Tumor microenvironment-responsive artesunate loaded Z-scheme heterostructures for synergistic photo-chemodynamic therapy of hypoxic tumor

Tumor microenvironment(TME)with the particular features of severe hypoxia,insufficient endogenous H2O2,and overexpression of glutathione(GSH)markedly reduced the antitumor efficacy of monotherapy.Herein,a TME-responsive multifunctional nanoplatform(Bi2S3@Bi@PDA-HA/Art NRs)was presented for synergistic photothermal therapy(PTT),chemodynamic therapy(CDT),and photodynamic therapy(PDT)to achieve better therapeutic outcomes.The Z-scheme heterostructured bismuth sulfide@bismuth nanorods(Bi2S3@Bi NRs)guaranteed excellent photothermal performance of the nanoplatform.Moreover,its ability to produce O2 and reactive oxygen species(ROS)synchronously could relieve tumor hypoxia and improve PDT outcomes.The densely coated polydopamine/ammonium bicarbonate(PDA/ABC)and hyaluronic acid(HA)layers on the surface of the nanoplatform enhanced the cancer-targeting capacity and induced the acidic TME-triggered in situ“bomb-like”release of Art.The CDT treatment was achieved by activating the released Art through intracellular Fe2+ions in an H2O2-independent manner.Furthermore,decreasing the glutathione peroxidase 4(GPX4)levels by Art could also increase the PDT efficiency of Bi2S3@Bi NRs.Owing to the synergistic effect,this nanoplatform displayed improved antitumor efficacy with minimal toxicity both in vitro and in vivo.Our design sheds light on the application of phototherapy combined with the traditional Chinese medicine monomer-artesunate in treating the hypoxic tumor.

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.

Nanoparticle-mediated synergistic anticancer effect of ferroptosis and photodynamic therapy:Novel insights and perspectives

Current antitumor monotherapy has many limitations,highlighting the need for novel synergistic anticancer strategies.Ferroptosis is an iron-dependent form of nonapoptotic cell death that plays a pivotal regulatory role in tumorigenesis and treatment.Photodynamic therapy(PDT)causes irreversible chemical damage to target lesions and is widely used in antitumor therapy.However,PDT’s effectiveness is usually hindered by several obstacles,such as hypoxia,excess glutathione(GSH),and tumor resistance.Ferroptosis improves the anticancer efficacy of PDT by increasing oxygen and reactive oxygen species(ROS)or reducing GSH levels,and PDT also enhances ferroptosis induction due to the ROS effect in the tumor microenvironment(TME).Strategies based on nanoparticles(NPs)can subtly exploit the potential synergy of ferroptosis and PDT.This review explores recent advances and current challenges in the landscape of the underlyingmechanisms regulating ferroptosis and PDT,as well as nano delivery system-mediated synergistic anticancer activity.These include polymers,biomimetic materials,metal organic frameworks(MOFs),inorganics,and carrier-free NPs.Finally,we highlight future perspectives of this novel emerging paradigm in targeted cancer therapies.

Cooperative coordination-mediated multi-component self-assembly of“all-in-one”nanospike theranostic nano-platform for MRI-guided synergistic therapy against breast cancer

Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation,high drug-loading efficiency,and excellent therapeutic efficacy.Herein,MnAs-ICG nanospike was generated by self-assembly of indocyanine green(ICG),manganese ions(Mn^(2+)),and arsenate(AsO_(4)^(3−))based on electrostatic and coordination interactions,effectively integrating the bimodal imaging ability of magnetic resonance imaging(MRI)and fluorescence(FL)imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an“all-in-one”theranostic nano-platform.The as-prepared MnAs-ICG nanospike had a uniform size,well-defined nanospike morphology,and impressive loading capacities.The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability,enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components.In vitro and in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect,prolonged blood circulation and increased tumor accumulation compared to their individual components,effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect.Taken together,this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.

