A General Molecular Structural Design for Highly Efficient Photopyroptosis that can be Activated within 10 s Irradiation.

Photopyroptosis is an emerging research branch of photodynamic therapy (PDT), whereas there remains a lack of molecular structural principles to fabricate photosensitizers for triggering a highly efficient pyroptosis. Herein, a general and rational structural design principle to implement this hypothesis, is proposed. The principle relies on the clamping of cationic moieties (e.g., pyridinium, imidazolium) onto one photosensitive core to facilitate a considerable mitochondrial targeting (both of the inner and the outer membranes) of the molecules, thus maximizing the photogenerated reactive oxygen species (ROS) at the specific site to trigger the gasdermin E-mediated pyroptosis. Through this design, the pyroptotic trigger can be achieved in a minimum of 10 s of irradiation with a substantially low light dosage (0.4 J cm⁻2), compared to relevant work reported (up to 60 J cm⁻2). Moreover, immunotherapy with high tumor inhibition efficiency is realized by applying the synthetic molecules alone. This structural paradigm is valuable for deepening the understanding of PDT (especially the mitochondrial-targeted PDT) from the perspective of pyroptosis, toward the future development of the state-of-the-art form of PDT.

Biodegradable zwitterionic polymer-cloaked defective metal-organic frameworks for ferroptosis-inducing cancer therapy.

Ferroptosis inhibits tumor growth by iron-dependently accumulating lipid peroxides (LPO) to a lethal extent, which can result from iron overload and glutathione peroxidase 4 (GPX4) inactivation. In this study, we developed biodegradable zwitterionic polymer-cloaked atorvastatin (ATV)-loaded ferric metal-organic frameworks (Fe-MOFs) for cancer treatment. Fe-MOFs served as nanoplatforms to co-deliver ferrous ions and ATV to cancer cells; the zwitterionic polymer membrane extended the circulation time of the nanoparticles and increased their accumulation at tumor sites. In cancer cells, the structure of the Fe-MOFs collapsed in the presence of glutathione (GSH), leading to the depletion of GSH and the release of ATV and Fe2+. The released ATV decreased mevalonate biosynthesis and GSH, resulting in GPX4 attenuation. A large number of reactive oxygen species were generated by the Fe2+-triggered Fenton reaction. This synergistic effect ultimately contributed to a lethal accumulation of LPO, causing cancer cell death. The findings both in vitro and in vivo suggested that this ferroptosis-inducing nanoplatform exhibited enhanced anticancer efficacy and preferable biocompatibility, which could provide a feasible strategy for anticancer therapy.

Ferroptosis-enhanced chemotherapy for triple-negative breast cancer with magnetic composite nanoparticles.

Triple-negative breast cancer (TNBC) causes great suffering to patients because of its heterogeneity, poor prognosis, and chemotherapy resistance. Ferroptosis is characterized by iron-dependent oxidative damage by accumulating intracellular lipid peroxides to lethal levels, and plays a vital role in the treatment of TNBC based on its intrinsic characteristics. To identify the relationship between chemotherapy resistance and ferroptosis in TNBC, we analyzed the single cell RNA-sequencing public dataset of GSE205551. It was found that the expression of Gpx4 in DOX-resistant TNBC cells was significantly higher than that in DOX-sensitive TNBC cells. Based on this finding, we hypothesize that inducing ferroptosis by inhibiting the expression of Gpx4 can reduce the resistance of TNBC to DOX and enhance the therapeutic effect of chemotherapy on TNBC. Herein, dihydroartemisinin (DHA)-loaded polyglutamic acid-stabilized Fe3O4 magnetic nanoparticles (Fe3O4-PGA-DHA) was combined with DOX-loaded polyaspartic acid-stabilized Fe3O4 magnetic nanoparticles (Fe3O4-PASP-DOX) for ferroptosis-enhanced chemotherapy of TNBC. Compared with Fe3O4-PASP-DOX, Fe3O4-PGA-DHA + Fe3O4-PASP-DOX demonstrated significantly stronger cytotoxicity against different TNBC cell lines and achieved significantly more intracellular accumulation of reactive oxygen species and lipid peroxides. Furthermore, transcriptomic analyses demonstrated that Fe3O4-PASP-DOX-induced apoptosis could be enhanced by Fe3O4-PGA-DHA-induced ferroptosis and Fe3O4-PGA-DHA + Fe3O4-PASP-DOX might trigger ferroptosis in MDA-MB-231 cells by inhibiting the PI3K/AKT/mTOR/GPX4 pathway. Fe3O4-PGA-DHA + Fe3O4-PASP-DOX showed superior anti-tumor efficacy on MDA-MB-231 tumor-bearing mice, providing great potential for improving the therapeutic effect of TNBC.

