design for versatile nanoscale coordination polymers presents a novel paradigm for effectively elevating CDT efficiency and tumor synergistic therapy.

A Review on Nanomaterial-based Strategies for Manipulating Tumor Microenvironment to Enhance Chemodynamic Therapy

Cancer is a leading cause of death worldwide,and a series of strategies has been reported for tumor-specific therapy.Currently,chemodynamic therapy(CDT)has become a research hotspot for antitumor treatment due to its advantages of high specificity,endogenous stimulation,and high biosafety.However,the therapeutic effects of CDT are normally limited in the complex tumor microenvironment(TME),such as insufficient acidity,tumor hypoxia,low hydrogen peroxide(H2O2),and high glutathione(GSH).Consequently,different kinds of multifunctional nanomaterials have been designed to manipulate TME conditions,which provided more opportunities to improve the efficiency of CDT.This review focuses on nanomaterial-based strategies for enhancing CDT through manipulating TME.Upon CDT enhancements,this review would provide a reference for the future development of efficient CDT nanomaterials.

Adenosine triphosphate-responsive carbon dots nanoreactors for T_(1)-weighted magnetic resonance imaging-guided tumor chemodynamic therapy

There are various strategies to conduct tumor microenvironment(TME)stimulus-responsive(e.g.,acid,H_(2)O_(2)or glutathione)nanoreactors for increasing the efficiency of chemodynamic therapy(CDT).Among these,the exploitation of adenosine triphosphate(ATP,another overexpressed biomarker in TME)-responsive nanoreactors for tumor CDT is still challenging.Herein,the ATP-responsive iron-doped CDs(FeCDs)were firstly prepared and then coassembled with glucose oxidase(GOx)to obtain FeCDs/GOx liposomes as ATP-responsive nanoreactors.Under TME conditions,the nanoreactors initially released FeCDs and GOx.Subsequently,with the existence of ATP,iron ions were rapidly released from the FeCDs to trigger Fenton/Fenton-like reactions for generating·OH.Meanwhile,the T_(1)-weighted magnetic resonance imaging(MRI)was achieved due to the released iron ions.Moreover,the GOx converted endogenous glucose in tumor to gluconic acid and H_(2)O_(2)to satisfy the requirement of·OH generation.In vitro as well as in vivo experiments illustrated that the obtained ATP-responsive CD nanoreactors could be used as a versatile nanotheranostics for simultaneously T_(1)-weighted MRI-guided tumor CDT.This work presents a new ATP-responsive nanoreactor with selfsupplied H_(2)O_(2)for multifunctional nanotheranostic applications.

Biocompatible CuO-decorated carbon nanoplatforms for multiplexed imaging and enhanced antitumor efficacy via combined photothermal therapy/chemodynamic therapy/chemotherapy

Inspired by the limitations of nanoparticles in cancer treatment caused by their low therapeutic effects and biotoxicity,biocompatible and photothermal enhanced copper oxide-decorated carbon nanospheres(CuO@CNSs)with doxorubicin hydrochloride(DOX)loading were constructed.CNSs as photothermal agents were synthesized by a hydrothermal reaction.CuO was adsorbed on the surface of CNSs,which improved the photothermal conversion efficiency due to the electron transitions between C-2 p and Cu-3 d.In addition,CuO would release Cu2+ions in the tumor microenvironment,which could produce hydroxyl radical(·OH)to induce cancer cells apoptosis via Haber-Weiss and Fenton-like reactions.DOX as a chemotherapeutic agent was located on the surface of CuO@CNSs by electrostatic adsorption and released quickly in the tumor microenvironment to kill cancer cells.The CuO@CNSs-DOX nanoplatforms realized the combination therapy of photothermal therapy(PTT),chemodynamic therapy(CDT),and chemotherapy(CT),which have strong potential for cancer treatment.