Mild hyperthermia-enhanced chemo-photothermal synergistic therapy using doxorubicin-loaded gold nanovesicles

Gold nanovesicles(GVs) with unique plasmonic property and large cavity hold great potential as a stimuli-responsive nanocarrier to deliver drugs for efficient tumor chemotherapy and other therapies synergistically.Herein,we developed doxorubicin-loaded gold nanovesicles(DGVs),offering infrared thermal(IRT) and photoacoustic(PA) dual-modal imaging guided mild hype rthermia-enhanced chemophotothermal cancer synergistic therapy.The DGVs are self-assembled by gold nanoparticles modified with amphiphilic copolymer in a predetermined concentration of doxorubicin through film rehydration method.Under the influence of laser excitation,the as-prepared DGVs exhibited good photothermal effect,which triggered the structural disruption of GVs and thus,allowed the efficient release of encapsulated DOX to enhance cell uptake for fluorescence imaging and tumor chemotherapy,respectively.In addition,DGVs also showed a strong PA and IRT signals in vivo.Our study demonstrated the potential of DGVs as stimuli-responsive drug delivery systems and cancer theranostics.

Black phosphorus quantum dots as multifunctional nanozymes for tumor photothermal/catalytic synergistic therapy

Nanozymes are nanomaterials with enzyme-like properties that have attracted significant interest owing to their high stability,easy preparation,and tunable catalytic properties,especially in the field of cancer therapy.However,the unfavorable catalytic effects of nanozymes in the acidic tumor microenvironment have limited their applications.Herein,we developed a biomimetic erythrocyte membrane-camouflaged ultrasmall black phosphorus quantum dots(BPQDs)nanozymes that simultaneously exhibited an exceptional near-infrared(NIR)photothermal property and dramatically photothermal-enhanced glucose oxidase(GOx)-like activity in the acidic tumor microenvironment.We demonstrated the engineered BPQDs gave a photothermal conversion efficiency of 28.9%that could rapidly heat the tumor up to 50℃ while effectively localized into tumors via homing peptide iRGD leading after intravenously injection.Meanwhile,the significantly enhanced GOx-like activity of BPQDs under NIR irradiation was capable of catalytical generating massive toxic reactive oxygen species via using cellular glucose.By combining the intrinsic photothermal property and the unique photothermal-enhanced GOx-like catalytic activity,the developed BPQDs were demonstrated to be an effective therapeutic strategy for inhibiting tumor growth in vivo.We believe that this work will provide a novel perspective for the development of nanozymes in tumor catalytic therapy.

Bacteria-Mediated Synergistic Cancer Therapy:Small Microbiome Has a Big Hope

The use of bacteria to specifically migrate to cancerous tissue and elicit an antitumor immune response provides a promising platform against cancer with significantly high potency.With dozens of clinical trials underway,some researchers hold the following views:“humans are nearing the first commercial live bacteria therapeutic.”However,the facultative anaerobe Salmonella typhimurium VNP20009,which is particularly safe and shows anticancer effects in preclinical studies,had failed in a phase I clinical trial due to low tumor regression and undesired dose-dependent side effects.This is almost certain to disappoint people’s inflated expectations,but it is noted that recent stateof-the-art research has turned attention to bacteria-mediated synergistic cancer therapy(BMSCT).In this review,the foundation of bacteria-mediated bio-therapy is outlined.Then,we summarize the potential benefits and challenges of bacterial bio-therapy in combination with different traditional anticancer therapeutic modalities(chemotherapy,photothermal therapy,reactive oxygen and nitrogen species therapy,immunotherapy,or prodrug-activating therapy)in the past 5 years.Next,we discuss multiple administration routes of BMSCT,highlighting potentiated antitumor responses and avoidance of potential side effects.Finally,we envision the opportunities and challenges for BMSCT development,with the purpose of inspiring medicinal scientists to widely utilize the microbiome approach in patient populations.

