Breaking the Redox Homeostasis: an Albumin-Based Multifunctional Nanoagent for GSH Depletion-Assisted Chemo-/Chemodynamic Combination Therapy

Redox homeostasis is vital for cell survival. Nowadays, developing novel nanoagents that can efficiently break the redox homeostasis, which includes improving the reactive oxygen species level while reducing the glutathione (GSH) level, has emerged as a promising but challenging strategy for tumor therapy. In this work, a novel albumin-based multifunctional nanoagent is developed for GSH-depletion assisted chemo-/chemodynamic combination therapy. Briefly, CuO and MnO_X are in situ co-grown inside the albumin molecules through a facile biomineralization process, followed by the conjugation of Pt (IV) prodrug to obtain the final nanoagent. Thereinto, copper species can produce •OH with optimal efficiency under weakly acidic conditions (pH = 6.5), while MnO_X can react with GSH, leading to the GSH depletion, which reduces the formation of GSH-Pt adducts and •OH consumption, thus favoring a better chemotherapy and chemodynamic therapy effect, respectively. Significantly, both GSH depletion and •OH generation contributes to the inhibited expression of GPX-4, which further increases the oxidative stress. Moreover, during the reaction between MnO_X and GSH or H₂O₂, Mn²⁺ ions are released for MR imaging while O₂ is produced for hypoxia relief. It is believed that the proposed strategy can provide a new perspective on effective tumor therapy.     

2D Core/Shell-Structured Mesoporous Silicene@Silica for Targeted and Synergistic NIR-II-Induced Photothermal Ablation and Hypoxia-Activated Chemotherapy of Tumors

Silicene nanosheets, the emerging 2D nanomaterial, as the third topology of silicon-composed materials with distinct physicochemical properties, is a desirable candidate for photothermal-conversion nanoagent (PTA) and drug-delivery nanosystems. Inspired by the individual physiochemical properties and structure features of mesoporous silica and 2D silicene, a distinctive 2D core/shell-structured multifunctional silicon-composed theranostic nanoplatform (Silicene@Silica) is constructed by coating a mesoporous silica layer onto the surface of 2D silicene nanosheets. The well-defined mesopores originating from mesoporous silica shell provide the reservoirs for guest drug molecules and the core of silicene produces heat shock upon NIR-II laser irradiation, aiming to induce the synergistic cancer-therapeutic modality. Importantly, when AQ4N, hypoxia-activated prodrug, is introduced into this system, this nanoplatform (Silicene@Silica–AQ4N) exhibits tumor microenvironment (TME)-responsive and synergistic hyperthermia-augmented therapeutic bioactivity. Such a nanoplatform can amplify the hypoxia of TME by destroying the tumor microcirculation and then further efficiently activate AQ4N, a DNA affinity agent and topoisomerase II inhibitor. The results reveal that this multifunctional theranostic nanoplatform can efficiently eliminate tumors without recurrence.     

Enzyme‐Mediated Tumor Starvation and Phototherapy Enhance Mild‐Temperature Photothermal Therapy

Compared with conventional tumor photothermal therapy (PTT), mild‐temperature PTT brings less damage to normal tissues, but also tumor thermoresistance, introduced by the overexpressed heat shock protein (HSP). A high dose of HSP inhibitor during mild‐temperature PTT might lead to toxic side effects. Glucose oxidase (GOx) consumes glucose, leading to adenosine triphosphate supply restriction and consequent HSP inhibition. Therefore, a combinational use of an HSP inhibitor and GOx not only enhances mild‐temperature PTT but also minimizes the toxicity of the inhibitor. However, a GOx and HSP inhibitor‐encapsulating nanostructure, designed for enhancing its mild‐temperature tumor PTT efficiency, has not been reported. Thermosensitive GOx/indocyanine green/gambogic acid (GA) liposomes (GOIGLs) are reported to enhance the efficiency of mild‐temperature PTT of tumors via synergistic inhibition of tumor HSP by the released GA and GOx, together with another enzyme‐enhanced phototherapy effect. In vitro and in vivo results indicate that this strategy of tumor starvation and phototherapy significantly enhances mild‐temperature tumor PTT efficiency. This strategy could inspire people to design more delicate platforms combining mild‐temperature PTT with other therapeutic methods for more efficient cancer treatment.     