Tumor cell membrane-camouflaged responsive nanoparticles enable MRI-guided immuno-chemodynamic therapy of orthotopic osteosarcoma

Osteosarcoma is a refractory bone disease in young people that needs the updating and development of effective treatment.Although nanotechnology is widely applied in cancer therapy,poor targeting and inadequate effi-ciency hinder its development.In this study,we prepared alendronate(ALD)/K7M2 cell membranes-coated hollow manganese dioxide(HMnO_(2))nanoparticles as a nanocarrier to load Ginsenoside Rh2(Rh2)for Mag-netic Resonance imaging(MRI)-guided immuno-chemodynamic combination osteosarcoma therapy.Subse-quently,the ALD and K7M2 cell membranes were successively modified on the surface of HMnO_(2) and loaded with Rh2.The tumor microenvironment(TME)-activated Rh2@HMnO_(2)-AM nanoparticles have good bone tumor-targeting and tumor-homing capabilities,excellent GSH-sensitive drug release profile and MRI capability,and attractive immuno-chemodynamic combined therapeutic efficiency.The Rh2@HMnO_(2)-AM nanoparticles can effectively trigger immunogenic cell death(ICD),activate CD4^(+)/CD8^(+)T cells in vivo,and upregulate BAX,BCL-2 and Caspase-3 in cellular level.Further results revealed that Rh2@HMnO_(2)-AM enhanced the secretion of IL-6,IFN-γand TNF-αin serum and inhibited the generation of FOXP3^(+)T cells(Tregs)in tumors.Moreover,the Rh2@HMnO_(2)-AM treatment significant restricted tumor growth in-situ tumor-bearing mice.Therefore,Rh2@HMnO_(2)-AM may serve as an effective and bio-friendly nanoparticle platform combined with immuno-therapy and chemodynamic therapy to provide a novel approach to osteosarcoma therapy.

Osteogenic and anti-tumor Cu and Mn-doped borosilicate nanoparticles for syncretic bone repair and chemodynamic therapy in bone tumor treatment

Critical bone defects caused by extensive excision of malignant bone tumor and the probability of tumor recurrence due to residual tumor cells make malignant bone tumor treatment a major clinical challenge.The present therapeutic strategy concentrates on implanting bone substitutes for defect filling but suffers from failures in both enhancing bone regeneration and inhibiting the growth of tumor cells.Herein,Cu and Mn-doped borosilicate nanoparticles(BSNs)were developed for syncretic bone repairing and anti-tumor treatment,which can enhance bone regeneration through the osteogenic effects of Cu^(2+) and Mn^(3+) ions and meanwhile induce tumor cells apoptosis through the hydroxyl radicals produced by the Fenton-like reactions of Cu^(2+) and Mn^(3+) ions.In vitro study showed that both osteogenic differentiation of BMSCs and angiogenesis of endothelial cells were promoted by BSNs,and consistently the critical bone defects of rats were efficiently repaired by BSNs through in vivo evaluation.Meanwhile,BSNs could generate hydroxyl radicals through Fenton-like reactions in the simulated tumor microenvironment,promote the generation of intracellular reactive oxygen species,and eventually induce tumor cell apoptosis.Besides,subcutaneous tumors of mice were effectively inhibited by BSNs without causing toxic side effects to normal tissues and organs.Altogether,Cu and Mn-doped BSNs developed in this work performed dual functions of enhancing osteogenesis and angiogenesis for bone regeneration,and inhibiting tumor growth for chemodynamic therapy,thus holding a great potential for syncretic bone repairing and anti-tumor therapy.

Tumor Microenvironment-Adaptive Nanoplatform Synergistically Enhances Cascaded Chemodynamic Therapy

Chemodynamic therapy(CDT),a noninvasive strategy,has emerged as a promising alternative to conventional chemotherapy for treating tumors.However,its therapeutic effect is limited by the amount of H_(2)O_(2),pH value,the hypoxic environment of tumors,and it has suboptimal tumor-targeting ability.In this study,tumor cell membrane-camouflaged mesoporous Fe_(3)O_(4) nanoparticles loaded with perfluoropentane(PFP)and glucose oxidase(GOx)are used as a tumor microenvironment-adaptive nanoplatform(M-mFeP@O_(2)-G),which synergistically enhances the antitumor effect of CDT.Mesoporous Fe_(3)O_(4) nanoparticles are selected as inducers for photothermal and Fenton reactions and as nanocarriers.GOx depletes glucose within tumor cells for starving the cells,while producing H2O2 for subsequent⋅OH generation.Moreover,PFP,which can carry O_(2),relieves hypoxia in tumor cells and provides O_(2) for the cascade reaction.Finally,the nanoparticles are camouflaged with osteosarcoma cell membranes,endowing the nanoparticles with homologous targeting and immune escape abilities.Both in vivo and in vitro evaluations reveal high synergistic therapeutic efficacy of M-mFeP@O_(2)-G,with a desirable tumor-inhibition rate(90.50%),which indicates the great potential of this platform for clinical treating cancer.