A computer-aided chem-photodynamic drugs self-delivery system for synergistically enhanced cancer therapy

The therapeutic strategy that gives consideration to the combination of photodynamic therapy and chemotherapy,has emerged as a potential development of effective anti-cancer medicine.Nevertheless,co-delivery of photosensitizers(PSs)and chemotherapeutic drugs in traditional carriers still remains great limitations due to low drug loadings and poor biocompatibility.Herein,we have utilized a computer-aided strategy to achieve a desired carrier-free self-delivery of pyropheophorbide a(PPa,a common PS)and podophyllotoxin(PPT,a classical chemotherapeutic drug)for synergistic cancer therapy.First,the computational simulation method identified the similar molecular sizes and rigid molecular structures between two drugs molecules.Based on the molecular docking,the intermolecular interactions were found to includeπ-πstackings,hydrophobic interactions and hydrogen bonds.Next,both drugs could co-assemble into nanoparticles(NPs)via one-step nanoprecipitation method.The various spectral experiments(UV,IR and FL)were conducted to evaluate the formation mechanism of spherical NPs.Moreover,in vitro and in vivo experiments systematically demonstrated that PPT/PPa NPs not only showed better cellular uptake efficiency,stronger cytotoxicity and higher accumulation in tumor sites,but also exhibited synergistic antitumor effect in female BALB/C bearing-4T1 tumor mice.Such a computer-aided design strategy of chem-photodynamic drugs self-delivery systems pave the way for efficient synergistic cancer therapy.

Play therapy in children with autism:Its role,implications,and limitations

Play is a pleasurable physical or mental activity that enhances the child’s skills involving negotiation abilities,problem-solving,manual dexterity,sharing,decision-making,and working in a group.Play affects all the brain's areas,structures,and functions.Children with autism have adaptive behavior,adaptive response,and social interaction limitations.This review explores the different applications of play therapy in helping children with autism disorder.Play is usually significantly impaired in children with autism.Play therapy is mainly intended to help children to honor their unique mental abilities and developmental levels.The main aim of play therapy is to prevent or solve psychosocial difficulties and achieve optimal child-healthy growth and development.Play therapy helps children with autism to engage in play activities of their interest and choice to express themselves in the most comfortable ways.It changes their way of self-expression from unwanted behaviors to more non-injurious expressive behavior using toys or activities of their choice as their words.Play therapy also helps those children to experience feeling out various interaction styles.Every child with autism is unique and responds differently.Therefore,different types of intervention,like play therapy,could fit the differences in children with autism.Proper evaluation of the child is mandatory to evaluate which type fits the child more than the others.This narrative review revised the different types of play therapy that could fit children with autism in an evidence-based way.Despite weak evidence,play therapy still has potential benefits for patients and their families.

Nanomedicine potentiates mild photothermal therapy for tumor ablation

The booming photothermal therapy(PTT)has achieved great progress in non-invasive oncotherapy,and paves a novel way for clinical oncotherapy.Of note,mild temperature PTT(mPTT)of 42–45°C could avoid treatment bottleneck of the traditional PTT,including nonspecific injury to normal tissues,vasculature and host antitumor immunity.However,cancer cells can resist mPTT via heat shock response and autophagy,thus leading to insufficient mPTT monotherapy to ablate tumor.To overcome the deficient antitumor efficacy caused by thermo-resistance of cancer cells and mono mPTT,synergistic therapies towards cancer cells have been conducted with mPTT.This review summarizes the recent advances in nanomedicine-potentiated mPTT for cancer treatment,including strategies for enhanced single-mode mPTT and mPTT plus synergistic therapies.Moreover,challenges and prospects for clinical translation of nanomedicine-potentiated mPTT are discussed.