Metal-organic-framework-based pyroptosis nanotuner with long blood circulation for augmented chemotherapy.

Pyroptosis is a proinflammatory form of cell death mediated by members of the gasdermin family, and is a powerful tool against cancer. Herein, a pH-responsive doxorubicin (DOX)-encapsulating zeolitic imidazolate framework-8 (ZIF-8) nanoparticle coated with a carboxybetaine-based zwitterionic polymer (DOX@ZIF-8@PCBMA) was prepared. Furthermore, decitabine (DAC) was loaded to obtain a pyroptosis nanotuner (DOX@ZIF-8@PCBMA-DAC). This nanotuner displayed extended blood circulation and enhanced tumor accumulation. In addition, the ZIF-8 structure and disulfide-crosslinked PCBMA coating endowed DOX@ZIF-8@PCBMA-DAC with acidic-pH- and glutathione-responsive degradation. The nanotuner could robustly activate caspase-3 to induce gasdermin E (GSDME)-dependent pyroptosis via the sustained release of DAC and DOX, contributing to excellent tumor suppression with negligible side effects, which may provide novel insights into traditional chemotherapy.

Carboxybetaine-Based Zwitterionic Polymer Nanogels with Long Blood Circulation for Cancer Therapy.

Given the advantages of antifouling capacity and good biocompatibility, zwitterionic polymers have been profoundly applied for drug delivery to improve the pharmacokinetics profile. Here, a zwitterionic polymer (poly (carboxybetaine methacrylate) (PCBMA)) nanogel was fabricated by one-step reflux precipitation polymerization for doxorubicin (DOX) loading. The obtained nanogels display favorable long blood circulation without priming immune responses as a result of the introduction of the zwitterionic group. Meanwhile, the disulfide bonds deriving from the crosslinker endow nanogels with excellent glutathione-responsive degradation and sufficient drug release under a reduction environment. The carboxylate groups originating from carboxybetaine provide modification sites to conjugate with fluorescent dye to achieve labeling and biodistribution tracking. Overall, under the significantly prolonging circulation and enhanced tumor accumulation through passive targeting, DOX-loaded PCBMA nanogels show a noticeable tumor inhibition effect in mouse colorectal cancer models, which may provide a delivery vehicle with great promise in cancer therapy.

Acid-Degradable Hydrogen-Generating Metal-Organic Framework for Overcoming Cancer Resistance/Metastasis and Off-Target Side Effects.

The development of stimuli-responsively degradable porous carriers for both controlled drug release and high biosafety is vitally important to their clinical translation, but still challenging at present. A new type of porphyrin-iron metal organic framework (Fe-MOF) nanocrystals is engineered here as acid-degradable drug carrier and hydrogen donor by the coordination between porphyrin and zero-valence Fe atom. Fe-MOF nanocrystals exhibit excellent acid-responsive degradation for H2 generation and simultaneous release of the loaded drug for combined hydrogen-chemotherapy of cancer multidrug resistance (MDR) and metastasis and for local hydrogen eradication of the off-target induced toxic side effects of the drug to normal cells/tissues. Mechanistically, released H2 assists chemotherapeutic drug to efficiently inhibit cancer metastasis by immunoactivating intratumoral M1-phenotype macrophages and consequently downregulating the expression of metastasis-related matrix metalloproteinase-2 (MMP-2) and can also downregulate the expressions of both P-glycoprotein (P-gp) protein and adenosine triphosphate (ATP) in MDR cancer cells to sensitize chemotherapeutic drug for enhanced damage to mitochondria and DNA. High anti-MDR/antimetastasis efficacies and high biocompatibility endow Fe-MOF nanocrystals and the Fe-MOF-based nanomedicine with high potential for clinical translation.

