A Supramolecular Photosensitizer System Based on Nano-Cu/ZIF-8 Capped with Water-Soluble Pillar[6]arene and Methylene Blue Host–Guest Complexations

Photodynamic therapy (PDT) as a safe, non-invasive modality for cancer therapy, in which the low oxygen and high glutathione in the tumor microenvironment reduces therapeutic efficiency. In order to overcome these problems, we prepared a supramolecular photosensitive system of O₂-Cu/ZIF-8@ZIF-8@WP6–MB (OCZWM), which was loaded with oxygen to increase the oxygen concentration in the tumor microenvironment, and the Cu²⁺ in the system reacted with glutathione (GSH) to reduce the GSH concentration to generate Cu⁺. It is worth noting that the generated Cu⁺ can produce the Fenton reaction, thus realizing the combination therapy of PDT and chemodynamic therapy (CDT) to achieve the purpose of significantly improving the anti-cancer efficiency.     

Programmed Release of Dihydroartemisinin for Synergistic Cancer Therapy Using a CaCO3 Mineralized Metal–Organic Framework

Dihydroartemisinin (DHA) has attracted increasing attention as an anticancer agent. However, using DHA to treat cancer usually depends on the synergistic effects of exogenous components, and the loss of DHA during delivery reduces its effectiveness in cancer therapy. Reported herein is a programmed release nanoplatform of DHA to synergistically treat cancer with a Fe‐TCPP [(4,4,4,4‐(porphine‐5,10,15,20‐tetrayl) tetrakis(benzoic acid)] NMOF (nanoscale MOF) having a CaCO₃ mineralized coating, which prevents DHA leakage during transport in the bloodstream. When the nanoplatform arrives at the tumor site, the weakly acidic microenvironment and high concentration of glutathione (GSH) trigger DHA release and TCPP activation, enabling the synergistic Fe²⁺‐DHA‐mediated chemodynamic therapy, Ca²⁺‐DHA‐mediated oncosis therapy, and TCPP‐mediated photodynamic therapy. In vivo experiments demonstrated that the nanoplatform showed enhanced anticancer efficiency and negligible toxicity.     

Construction of a Single-Atom Nanozyme for Enhanced Chemodynamic Therapy and Chemotherapy

To fulfill the demand of precision and personalized medicine, single-atom catalysts (SACs) have emerged as a frontier in biomedical fields due to enzyme-mimic catalysis. Herein, we present a biocompatible and versatile nanoagent consisting of single-atom iron-containing nanoparticles (SAF NPs), DOX and A549 cell membrane (CM). The designed porous iron-based SACs originally served as a drug-carrying nanoplatform to release DOX selectively in a tumor microenvironment (TME) for chemotherapy (CT) due to their high loading capacity (155 %) for DOX; this signifies that SACs are promising candidates for universal cargo delivery. Besides, the designed single-atom nanoagent can perform like peroxidase, which effectively triggers an in situ tumor-specific Fenton reaction to generate abundant toxic hydroxyl radicals (⋅OH) selectively in the acidic TME for chemodynamic therapy (CDT). With the combination of CDT and CT, the constructed SAF NPs@DOX@CM nanoagent demonstrates better in vivo therapeutic performance than single-pathway therapy. In the meantime, after modification with CM, SAF NPs@DOX@CM can achieve homologous binding to target tumor tissues and avoid early clearance. This study presents a type of multifunctional SACs for enhanced cancer treatment via the capacity of a drug carrier combined with the enzymatic therapies of single-atom catalytic sites.     