A proton-catalyzing prodrug for PDT and glycolysis inhibition-synergistic therapy of tumor in spatiotemporal dimensions

The reactive oxygen species(ROS)generation from photosensitizer in photodynamic therapy(PDT)is limited by tumor hypoxia.Even type-I photosensitizers,e.g.,sulfur-substituted Nile blue,still rely on oxygen as the main center for transferring electrons to generate ROS.Cutting off the pathway of oxygen consumption in tumor can help photosensitizers overcome the limitation of low oxygen,in order to efficiently generate more ROS.It is known that glycolysis inhibitor 3-bromopyruvic acid(3-BP),which could specially target mitochondria,can provide more oxygen by inhibiting oxidative phosphorylation.Herein,we successfully designed and synthesized a new 3-BP-coupled sulfur-substituted Nile blue as prodrug(NBBP)for chemical/photodynamic synergistic therapy.Major results indicated that the protons in tumor catalyzed the hydrolysis of NBBP,inhibited photoinduced electron transfer between 3-BP and the photosensitizer in NBBP and further assisted the photosensitizer to be localized in mitochondria,utilizing local oxygen as much as possible and kill tumor cells more efficiently.Moreover,the glycolysis inhibition-induced autophagy was combined with PDT-induced autophagy,which could promote the deaths of tumor cells.Unlike other remedies exploiting nanomaterials,this construction method of NBBP achieves the efficient synergy of photodynamic therapy and glycolysis inhibition,stronger than their theoretical addition,in spatiotemporal dimensions.Our study provides not only a highly efficient platform for tumor therapy but also a design approach for prodrugs with synergistic effects.

Dual-targeted nanoformulation with Janus structure for synergistic enhancement of sonodynamic therapy and chemotherapy

The accurate delivery of nanoparticles and organic small molecule drugs remains a serious challenge in nanoparticle-based tumor therapy.Dual-targeted therapy combining tumor cell targeting and organelle targeting is an effective solution.Here,an anticancer nanoformulation accurate delivery system was prepared using hyaluronic acid (HA) targeting CD44 receptors on the surface of tumor cells and IR780iodine (IR780) targeting mitochondrial for delivery.The system is based on an ultra-small Janus structured inorganic sensitizer TiO_(2-x)@NaGdF_(4) nanoparticles (TN NPs) prepared by one-step pyrolysis,further loaded with organic small molecule acoustic sensitizer IR780 and mitochondrial hexokinase Ⅱ inhibitor lonidamine (LND),followed by encapsulation of HA.Ultra-small size nanoparticles exhibit strong tissue penetration,tumor inhibition and in vivo metabolism.Under ultrasound radiation,TN NPs and IR780could produce a synergistic effect,effectively increased the efficiency of reactive oxygen species (ROS)production.Meanwhile,the released IR780 could smoothly target the mitochondria,and the ROS produced by IR780 can destroy the mitochondrial structure and disrupt the mitochondrial respiration.LND could inhibit the energy metabolism of tumor cells by reducing the activity of hexokinase Ⅱ (HK Ⅱ),which further accelerates the process of apoptosis.Furthermore,since the Janus structure allows the integration of multifunctional components into a single system,TN NPs can not only serve as an acoustic sensitizer to generate ROS,but the Gd element contained can also act as the nuclear magnetic resonance (MR)imaging contrast agent,suggesting that the nanoformulation can enable imaging-guided diagnosis and therapy.In conclusion,a new scheme to enhance sonodynamic therapy (SDT) and chemotherapy synergistically is proposed here based on ultra-small dual-targeted nanoformulation with Janus structure in the ultrasound radiation environment.

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.

Glutathione-depleted cyclodextrin pseudo-polyrotaxane nanoparticles for anti-inflammatory oxaliplatin(Ⅳ) prodrug delivery and enhanced colorectal cancer therapy