Simvastatin induced ferroptosis for triple-negative breast cancer therapy.

Triple-negative breast cancer (TNBC), a management of aggressive breast cancer, remains an unmet medical challenge. Although a wave of efforts had spurred to design novel therapeutic method of TNBC, unpredictable prognosis with lacking effective therapeutic targets along with the resistance to apoptosis seriously limited survival benefits. Ferroptosis is a non-apoptotic form of cell death that is induced by excessive lipid peroxidation, which provide an innovative way to combat cancer. Emerging evidence suggests that ferroptosis plays an important role in the treatment of TNBC cells. Herein, a novel ferroptosis nanomedicine was prepared by loading simvastatin (SIM), a ferroptosis drug, into zwitterionic polymer coated magnetic nanoparticles (Fe3O4@PCBMA) to improve the therapeutic effect of TNBC. The as-obtained Fe3O4@PCBMA-SIM nanoparticles demonstrated more cytotoxicity against MDA-MB-231 than MCF-7 due to the higher expression of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which demonstrated that statins could effectively kill TNBC. Further experiments showed that SIM could inhibit the expression of HMGCR to downregulate the mevalonate (MVA) pathway and glutathione peroxidase 4 (GPX4), thereby inducing cancer cell ferroptosis. What's more, PCBMA endows Fe3O4@PCBMA longer blood circulation performance to enhance their accumulation at tumor sites. Given that Fe3O4 have proven for clinical applications by the U.S. Food and Drug Administration (FDA) and SIM could induce cancer cell ferroptosis, the developed Fe3O4@PCBMA-SIM nanosystem would have great potential in clinics for overcoming the drug resistance brought about by apoptotic drugs to cancer cells.

Photocatalysis-mediated drug-free sustainable cancer therapy using nanocatalyst.

Drug therapy unavoidably brings toxic side effects and drug content-limited therapeutic efficacy although many nanocarriers have been developed to improve them to a certain extent. In this work, a concept of drug-free therapeutics is proposed and defined as a therapeutic methodology without the use of traditional toxic drugs, without the consumption of therapeutic agents during treatment but with the inexhaustible therapeutic capability to maximize the benefit of treatment, and a Z-scheme SnS1.68-WO2.41 nanocatalyst is developed to achieve near infrared (NIR)-photocatalytic generation of oxidative holes and hydrogen molecules for realizing combined hole/hydrogen therapy by the drug-free therapeutic strategy. Without the need of any drug and other therapeutic agent assistance, the nanocatalyst oxidizes/consumes intratumoral over-expressed glutathione (GSH) by holes and simultaneously generates hydrogen molecules in a lasting and controllable way under NIR irradiation. Mechanistically, generated hydrogen molecules and GSH consumption inhibit cancer cell energy and destroy intratumoral redox balance, respectively, to synergistically damage DNA and induce tumor cell apoptosis. High efficacy and biosafety of combined hole/hydrogen therapy of tumors are achieved by the nanocatalyst. The proposed catalysis-based drug-free therapeutic strategy breaks a pathway to realize high efficacy and low toxicity of cancer treatment.

A phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug with a long circulation time and charged conversion for enhanced chemotherapy.