GSH/ROS Dual-Responsive Supramolecular Nanoparticles Based on Pillar[6]arene and Betulinic Acid Prodrug for Chemo–Chemodynamic Combination Therapy

Chemodynamic therapy (CDT) based on intracellular Fenton reactions is attracting increasing interest in cancer treatment. A simple and novel method to regulate the tumor microenvironment for improved CDT with satisfactory effectiveness is urgently needed. Therefore, glutathione (GSH)/ROS (reactive oxygen species) dual-responsive supramolecular nanoparticles (GOx@BNPs) for chemo–chemodynamic combination therapy were constructed via host–guest complexation between water-soluble pillar[6]arene and the ferrocene-modified natural anticancer product betulinic acid (BA) prodrug, followed by encapsulation of glucose oxidase (GOx) in the nanoparticles. The novel supramolecular nanoparticles could be activated by the overexpressed GSH and ROS in the tumor microenvironment (TME), not only accelerating the dissociation of nanoparticles—and, thus, improving the BA recovery and release capability in tumors—but also showing the high-efficiency conversion of glucose into hydroxyl radicals (·OH) in succession through intracellular Fenton reactions. Investigation of antitumor activity and mechanisms revealed that the dramatic suppression of cancer cell growth induced by GOx@BNPs was derived from the elevation of ROS, decrease in ATP and mitochondrial transmembrane potential (MTP) and, finally, cell apoptosis. This work presents a novel method for the regulation of the tumor microenvironment for improved CDT, and the preparation of novel GSH/ROS dual-responsive supramolecular nanoparticles, which could exert significant cytotoxicity against cancer cells through the synergistic interaction of chemodynamic therapy, starvation therapy, and chemotherapy (CDT/ST/CT).     

A Gene-Editable Palladium-Based Bioorthogonal Nanoplatform Facilitates Macrophage Phagocytosis for Tumor Therapy

Macrophage phagocytosis of tumor cells has emerged as an attractive strategy for tumor therapy. Nevertheless, immunosuppressive M2 macrophages in the tumor microenvironment and the high expression of anti-phagocytic signals from tumor cells impede therapeutic efficacy. To address these issues and improve the management of malignant tumors, in this study we developed a gene-editable palladium-based bioorthogonal nanoplatform, consisting of CRISPR/Cas9 gene editing system-linked Pd nanoclusters, and a hyaluronic acid surface layer (HBPdC). This HBPdC nanoplatform exhibited satisfactory tumor-targeting efficiency and triggered Fenton-like reactions in the tumor microenvironment to generate reactive oxygen species for chemodynamic therapy and macrophage M1 polarization, which directly eliminated tumor cells, and stimulated the antitumor response of macrophages. HBPdC could reprogram tumor cells through gene editing to reduce the expression of CD47 and adipocyte plasma membrane-associated protein, thereby promoting their recognition and phagocytosis by macrophages. Moreover, HBPdC induced the activation of sequestered prodrugs via bioorthogonal catalysis, enabling chemotherapy and thereby enhancing tumor cell death. Importantly, the Pd nanoclusters of HBPdC were sufficiently cleared through basic metabolic pathways, confirming their biocompatibility and biosafety. Therefore, by promoting macrophage phagocytosis, the HBPdC system developed herein represents a highly promising antitumor toolset for cancer therapy applications.     

Two-dimensional LDH nanodisks modified with hyaluronidase enable enhanced tumor penetration and augmented chemotherapy

The condensed tumor extracellular matrix(ECM) consisting of cross-linked hyaluronic acid(HA) is one of the key factors that result in the aberrant tumor microenvironment and severely impair drug delivery and tumor penetration. Herein, we report a simple design of a hyaluronidase(HAase)-modified layered double hydroxide(LDH) nanoplatform loaded with anticancer drug doxorubicin(DOX) for enhanced tumor penetration and augmented chemotherapy. In our approach, LDH nanodisks were synthesized via a co-precipitation method, modified with HAase by electrostatic attraction, and finally physically loaded with DOX. The formulated DOX/LDH-HAase complexes show a high DOX loading percentage of 34.2% with good colloidal stability, retain 86.1% of the enzyme activity, and release DOX in a pH-responsive manner having a faster release rate under slightly acidic tumor microenvironment than that under a physiological condition. With the catalytic activity of HAase to digest the HA nearby the cancer cells, the developed DOX/LDH-HAase complexes enable more significant uptake by cancer cells and penetration in 3-dimensional tumor spheroids than enzyme-free DOX/LDH complexes, thus displaying much better antitumor efficacy in vitro than the latter. The more significant tumor penetration and inhibition of the DOX/LDH-HAase complexes than that of the DOX/LDH complexes was further demonstrated by in vivo tumor imaging and therapeutic activity assessments. Our study suggests a unique nanomedicine platform combined with both anticancer drug and enzyme for improved tumor penetration and chemotherapy, which is promising for effective chemotherapy of different types of stroma-rich tumors.     