Oxaliplatin(Oxa) is the first-line chemotherapeutic drug for the treatment of colorectal cancer(CRC). However, long-term Oxa chemotherapy can induce inflammation and increase the levels of cyclooxygenase-2(COX-2) and prostaglandin E2(PGE2), which can promote tumor metastasis. Moreover,high glutathione(GSH) levels in CRC cells significantly reduce Oxa sensitivity and seriously restrict the clinical application of Oxa. Herein, an Oxa(Ⅳ) prodrug with anti-inflammatory properties(desmethyl naproxe, DN) and GSH-depleting cyclodextrin pseudo-polyrotaxane carriers were prepared and further self-assembled into micellar nanoparticles(designated DNPt@PPRI). The relesae of DN from DNPt@PPRI can reduce the level of PGE2 to inhibit inflammation and tumor metastasis by decreasing COX-2 protein,and also synergize with Oxa to inhibit tumor. More importantly, GSH depletion can reduce the detoxification of Oxa and further enhance chemotherapy-induced apoptosis. DNPt@PPRI have a good GSH depletion ability to enhance the sensitivity of Oxa, indicating a potential in the synergistic chemotherapy and chemo-sensitization of colorectal cancer.

Near-Infrared Light-Activatable Melanized Paclitaxel Nano-Self-Assemblies for Synergistic Anti-tumor Therapy

Building self-assembly nanostructures is an important way to overcome the limitations of paclitaxel in tumor therapy.However,this strategy is also faced with challenges,such as difficulties in efficient release and the potential for drug resistance.Herein,we developed a near-infrared light-activatable melanized paclitaxel self-assembly nanoparticles for synergistic anti-tumor therapy.In this strategy,paclitaxel dimer prodrugs were synthesized and paclitaxel nanoparticles were obtained through self-assembly.Finally,the paclitaxel dimer nanoparticles were capped with polydopamine(PDA,melanoidin)and human serum albumin(HSA).The disulfide bonds in paclitaxel dimeric prodrug specifically respond to high concentrations of glutathione(GSH)and reactive oxygen species(ROS)in tumor cells.PDA enhances the biocompatibility of the drug molecules and imparts near-infrared photothermal conversion capability to the nano-self-assemblies.Both the in vitro and in vivo experiments demonstrated that this paclitaxel nanoprodrug exhibited enhanced tumor therapeutic efficacy under near-infrared light irradiation.

Carbon dots with two-photon fluorescence imaging for efficient synergistic trimodal therapy

Applying the fluorescent carbon dots as smart materials in anticancer therapy is of great interest.However,carbon dots for multimodal synergistic anticancer therapy,especially for the triple modality,is rarely reported.Herein,we successfully synthesized OCDs by citric acid and(1R,2S)-2-amino-1,2-diphenylethan-1-ol,which show aggregation-induced emission property and two-photon fluorescence imaging.Meanwhile,OCDs are ideal photosensitizers for photothermal therapy under 808 nm and TypeⅠphotodynamic therapy with white light.Hydroxyl radicals,generated by TypeⅠphotodynamic therapy based on OCDs can transform protumoral M2 macrophages into antitumoral M1 macrophages,which exhibited immunotherapy ability.The synergism trimodal of OCDs results in potent anticancer efficacy,showing great potential in cancer therapy.

Tailored core-shell dual metal-eorganic frameworks as a versatile nanomotor for effective synergistic antitumor therapy

Malignant tumor has become an urgent threat to global public healthcare.Because of the heterogeneity of tumor,single therapy presents great limitations while synergistic therapy is arousing much attention,which shows desperate need of intelligent carrier for co-delivery.A core-shell dual metaleorganic frameworks(MOFs)system was delicately designed in this study,which not only possessed the unique properties of both materials,but also provided two individual specific functional zones for co-drug delivery.Photosensitizer indocyanine green(ICG)and chemotherapeutic agent doxorubicin(DOX)were stepwisely encapsulated into the nanopores of MIL-88 core and ZIF-8 shell to construct a synergistic photothermal/photodynamic/chemotherapy nanoplatform.Except for efficient drug delivery,the MIL-88 could be functioned as a nanomotor to convert the excessive hydrogen peroxide at tumor microenvironment into adequate oxygen for photodynamic therapy.The DOX release from MIL-88-ICG@ZIF-8-DOX nanoparticles was triggered at tumor acidic microenvironment and further accelerated by near-infrared(NIR)light irradiation.The in vivo antitumor study showed superior synergistic antitumor effect by concentrating the nanoparticles into dissolving microneedles as compared to intravenous and intratumoral injection of nanoparticles,with a significantly higher inhibition rate.It is anticipated that the multi-model synergistic system based on dual-MOFs was promising for further biomedical application.

Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death(ICD)to provoke a robust immune response for metastasis control.Here,a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation,chemodynamic(CDT)and photothermal therapy.Ultrasmall Fe S-GOx nanodots were synthesized with glucose oxidase(GOx)as template and induced by paclitaxel(PTX)to form self-assembling Fe S-GOx@PTX(FGP)via hydrophobic interaction.After accumulated at tumor sites,FGP disassembles to smaller Fe S-GOx for enhanced deep tumor penetration.GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide(H2O2)as starvation therapy.Fenton reaction involving the regenerated H_(2)O_(2) in turn produced more hydroxyl radicals for enhanced CDT.Following near-infrared laser at 808 nm,FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy.The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation.In combination with anti-CTLA4 checkpoint blockade,FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes.Our work presents a promising strategy for primary tumor and metastasis inhibition.

Degradable Hybrid CuS Nanoparticles for Imaging-Guided Synergistic Cancer Therapy via Low-Power NIR-II Light Excitation

Near-infrared(NIR)-II light-excitable photonic agents capable of generating tumor hyperthermia and cytotoxic free radicals are promising for synergistic phototherapy of tumors.However,the lack of NIR-II excitable agents makes it challenging to achieve combinational tumor phototherapy.Here,the authors have reported on a tumor-targeting and degradable hybrid copper sulfide(CuS)nanoparticle(AIBA@CuS-FA)via loading a hydrophilic Azo initiator(AIBA)into an amphiphilic lipid-encapsulating CuS nanoparticle.AIBA@CuS-FA shows high photothermal conversion efficiency(PCE≈47.5%)at 1064 nm,enabling heat production to trigger tumor hyperthermia and thermal decomposition of AIBA into cytotoxic free alkyl radicals upon irradiation with a 1064-nm laser under low-power density(0.5 W/cm2).Moreover,alkyl radicals can drive degradation of AIBA@CuS-FA and embedded CuS nanodisks,releasing Cu^(2+)ions that can catalyze a Fenton-like reaction for hydroxyl radical(•OH)production to promote tumor therapy.Findings demonstrate promise for combinational photothermal therapy(PTT),oxygen-independent alkyl radical therapy,and chemodynamic therapy(CDT)of tumors.

Tumor-microenvironment activated programmable synergistic cancer therapy by bioresponsive rare-earth nanocomposite

Synergistic chemotherapy-photothermal therapy(CT-PTT)can improve the cancer treatment efficacy,but its treatment effect is still limited by factors such as targeting efficiency and treatment sequence.Herein,a H_(2)S-responsive metal organic frameworks(MOFs)coated rare-earth nanocomposite(csEr@-MOF)was constructed and loaded with a chemotherapeutic drug(DOX)and a heat shock protein(HSP)inhibitor(Shepherdin).As the drug-loaded csEr@MOF reaches the H_(2)S-riched colorectal tumor region,based on the reaction between H_(2)S and MOF,Shepherdin is released for inhibiting the function of HSPs,the generated CuS is used for PTT and DOX is released for CT.Through being monitored by ratiometric imaging of rare-earth nanocomposite,it is possible to perform the precise treatment timing for PTT.With the help of Shepherdin,the treatment effect of PTT was enhanced.Therefore,programmable CT-PTT synergistic cancer therapy activated by a single H_(2)S trigger is achieved in vitro and in vivo.This work provides new ideas for designing tumor microenvironment-responsive therapeutic agents for programmable synergistic therapy with better targeting and therapeutic efficiency.