Rising Mesopores to Realize Direct Electrochemistry of Glucose Oxidase toward Highly Sensitive Detection of Glucose

Direct electrochemistry, a direct electron transfer process between enzymes and electrode possesses, has important fundamental significance in bioelectrochemistry while offering very efficient electrocatalysis for enzyme‐based sensors. Herein, the pore structure of bacterial cellulose porous carbon nanofibers (BPCNFs) is tailored by controlled thermal carbonization. It is discovered that rising mesopores can realize a fast direct electrochemistry of glucose oxidase (GOx) for highly sensitive detection of glucose, achieving a sensitivity of 123.28 µA mmol L^?1 cm^?2 and a detection limit of 0.023 µmol L^?1. The enhancement mechanism for the mesopores is ascribed to the most adequate mesopores of BPCNF₉₀₀, which offer size‐matched “nests” to trap GOx for intimate contacts with the conductive carbon nanofiber enabling fast direct electrochemistry. In addition, with the BPCNF₉₀₀ sensing platform, the mechanisms for GOx‐direct‐electrochemistry‐catalyzed glucose oxidation and oxygen reduction are systematically investigated to further clarify the confusions of glucose sensing in air and N₂‐saturated solutions. This work demonstrates fundamental insights for the direct electrochemistry enabled by rationally designing a pore structure matching the target proteins, thus possessing universal significance in protein‐based electrochemical devices while offering a facile route to fabricate a highly sensitive glucose sensor for practical clinic diagnosis.     

A Traceable,Sequential Multistage-Targeting Nanoparticles Combining Chemo/Chemodynamic Therapy for Enhancing Antitumor Efficacy

Although chemodynamic therapy (CDT) can effectively inhibit tumor growth and metastasis, it is challenging to eliminate tumors. Generally, CDT needs to combine with extra therapeutic modes for enhancing antitumor efficacy. Here, novel nanoparticles (BDTLAG NPs) are constructed via self-assembly of cancer cell targeting prodrug (Bio-PEG_2K-S-S-CPT), organic CDT agents (TPP-PEG_2K-LND, TPP-PEG_2K-TOS), pH-responsive prodrug (PEG_2K-NH-N-DOX), T1-enhanced magnetic resonance imaging contrast agents (Gd-DTPA-N16-16), and anti-angiogenic drug combrestatinA4 (CA4), realizing chemo(CT)-chemodynamic combination therapy. The mechanism of BDTLAG NPs for enhancing antitumor efficacy involves: (i) BDTLAG NPs is accumulated in the tumor tissue by passive targeting; (ii) CA4 is released and specifically destroys angiogenesis, and the remaining BDTLG NPs enter the tumor cell via active targeting; (iii) the acid/glutathione (GSH)-responsive prodrug release and GSH depletion; (iv) TPP-PEG_2K-LND and TPP-PEG_2K-TOS are accumulated in the tumor cell mitochondria due to mitochondria-targeting, and is accompanied by endogenous reactive oxygen species bursts. This current strategy of single NPs that integrates spatiotemporally CT, CDT, GSH depletion, and MR imaging functions reflects the “all in one” concept, which provides a new opportunity for enhancing antitumor efficacy.     

Biodegradable Calcium Phosphate Nanotheranostics with Tumor-Specific Activatable Cascade Catalytic Reactions-Augmented Photodynamic Therapy