FeOOH-loaded mesoporous silica nanoparticles as a theranostic platform with pH-responsive MRI contrast enhancement and drug release

The development of stimuli-responsive theranostic platforms is of great demand for efficient cancer treatment because they can enhance diagnostic specificity and sensitivity.In this work,we report a p H-responsive theranostic nanoplatform based on Fe OOH clusters loaded mesoporous silica nanoparticles(Fe@MSNs).The as-synthesized Fe@MSNs possess activatable T_1magnetic resonance imaging(MRI)performance that can respond to the acidic microenvironment of solid tumor to turn on T_1singals by releasing paramagnetic Fe~(3+)ions.The Fe@MSNs are biocompatible without appreciable cytotoxicity.Moreover,the unique mesoporous structure endows the Fe@MSNs with significant advantages to effectively deliver chemotherapeutic drug for inhibiting the growth of solid tumor.We believe that this novel p H-responsive theranostic nanoplatform holds great promise in cancer treatment.     

Triple-Layered Metal-Organic Framework Hybrid for Tandem Response-Driven Enhanced Chemotherapy

The precise release of drugs is essential to improve cancer therapeutic efficacy. In this work, a tandem responsive strategy was developed based on a triple-layered metal-organic framework (MOF) hybrid. The MOF nanoprobe was stepwise fabricated with a telomerase-responsive inner, a pH-sensitive MOF filling and H₂O₂-responsive coordination complex shell of Fe³⁺ and eigallocatechin gallate (EGCG). In the tumor microenvironment, the shell was dissociated by endogenous H₂O₂ and simultaneously produced highly reactive hydroxyl radicals by a Fenton reaction. Meanwhile, the released EGCG could downregulate the expression of P-glycoprotein responsible for drug resistance. After the dissociation of the framework by protons, telomerase could trigger the release of the drug from the DNA duplex on the exposed inner shell. By integrating confined drug release, inhibited efflux pump and chemodynamic therapy, the all-in-one chemotherapy strategy was identified with enhanced therapeutic efficacy in drug-resistant cancer cells.     

A pH-responsive ultrathin Cu-based nanoplatform for specific photothermal and chemodynamic synergistic therapy

Noninvasive tumor therapy requires a new generation of bionanomaterials towards sensitive response to the unique tumor microenvironment to achieve accurate and effective treatment. Herein, we have developed a tumor therapy nanoplatform by immobilizing natural glucose oxidase (GOD) onto Cu-based layered double hydroxide (CuFe-LDH) nanosheets, which for the first time integrates acid-enhanced photothermal therapy (PTT), and pH-responsive and heat-facilitated chemodynamic therapy (CDT) simultaneously. As demonstrated by EXAFS and HRTEM, CuFe-LDH nanosheets possess a considerable number of defects caused by different acid conditions, resulting in a significantly acid-enhanced photothermal conversion efficiency (83.2% at pH 5.4 vs. 46.0% at pH 7.4). Moreover, GOD/CuFe-LDH nanosheets can convert a cascade of glucose into hydroxyl radicals (˙OH) under tumor acid conditions, which is validated by a high maximum velocity (V_max = 2.00 × 10⁻⁷ M) and low Michaelis–Menten constant (K_M = 12.01 mM). With the combination of PTT and CDT, the tumor tissue in vivo is almost eliminated with low-dose drug injection (1 mg kg⁻¹). Therefore, this novel pH-responsive Cu-based nanoplatform holds great promise in tumor-specific CDT/PTT synergistic therapy.