Ferric oxide nanosheet-engineered Mg alloy for synergetic osteosarcoma photothermal/chemodynamic therapy

Osteosarcoma(OS)is a malignant tumor with a high rate of recurrence.Recently,biodegradable Mg-based implants have become a new therapeutic platform for bone-related diseases.However,poor biosafety and deficient intelligent tumor-killing ability of Mg-based implants are still the main challenges for the pre-cise treatment of OS.Herein,based on the excellent catalytic and photothermal conversion properties of nanozyme ferric oxide(Fe_(3)O_(4)),a novel two-step hydrothermal method for in situ preparation of Fe_(3)O_(4)nanosheets on the surface of plasma electrolytic oxidation(PEO)-treated Mg alloy using Mg-Fe layered double hydroxides(Mg-Fe LDH)as precursor was proposed.Compared with Mg alloy,there were no obvious corrosion cracks on the surface of Fe_(3)O_(4)nanosheets-coated Mg alloy(Fe_(3)O_(4)-NS)immersed in 0.9 wt.%NaCl for 14 days,which demonstrated the corrosion resistance of Mg alloy was significantly enhanced.Cytocompatibility experiments and hemolysis assay confirmed the great biocompatibility of Fe_(3)O_(4)-NS,especially,hemolysis ratio was lower than 1%.Meanwhile,Fe_(3)O_(4)-NS presented excellent cat-alytic oxidation capacity in the presence of H_(2)O_(2),and its temperature can significantly increase from 27℃to approximately 56℃under NIR irradiation.Therefore,intelligent responsive Fe_(3)O_(4)nanosheets-engineered Mg-based implants demonstrated excellent antitumor properties in vivo and in vitro due to their photothermal and chemodynamic synergetic effects.This study provides a novel approach for the preparation of Fe_(3)O_(4)coatings on the surface of Mg alloys and a new strategy for the treatment of OS.

Novel theranostic nanoagent based on CuMo_(2)S_(3)-PEG-Gd for MRI-guided photothermal/photodynamic/chemodynamic therapy

Cancer is a severe disease,which have troubled human being for a long time.The development of nanotechnology has provided a new way for cancer treatment.It is a promising strategy to integrate imaging and therapeutic functions into one single nanoplatform to achieve efficient combination of diagnosis and treatment.Herein,we exploited novel CuMo_(2)S_(3)-PEG-Gd nanocomposites(NCs)for magnetic resonance imaging(MRI),guiding the photothermal therapy(PTT)/photodynamic therapy(PDT)/chemodynamic therapy(CDT).The experimental results showed that CuMo_(2)S_(3)-PEG-Gd NCs have a high photothermal conversion efficiency(40.6%),excellent biocompatibility and good biosecurity.The CuMo_(2)S_(3)-PEGGd NCs exhibited a clear MRI performance for tumor due to connecting Gd,which can guide in vivo therapy to improve the therapeutic effect.Moreover,both in vitro and in vivo therapeutic results of CuMo_(2)S_(3)-PEG-Gd NCs exhibited that the PTT/PDT/CDT achieved a remarkably synergistic effect,which could efficiently inhibit the tumor growth.Thus,CuMo_(2)S_(3)-PEG-Gd NCs,which integrated imaging with multiple therapies,have a good potential as theranostic agent for tumor.

Hydrogen peroxide-generating nanomedicine for enhanced chemodynamic therapy

Chemodynamic therapy(CDT)is an emerging endogenous stimulation activated tumor treatment approach that exploiting iron-containing nanomedicine as catalyst to convert hydrogen peroxide(H_(2)O_(2))into toxic hydroxyl radical(·OH)through Fenton reaction.Due to the unique characteristics(weak acidity and the high H_(2)O_(2) level)of the tumor microenvironment,CDT has advantages of high selectivity and low side effect.However,as an important substrate of Fenton reaction,the endogenous H_(2)O_(2) in tumor is still insufficient,which may be an important factor limiting the efficacy of CDT.In order to optimize CDT,various H_(2)O_(2)-generating nanomedicines that can promote the production of H_(2)O_(2) in tumor have been designed and developed for enhanced CDT.In this review,we summarize recently developed nanomedicines based on catalytic enzymes,nanozymes,drugs,metal peroxides and bacteria.Finally,the challenges and possible development directions for further enhancing CDT are prospected.