Photodynamic therapy (PDT) is exploited as a promising strategy for cancer treatment. However, the hypoxic solid tumor and the lack of tumor-specific photosensitizer administration hinder the further application of oxygen (O₂)-dependent PDT. In this study, a biodegradable and O₂ self-supplying nanoplatform for tumor microenvironment (TME)-specific activatable cascade catalytic reactions-augmented PDT is reported. The nanoplatform (named GMCD) is constructed by coloading catalase (CAT) and sinoporphyrin sodium (DVDMS) in the manganese (Mn)-doped calcium phosphate mineralized glucose oxidase (GOx) nanoparticles. The GMCD can effectively accumulate in tumor sites to achieve an “off to on” fluorescence transduction and a TME-activatable magnetic resonance imaging. After internalization into cancer cells, the endogenous hydrogen peroxide (H₂O₂) can be catalyzed to generate O₂ by CAT, which not only promotes GOx catalytic reaction to consume more intratumoral glucose, but also alleviates tumor hypoxia and enhances the production of cytotoxic singlet oxygen from light-triggered DVDMS. Moreover, the H₂O₂ generated by GOx-catalysis can be converted into highly toxic hydroxyl radicals by Mn²⁺-mediated Fenton-like reaction, further amplifying the oxidative damage of cancer cells. As a result, GMCD displays superior therapeutic effects on 4T1-tumor bearing mice by a long term cascade catalytic reactions augmented PDT.     

Persistent Regulation of Tumor Microenvironment via Circulating Catalysis of MnFe2O4@Metal–Organic Frameworks for Enhanced Photodynamic Therapy

Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe₂O₄@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe₂O₄) as the nanoenzyme. The synthetic MnFe₂O₄@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H₂O₂ to produce O₂ to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe₂O₄@MOF is able to persistently consume GSH in the presence of H₂O₂, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application.     

Co–Ferrocene MOF/Glucose Oxidase as Cascade Nanozyme for Effective Tumor Therapy

Chemodynamic therapy (CDT), enabling selective therapeutic effects and low side effect, attracts increasing attention in recent years. However, limited intracellular content of H₂O₂ and acid at the tumor site restrains the lasting Fenton reaction and thus the anticancer efficacy of CDT. Herein, a nanoscale Co–ferrocene metal–organic framework (Co‐Fc NMOF) with high Fenton activity is synthesized and combined with glucose oxidase (GOx) to construct a cascade enzymatic/Fenton catalytic platform (Co‐Fc@GOx) for enhanced tumor treatment. In this system, Co‐Fc NMOF not only acts as a versatile and effective delivery cargo of GOx molecules to modulate the reaction conditions, but also possesses excellent Fenton effect for the generation of highly toxic ?OH. In the tumor microenvironment, GOx delivered by Co‐Fc NMOF catalyzes endogenous glucose to gluconic acid and H₂O₂. The intracellular acidity and the on‐site content of H₂O₂ are consequently promoted, which in turn favors the Fenton reaction of Co‐Fc NMOF and enhances the generation of reactive oxygen species (ROS). Both in vitro and in vivo results demonstrate that this cascade enzymatic/Fenton catalytic reaction triggered by Co‐Fc@GOx nanozyme enables remarkable anticancer properties.     

Metal–Organic Framework Assisted and Tumor Microenvironment Modulated Synergistic Image‐Guided Photo‐Chemo Therapy

The complex tumor microenvironment (TME) and nonspecific drug targeting limit the clinical efficacy of photodynamic therapy in combination with chemotherapy. Herein, a metal–organic framework (MOF) assisted strategy is reported that modulates TME by reducing tumor hypoxia and intracellular glutathione (GSH) and offers targeted delivery and controlled release of the trapped chemodrug. Platinum(IV)‐diazido complex (Pt(IV)) is loaded inside a Cu(II) carboxylate‐based MOF, MOF‐199, and an aggregation‐induced‐emission photosensitizer, TBD, is conjugated to polyethylene glycol for encapsulating Pt(IV)‐loaded MOF‐199. Once the fabricated TBD‐Pt(IV)@MOF‐199 nanoparticles are internalized by cancer cells, MOF‐199 consumes intracellular GSH and decomposes to fragments to release Pt(IV). Upon light irradiation, the released Pt(IV) generates O₂ that relieves hypoxia and produces Pt(II)‐based chemodrug inside cancer cells. Concomitantly, efficient reactive oxygen species generation and bright emission are afforded by TBD, resulting in synergistic image‐guided photo‐chemo therapy with enhanced efficacies and mitigated side effects.     