A pH-responsive multifunctional nanosystem was synthesized by loading glucose oxidase (GOD) onto CuFe-layered double hydroxide (LDH) nanosheets, which exhibited synchronous acid-enhanced/responsive photothermal and chemodynamic synergistic therapy.     

Tumor Microenvironment Stimuli-Responsive Fluorescence Imaging and Synergistic Cancer Therapy by Carbon-Dot–Cu2+ Nanoassemblies

A method is developed to fabricate tumor microenvironment (TME) stimuli-responsive nanoplatform for fluorescence (FL) imaging and synergistic cancer therapy via assembling photosensitizer (chlorine e6, Ce6) modified carbon dots (CDs-Ce6) and Cu²⁺. The as-obtained nanoassemblies (named Cu/CC nanoparticles, NPs) exhibit quenched FL and photosensitization due to the aggregation of CDs-Ce6. Their FL imaging and photodynamic therapy (PDT) functions are recovered efficiently once they entering tumor sites by the stimulation of TME. Introducing of Cu²⁺ not only provides extra chemodynamic therapy (CDT) function through reaction with hydrogen peroxide (H₂O₂), but also depletes GSH in tumors by a redox reaction, thus amplifying the intracellular oxidative stress and enhancing the efficacy of reactive oxygen species (ROS) based therapy. Cu/CC NPs can act as a FL imaging guided trimodal synergistic cancer treatment agent by photothermal therapy (PTT), PDT, and thermally amplified CDT.     

MnOx Nanospikes as Nanoadjuvants and Immunogenic Cell Death Drugs with Enhanced Antitumor Immunity and Antimetastatic Effect

Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnO_x nanospikes (NSs) as tumor microenvironment (TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnO_x NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.     

Self-oxygenated co-assembled biomimetic nanoplatform for enhanced photodynamic therapy in hypoxic tumor

Photodynamic therapy (PDT) has shown great application potential in cancer treatment and the important manifestation of PDT in the inhibition of tumors is the activation of immunogenic cell death (ICD) effects. However, the strategy is limited in the innate hypoxic tumor microenvironment. There are two key elements for the realization of enhanced PDT: specific cellular uptake and release of the photosensitizer in the tumor, and a sufficient amount of oxygen to ensure photodynamic efficiency. Herein, self-oxygenated biomimetic nanoparticles (CS@M NPs) co-assembled by photosensitizer prodrug (Ce6-S-S-LA) and squalene (SQ) were engineered. In the treatment of triple negative breast cancer (TNBC), the oxygen carried by SQ can be converted to reactive oxygen species (ROS). Meanwhile, glutathione (GSH) consumption during transformation from Ce6-S-S-LA to chlorin e6 (Ce6) avoided the depletion of ROS. The co-assembled (CS NPs) were encapsulated by homologous tumor cell membrane to improve the tumor targeting. The results showed that the ICD effect of CS@M NPs was confirmed by the significant release of calreticulin (CRT) and high mobility group protein B1 (HMGB1), and it significantly activated the immune system by inhibiting the hypoxia inducible factor-1alpha (HIF-1α)-CD39-CD73-adenosine a2a receptor (A2AR) pathway, which not only promoted the maturation of dendritic cells (DC) and the presentation of tumor specific antigens, but also induced effective immune infiltration of tumors. Overall, the integrated nanoplatform implements the concept of multiple advantages of tumor targeting, reactive drug release, and synergistic photodynamic therapy-immunotherapy, which can achieve nearly 90% tumor suppression rate in orthotopic TNBC models.     