In recent years, zeolitic imidazolate framework-8 (ZIF-8) has become an attractive metal organic framework (MOF) material in drug delivery for cancer chemotherapy. However, as a drug delivery system, ZIF-8 still shows some disadvantages, such as short blood circulation time and poor tumor targeting, leading to reduced drug delivery efficiency and unsatisfactory treatment. Herein, we developed a phosphorylcholine-based zwitterionic copolymer coated ZIF-8 nanodrug (DOX@ZIF-8@P(MPC-co-C7A)), and the obtained nanodrug was prepared via a charge-conversional zwitterionic copolymer coating on DOX@ZIF-8 composites. In this system, DOX was encapsulated in the framework of ZIF-8, which could reduce the drug leakage in the bloodstream. The phosphorylcholine-based zwitterionic copolymer effectively extended the blood circulation time, resulting in enhanced tumor accumulation of the nanodrug. Once the nanodrug reached the tumor site, the surface charge of the system could rapidly convert to positive, resulting in an enhanced tumor cellular uptake. Finally, in the acidic environment inside intracellular organelles, DOX will be released rapidly for chemotherapy owing to the fast disintegration of ZIF-8 frameworks. Therefore, the obtained nanodrug could effectively inhibit the growth of A549-bearing tumors (93.2% tumor inhibition rate) with negligible side effects. Overall, this work significantly improved the drug delivery efficiency of ZIF-8, which may pave the way for the biomedical applications of ZIF-8 crystals in anti-tumor drug delivery.

Dihydroartemisinin-Loaded Magnetic Nanoparticles for Enhanced Chemodynamic Therapy.

Recently, chemodynamic therapy (CDT) has represented a new approach for cancer treatment with low toxicity and side effects. Nonetheless, it has been a challenge to improve the therapeutic effect through increasing the amount of reactive oxygen species (ROS). Herein, we increased the amount of ROS agents in the Fenton-like reaction by loading dihydroartemisinin (DHA) which was an artemisinin (ART) derivative containing peroxide groups, into magnetic nanoparticles (MNP), thereby improving the therapeutic effect of CDT. Blank MNP were almost non-cytotoxic, whereas three MNP loading ART-based drugs, MNP-ART, MNP-DHA, and MNP-artesunate (MNP-AS), all showed significant killing effect on breast cancer cells (MCF-7 cells), in which MNP-DHA were the most potent. What's more, the MNP-DHA showed high toxicity to drug-resistant breast cancer cells (MCF-7/ADR cells), demonstrating its ability to overcome multidrug resistance (MDR). The study revealed that MNP could produce ferrous ions under the acidic condition of tumor microenvironment, which catalyzed DHA to produce large amounts of ROS, leading to cell death. Further experiments also showed that the MNP-DHA had significant inhibitory effect on another two aggressive breast cancer cell lines (MDA-MB-231 and MDA-MB-453 cells), which indicated that the great potential of MNP-DHA for the treatment of intractable breast cancers.

Zwitterionic Polymer Coating of Sulfur Dioxide-Releasing Nanosystem Augments Tumor Accumulation and Treatment Efficacy.

Multiple drug resistance (MDR) exhibited by cancer cells and low intratumor accumulation of chemotherapeutics are the main obstacles in cancer chemotherapy. Herein, the preparation of a redox-responsive sulfur dioxide (SO2 )-releasing nanosystem, with high SO2 -loading capacity, aimed at improving the treatment efficacy of cancers exhibiting MDR is described. The multifunctional nanomedicine (MON-DN@PCBMA-DOX) is designed and constructed by coating mesoporous organosilica nanoparticles with a zwitterionic polymer, poly(carboxybetaine methacrylate) (PCBMA), which can concurrently load SO2 prodrug molecules (DN, 2,4-dinitrobenzenesulfonylchloride) and chemotherapeutics (DOX, doxorubicin). The generated SO2 molecules can sensitize cells to chemotherapy and overcome the MDR by downregulating the expression of P-glycoprotein. Furthermore, the PCBMA coating prolongs the blood circulation time of the inner core, leading to an increased intratumor accumulation of the nanomedicine. Owing to the prolonged blood circulation, enhanced tumor accumulation, and SO2 sensitization of cells to chemotherapy, the nanomedicine exhibits excellent tumor suppression with a tumor inhibition rate of 94.8%, and might provide a new platform for cancer therapy.