Mesothelin targeted nano-system enhanced chemodynamic therapy and tirapazamine chemotherapy via lactate depletion

The enhanced permeability and retention(EPR)effect alone is not enough for nanoparticles to reach the target.Combination of active and passive targeting may be an effective drug delivery route.Hollow ferric-tannic acid complex nanocapsules(HFe-TA)may effectively degrade and release Fe^(2+) ions,Fe^(2+)ions induce the production of·OH,however,the fenton reaction needs amount of H_(2)O_(2)to enhance chemodynamic therapy.Due to their deficiencies,such nanoparticles cannot realize intravenous drug delivery.Here,the mesothelin-targeted membrane(MTM)was constructed to realize accurate delivery nano-system,mesothelin antibody was expressed on the 293T cell membrane to prepare a MTM.Lactate oxidase(Lox)was loaded on HFe-TA to obtain Lox@HFe-TA.Lox@HFe-TA was coated with MTM to develop the MTM nanosystem.Tirapazamine(TPZ)therapy also requires hypoxia circumstance.The MTM nanosystem combined with TPZ can significantly kill tumour cells and inhibit metastasis in vivo and in vitro.We also tested the biological safety of the treatment.In this study,we overcame the EPR defects via the MTM nanosystem,which can realize acute targeted delivery to the tumour site,lactate depletion,promoted reactive oxygen species(ROS)induction,enhanced the effect of TPZ,demonstrating a potential synergistic combination of cancer therapy with better efficacy and biosafety.

Mesoporous polydopamine delivery system for intelligent drug release and photothermal-enhanced chemodynamic therapy using MnO_(2) as gatekeeper

The non-specific leakage of drugs from nanocarriers seriously weakened the safety and efficacy of chemotherapy,and it was very critical of constructing tumor microenvironment(TME)-responsive delivery nanocarriers,achieving the modulation release of drugs.Herein,using manganese dioxide(MnO_(2))as gatekeeper,an intelligent nanoplatform based on mesoporous polydopamine(MPDA)was developed to deliver doxorubicin(DOX),by which the DOX release was precisely controlled,and simultaneously the photothermal therapy(PTT)and chemodynamic therapy(CDT)were realized.In normal physiological environment,the stable MnO_(2)shell effectively avoided the leakage of DOX.However,in TME,the overexpressed glutathione(GSH)degraded MnO_(2)shell,which caused the DOX release.Moreover,the photothermal effect of MPDA and the Fenton-like reaction of the generated Mn^(2+)further accelerated the cell death.Thus,the developed MPDA-DOX@MnO_(2)nanoplatform can intelligently modulate the release of DOX,and the combined CDT/PTT/chemotherapy possessed high-safety and high-efficacy against tumors.

Copper-mediated chemodynamic therapy with ultra-low copper consumption by doping cupric ion on cross-linked(R)-(+)-lipoic acid nanoparticles

Cu-mediated chemodynamic therapy(CDT)has attracted prominent attention owing to its advantages of pH independence and high efficiency comparing to Fe-mediated CDT,while the application of Cu-based CDT agents was impeded due to the high copper consumption caused by the metabolism loss of copper and the resultant potential toxicity.Herein,we developed a new copper-mediated CDT agent with extremely low Cu usage by anchoring copper on cross-linked lipoic acid nanoparticles(Cu@cLAs).After endocytosis into tumor cells,the Cu@cLAs were dissociated into LA and dihydrolipoic acid(DHLA)(reduced form of LA)and released Cu^(2+)and Cu+(oxidized form of Cu^(2+)),the two redox couples recycled each other in cells to achieve the efficient killing of cancer cells by delaying metabolic loss and increasing the ROS level of tumor cells.The self-recycling was confirmed in cells by the sustained high Cu/DHLA content and persistent ROS generation process.The antitumor study based on the MCF-7/R nude mice gave the Cu@cLAs a tumor inhibitory rate up to 77.9%at the copper of 0.05 mg kg^(−1),the first dosage reported so far lower than that of normal serum copper(0.83±0.21 mg kg^(−1)).This work provides not only a new promising clinical strategy for the copper excessive use in copper-mediated CDT,but also gives a clue for other metal mediated disease therapies with the high metal consumption.