A pH-response multifunctional nanoplatform based on NaGdF4:Yb,Er,Fe@Ce6@mSiO2-DOX for synergistic photodynamic/chemotherapy of cancer cells

Cancer is one of the major diseases that seriously threaten human health. Drug delivery nanoplatforms for tumor treatment have attracted increasing attention owing to their unique advantages such as good specificity and few side effects. This study aimed to fabricate a pH-responsive drug release multifunctional nanoplatform NaGdF₄:Yb,Er,Fe@Ce6@mSiO₂-DOX. In the platform, Fe³⁺ doping enhanced the fluorescence intensity of NaGdF₄:Yb, Er by 5.8 folds, and the mSiO₂ shell substantially increased the specific surface area of nanomaterials (559.257 m²/g). The loading rates of chlorin e6 and doxorubicin hydrochloride (DOX) on NaGdF₄:Yb,Er,Fe@Ce6@mSiO₂-DOX reached 28.58 ± 0.85% and 87.53 ± 5.53%, respectively. Additionally, the DOX release rate from the nanoplatform was only 24.4% after 72 h at pH 7.4. However, under tumor microenvironment conditions (pH 5.0), the release rate of DOX increased to 85.3% after 72 h. The nanoplatform could generate reactive oxygen species (ROS) under 980 nm near-infrared excitation. Moreover, the nanoplatform exhibited a strong comprehensive killing efficiency against cancer cells. The viabilities of HeLa, MCF-7, and HepG2 cancer cells were only 18.5, 11.4, and 9.3%, respectively, after being treated with a combination of photodynamic therapy and chemotherapy. The constructed nanoplatform exhibits great application potential in cancer treatment.     

Magnetic-Optical Imaging for Monitoring Chemodynamic Therapy

Chemodynamic therapy kills cancer cells with reactive oxygen species generated by endogenous triggers in the tumor microenvironment. Although chemodynamic therapy is blossoming in recent years, their therapy process still faces a series of hampers. The unknown catalytic activity of chemodynamic therapy reagents may lead to unpredictable therapy effects, so it is necessary to reveal the therapeutic mechanism of chemodynamic therapy and develop self-monitoring probes. In this mini-review, we summarize and illustrate the most recent progress of chemodynamic therapy, focusing on the applications of magnetic imaging and optical imaging probe for monitoring cancer chemodynamic therapy. Furthermore, we also discuss the potential challenges and the further directions of this field.     

X-Ray-triggered Carbon Monoxide and Manganese Dioxide Generation based on Scintillating Nanoparticles for Cascade Cancer Radiosensitization

Carbon monoxide (CO) is an endogenous signaling molecule with broad therapeutic effects. Here, a multifunctional X-ray-triggered carbon monoxide (CO) and manganese dioxide (MnO₂) generation nanoplatform based on metal carbonyl and scintillating nanoparticles (SCNPs) is reported. Attributed to the radioluminescent characteristic of SCNPs, UV-responsive Mn₂(CO)₁₀ is not only indirectly activated to release CO by X-ray but can also be degraded into MnO₂. A high dose of CO can be used as a glycolytic inhibitor for tumor suppression; it will also sensitize tumor cells to radiotherapy. Meanwhile MnO₂, as the photolytic byproduct of Mn₂(CO)₁₀, has both glutathione (GSH) depletion and Fenton-like Mn²⁺ delivery properties to produce highly toxic hydroxyl radical (⋅OH) in tumors. Thus, this strategy can realize X-ray-activated CO release, GSH depletion, and ⋅OH generation for cascade cancer radiosensitization. Furthermore, X-ray-activated Mn²⁺ in vivo demonstrates an MRI contrast effect, making it a potential theranostic nanoplatform.     