A Highly Efficient Electrochemical Biosensing Platform by Employing Conductive Nanocomposite Entrapping Magnetic Nanoparticles and Oxidase in Mesoporous Carbon Foam

A conductive multi‐catalyst system consisting of Fe₃O₄ magnetic nanoparticles (MNPs) and oxidative enzymes co‐entrapped in the pores of mesoporous carbon is developed as an efficient and robust electrochemical biosensing platform. The construction of the nanocomposite begins with the incorporation of MNPs by impregnating Fe(NO₃)₃ on a wall of mesoporous carbon followed by heat treatment under an Ar/H₂ atmosphere, which results in the formation of magnetic mesoporous carbon (MMC). Glucose oxidase (GOx) is subsequently immobilized in the remaining pore spaces of the MMC by using glutaraldehyde crosslinking to prevent enzyme leaching from the matrix. H₂O₂ generated by the catalytic action of GOx in proportion to the amount of target glucose is subsequently reduced into H₂O by the peroxidase mimetic activity of MNPs generating cathodic current, which can be detected through the conductive carbon matrix. To develop a robust and easy‐to‐use electrocatalytic biosensing platform, a carbon paste electrode is prepared by mechanically mixing the nanocomposite or MMCs and mineral oil. Using this strategy, H₂O₂ and several phenolic compounds are amperometrically determined employing MMCs as peroxidase mimetics, and target glucose was successfully detected over a wide range of 0.5 × 10^?3 to 10 × 10^?3 M , which covers the actual range of glucose concentration in human blood, with excellent storage stability of over two months at room temperature. Sensitivities of the biosensor (19 to 36 nA mM ^?1) are about 7–14 times higher than that of the biosensor using immobilized GOx in mesoporous carbon without MNPs under optimized condition. The biosensor is of considerable interest because of its potential for expansion to any oxidases, which will be beneficial for use in practical applications by replacing unstable organic peroxidase with immobilized MNPs in a conductive carbon matrix.     

Sulfite-Inserted MgAl Layered Double Hydroxides Loaded with Glucose Oxidase to Enable SO2-Mediated Synergistic Tumor Therapy

As a type of unique gaseous molecules, SO₂ presents capabilities in the feasible cellular influx and the induction of apoptosis by generating intracellular toxic radicals. Developing therapeutic platforms to enable effective SO₂ gas release at the tumor site is highly demanded in the exploration of more “green” and effective treatment protocols for cancer therapy but remains challenging. Here for the first time, fine nanosheets composing of Mg-Al layered double hydroxides (MgAl LDH) are synthesized and inserted with sulfite in its layered structures (MgAl-SO₃ LDH). After the loading of glucose oxidase (GOx/MgAl-SO₃ LDH), the composite nanosheets present the controllable SO₂ gas release in an acidic responsive manner. Owing to the glycolysis effect of GOx, the gluconic acid generated agitates the intracellular SO₂ release from nanosheets, and excessive H₂O₂ reacts with SO₂ effectively and facilitates the production of toxic radicals, inducing remarkable oxidative damages to tumor cells. Meanwhile, the consumption of intracellular glucose by GOx/MgAl-SO₃ LDH depletes the energy supply of tumor cells, favoring the tumor inhibition both in vitro and in vivo in a synergistic fashion. Therefore, this study has provided distinctive perspectives in the exploration of therapeutic platforms with green functionalities and biodegradability for effective tumor treatment.     

Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma

O₂‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O₂‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O₂‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O₂‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.     

GSH-Depleted Nanozymes with Dual-Radicals Enzyme Activities for Tumor Synergic Therapy

Although inspiring progress has been achieved in tumor nanocatalytic therapies based on tailor-made nanozymes for converting hydrogen peroxide into reactive oxygen species (ROS) efficiently, most cytotoxic hydroxyl radicals do not spread far enough within a cell to damage the primary organelles for effective tumor therapy due to their short half-life time (≈1 µs). Developing a novel nanocatalyst platform involving longer half-life time ROS is desired. To this end, Fe₃O₄-Schwertmannite nanocomposites (Fe₃O₄-Sch) with triple-effect tumor therapy are constructed through a facile method. The Schwertmannite shell converts the ^•OH produced by Fe₃O₄ via the Fenton reaction into sulfate radicals with a longer half-life time (30 µs). Combination of dual radicals exhibits overwhelming tumor inhibition efficacy. The nanocomposites also show the multifunctionality of good photothermal efficiency (33.2%) and synergistic oxidative stress amplification upon glutathione biosynthesis (GSH) depletion by the l -buthionine sulfoximine (BSO) molecules loaded in the hollow Fe₃O₄ cores. The comprehensive properties of the nanoplatform including the dual-radical production, Fe₃O₄ nanocrystal mediated PTT, and the BSO mediated GSH depletion result in remarkable tumor inhibition both in vitro and in vivo, which may pave a way to constructing a synergic catalytic nanoplatform for efficient tumor therapy.     