A glutathione activatable pro-drug-photosensitizer for combined chemotherapy and photodynamic therapy

During cancer treatment, chemotherapeutic drugs always result in severe side-effects and drug resistance. Therefore, combining cheomtherapy with other therapeutic modalities, such as photodynamic therapy (PDT) and designing an activable platform is promising for precise and efficient anticancer treatment. Herein, we report a “pro-drug-photosensitizer” agent, LMB-S-CPT, bearing a disulfide bond as the glutathione (GSH)-activatable linker. LMB-S-CPT can be selectively activated by GSH to release activated drug, camptothecin (CPT), for chemotherapy and activated photosensitizer, methylene blue (MB), for PDT. LMB-S-CPT exhibits excellent tumor-activatable performance when injected into tumor-bearing mice, as well as specific cancer therapy with negligible toxic side effects. The activatable pro-drug-photosensitizer offers a new strategy for chemo-photodynamic therapy and displays precise, selective and excellent antitumor effect.     

Tumor microenvironment-responsive MnSiO3-Pt@BSA-Ce6 nanoplatform for synergistic catalysis-enhanced sonodynamic and chemodynamic cancer therapy

Compared with traditional photodynamic therapy （PDT）,ultrasound （US） triggered sonodynamic therapy （SDT） has a wide application prospect in tumor therapy because of its deeper penetration depth.Herein,a novel MnSiO₃-Pt （MP） nanocomposite composed of Mn Si O₃nanosphere and noble metallic Pt was successfully constructed.After modification with bovine serum albumin （BSA） and chlorine e6 （Ce6）,the multifunctional nanoplatform Mn Si O₃-Pt@BSA-Ce6 （MPBC） realized the m...     

A dual-responsive hyaluronic acid nanocomposite hydrogel drug delivery system for overcoming multiple drug resistance

Chemotherapy is restricted by efficient drug outflow due to the multiple drug resistance (MDR) in heterogenous nature of tumor. Herein, we present a dual-responsive hyaluronic acid (HA) nanocomposite hydrogel that can not only response to the tumor microenvironment but also enhance chemotherapy. This HA hydrogel consists of a core-shell SiO₂ (GOD@SiO₂-Arg) and mesoporous silica nanoparticles (MSNs) with doxorubicin (DOX) as the cargo (DOX@MSN). It could rapidly release the GOD@SiO₂-Arg nanoparticles at the low pH tumor-specific environment due to the cleavage of imine bond. GOD@SiO₂-Arg activated by over-expressed glutathione (GSH) in tumor cells releases GOD due to the cleavage of disulfide bonds, which could oxidize glucose to produce hydrogen peroxide (H₂O₂) for in situ NO generation via reaction between Arg and H₂O₂. The validity of this study might provide a method to modulate the tumor microenvironment for enhancing chemotherapy.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.     

Tumor‐Microenvironment‐Induced Degradation of Ultrathin Gadolinium Oxide Nanoscrolls for Magnetic‐Resonance‐Imaging‐Monitored,Activatable Cancer Chemotherapy

The development of biodegradable inorganic nanoparticles with a tumor microenvironment‐activated therapeutic mode of action is urgently needed for precision cancer medicine. Herein, the synthesis of ultrathin lanthanide nanoscrolls (Gd₂O₃ NSs) is reported, which biodegrade upon encountering the tumor microenvironment. The Gd₂O₃ NSs showed highly controlled magnetic properties, which enabled their high‐resolution magnetic resonance imaging (MRI). Importantly, Gd₂O₃ NSs degrade in a pH‐responsive manner and selectively penetrate tumor tissue, enabling the targeted release of anti‐cancer drugs. Gd₂O₃ NSs can be efficiently loaded with an anti‐cancer drug (DOX, 80 %) and significantly inhibit tumor growth with negligible cellular and tissue toxicity both in vitro and in vivo. This study may provide a novel strategy to design tumor microenvironment‐responsive inorganic nanomaterials for biocompatible bioimaging and biodegradation‐enhanced cancer therapy.