Biodegradable Nanoscale Coordination Polymers for Targeted Tumor Combination Therapy with Oxidative Stress Amplification

Nowadays various inorganic nanoparticles that generate highly reactive hydroxyl radical ( · OH) on the basis of Fenton‐like catalytic activity of metal ions have been designed for chemodynamic therapy. However, the high level of adaptive antioxidants [glutathione (GSH)] in cancer cells could effectively consume · OH to compromise the treatment efficiency and biosafety of these inorganic nanoparticles, and this is a general concern in chemodynamic therapy. Herein, a new biodegradable nanoscale coordination polymer (NCP) is developed by integration of cisplatin prodrug (DSCP) and iron (III) ions through a reverse microemulsion method. The DSCP in the NCPs could react with GSH to release free cisplatin, while the iron (III) ions could be reduced by GSH into iron (II) to enable Fenton reaction, subsequently leading to amplified intracellular oxidative stress. After surface modification of polyethylene glycol (PEG) and cyclo[Arg‐Gly‐Asp‐D‐Phe‐Lys(mpa)] peptide (cRGD), Fe‐DSCP‐PEG‐cRGD shows an excellent targeting effect against α_vβ₃‐integrin overexpressed tumor cells. Furthermore, Fe‐DSCP‐PEG‐cRGD enables significant chemo and chemodynamic therapy with dramatically enhanced therapeutic efficiency in comparison to relative monotherapies. Importantly, Fe‐DSCP‐PEG‐cRGD could be efficiently cleared out from mice through feces and urine postinjection 7 days. The NCP presented in this work is simple and economical, which shows great biodegradability and biosafety for potential clinical translation.     

Ultrasound‐Activated Oxygen and ROS Generation Nanosystem Systematically Modulates Tumor Microenvironment and Sensitizes Sonodynamic Therapy for Hypoxic Solid Tumors

Sonodynamic therapy (SDT) is noninvasive and possesses high body‐penetration depth, showing great potential for the treatment of deep‐seated solid tumors. The efficacy of SDT, however, is limited by widespread hypoxia in solid tumors. Given this, an ultrasound‐activated nanosystem is developed by integrating ferrate(VI) and protoporphyrin IX into biodegradable hollow mesoporous organosilica nanoplatforms, followed by assembling a phase‐change material of lauric acid. The ferrate(VI) effectively reacts with water as well as overexpressed hydrogen peroxide and glutathione (GSH) in tumor cells, leading to tumor‐microenvironment‐independent oxygen production and in situ GSH depletion in tumors. More importantly, significant reactive oxygen species (ROS) overproduction is simultaneously achieved by protoporphyrin‐augmented SDT and intracellular Fenton chemistry. Furthermore, the mild hyperthermia induced by ultrasound can trigger the phase change of lauric acid, achieving ultrasound‐responsive control over the release of oxygen and ROS, and the depletion of GSH. The simultaneous oxygen generation, in situ GSH depletion, and ROS overproduction play a synergetic role in sensitizing SDT toward hypoxic solid tumors, which is verified by the remarkable improvement of hypoxic environments and more significant growth inhibition of SDT against osteosarcoma both in vitro and in vivo, showing promising application in hypoxic solid tumor treatment.     

A Yolk–Shell Nanoplatform for Gene‐Silencing‐Enhanced Photolytic Ablation of Cancer

Noninvasive near‐infrared (NIR) light responsive therapy is a promising cancer treatment modality; however, some inherent drawbacks of conventional phototherapy heavily restrict its application in clinic. Rather than producing heat or reactive oxygen species in conventional NIR treatment, here a multifunctional yolk–shell nanoplatform is proposed that is able to generate microbubbles to destruct cancer cells upon NIR laser irradiation. Besides, the therapeutic effect is highly improved through the coalition of small interfering RNA (siRNA), which is codelivered by the nanoplatform. In vitro experiments demonstrate that siRNA significantly inhibits expression of protective proteins and reduces the tolerance of cancer cells to bubble‐induced environmental damage. In this way, higher cytotoxicity is achieved by utilizing the yolk–shell nanoparticles than treated with the same nanoparticles missing siRNA under NIR laser irradiation. After surface modification with polyethylene glycol and transferrin, the yolk–shell nanoparticles can target tumors selectively, as demonstrated from the photoacoustic and ultrasonic imaging in vivo. The yolk–shell nanoplatform shows outstanding tumor regression with minimal side effects under NIR laser irradiation. Therefore, the multifunctional nanoparticles that combining bubble‐induced mechanical effect with RNA interference are expected to be an effective NIR light responsive oncotherapy.     

Cancer Cell Membrane‐Biomimetic Oxygen Nanocarrier for Breaking Hypoxia‐Induced Chemoresistance

The inadequate oxygen supply in solid tumor causes hypoxia, which leads to drug resistance and poor chemotherapy outcomes. To solve this problem, a cancer cell membrane camouflaged nanocarrier is developed with a polymeric core encapsulating hemoglobin (Hb) and doxorubicin (DOX) for efficient chemotherapy. The designed nanoparticles (DHCNPs) retain the cancer cell adhesion molecules on the surface of nanoparticles for homologous targeting and possess the oxygen‐carrying capacity of Hb for O₂‐interfered chemotherapy. The results show that DHCNPs not only achieve higher tumor specificity and lower toxicity by homologous targeting but also significantly reduce the exocytosis of DOX via suppressing the expressions of hypoxia‐inducible factor‐1α, multidrug resistance gene 1, and P‐glycoprotein, thus resulting in safe and high‐efficient chemotherapy. This work presents a new paradigm for targeted oxygen interference therapy by conquering hypoxia‐involved therapeutic resistance and achieves effective treatment of solid tumors.     

Reactive Oxygen Species–Activatable Liposomes Regulating Hypoxic Tumor Microenvironment for Synergistic Photo/Chemodynamic Therapies

Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)‐activatable liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe₃O₄ features ROS‐cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe₃O₄ and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H₂O₂ promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H₂O₂ to generate ?OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.     

GSH‐Depleted PtCu3 Nanocages for Chemodynamic‐ Enhanced Sonodynamic Cancer Therapy

The ultrahigh concentration of glutathione (GSH) inside tumors destroys reactive oxygen species (ROS)‐based therapy, improving the outcome of chemodynamic therapy (CDT)‐enhanced sonodynamic therapy (SDT) by depleting GSH is full of great challenge. Herein, PtCu₃ nanocages are first reported as acting as a sonosensitizer with highly efficient ROS generation under ultrasound irradiation. In addition, PtCu₃ nanocages can act as horseradish peroxidase‐like nanozymes, catalyzing the decomposition of H₂O₂ into ^?OH under acidic conditions for CDT. Surprisingly, PtCu₃ nanocages can act as another kind of nanozyme, mimicking glutathione peroxidase (GSH‐Px), which plays an important role in accelerating GSH depletion by oxidizing molecules, further weakening the capacity of tumor cells scavenging ROS by GSH. Both in vitro and in vivo studies demonstrate that PtCu₃ nanocages perform well in reducing GSH level for CDT‐enhanced SDT. Moreover, utilizing the high absorption in the near‐infrared region and strong X‐ray attenuation ability, the PtCu₃ nanocages are able to conduct photoacoustic/computed tomography dual‐modal imaging‐guided combined cancer therapy. It is worth mentioning that PtCu₃ nanocages cause minimal toxicity to normal tissues at therapeutic doses. This work highlights the use of PtCu₃ nanocages for effective CDT‐enhanced SDT via GSH depletion.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.