Metal-Organic Framework Nanoparticles with Near-Infrared Dye for Multimodal Imaging and Guided Phototherapy.

From the conception of atom economy to develop multifunctional nanomaterials, it is important to construct nanomaterials by maximizing functional units while minimizing unnecessary components. Noteworthy, metal-organic framework (MOF) nanoparticles are excellent examples to meet this idea. Current approaches for multifunctional MOFs are mainly based on encapsulation of functional molecules or multistep modification; however, high risk for leakage and burst release and time-consuming and complicated organic synthesis limit their applications. Here, we report a one-pot approach to build the defect structure of a metal organic framework with near-infrared dye (cypate), which is based on the interaction between Fe3+ and carboxyl group of cypate molecules, to construct a multifunctional MOF. Moreover, this system can achieve multimodal imaging guided phototherapy. Subsequently, the precise cancer phototherapy is investigated in vivo, and the tumors are entirely eliminated without obvious side effects, demonstrating the high efficacy and safety of this multifunctional platform. Hence, it is expected that not only this system is simple, safe, and highly effective but also our method of creating defect structures of MOFs will open a new way to develop multifunctional nanoplatforms for bioapplications.

Multifunctional nanoplatform for photoacoustic imaging-guided combined therapy enhanced by CO induced ferroptosis.

A multifunctional CO/thermo/chemotherapy nanoplatform is here reported, which is composed of mesoporous carbon nanoparticles (MCN) as near infrared (NIR)-responsive drug carrier, doxorubicin (DOX) as chemotherapeutic drug and triiron dodecacarbonyl (FeCO) as thermosensitive CO prodrug. The nanoplatform could absorb near-infrared (NIR) light and convert it into ample heat to trigger CO release and could also release DOX in the acidic tumor microenvironment. More importantly, the generated CO molecules successfully increase cancer cell sensitivity to chemotherapeutics by the ferroptosis pathway. Subsequently, under the guidance of photoacoustic imaging, the FeCO-DOX@MCN nanoplatform demonstrates high treatment efficacies in vitro and in vivo by combination of chemotherapy, photothermal therapy and gas therapy. This multifunctional platform with excellent antitumor efficacy has great potential in precision cancer therapy.

Erythrocyte-cancer hybrid membrane-camouflaged melanin nanoparticles for enhancing photothermal therapy efficacy in tumors.

Cell membrane coating has emerged as an intriguing biomimetic strategy to endow nanomaterials with functions and properties inherent to source cells for various biomedical applications. Hybrid membrane of different types of cells could be coated onto nanoparticle surface to achieve additional functions. Herein, we fused red blood cell (RBC) membrane together with MCF-7 cell membrane and fabricated an erythrocyte-cancer (RBC-M) hybrid membrane-camouflaged melanin nanoparticle (Melanin@RBC-M) platform for enhancing therapeutic efficacy of photothermal therapy (PTT). The fused RBC-M hybrid membrane vesicles retained both RBC and MCF-7 cell membrane proteins and the resultant Melanin@RBC-M exhibited prolonged blood circulation and homotypic targeting to source MCF-7 cells simultaneously. Interestingly, increasing MCF-7 membrane components in RBC-M significantly enhanced the homotypic targeting function of Melanin@RBC-M while increasing RBC membrane components in RBC-M effectively reduced the cellular uptake of Melanin@RBC-M by macrophages and improved their circulation time in the blood. After intravenous injection into MCF-7 tumor-bearing athymic nude mice, Melanin@RBC-M with 1:1 membrane protein weight ratio of RBC to MCF-7 exhibited significantly higher tumor accumulation and better PTT efficacy compared with other Melanin@RBC-M with different membrane protein weight ratios as well as pristine melanin nanoparticles, due to the optimal balance between prolonged blood circulation and homotypic targeting. In addition, in vitro photoacoustic results revealed that Melanin@RBC-M had a photoacoustic signal enhancement with the increase of nanoparticle size (64 → 148 nm) and the photoacoustic amplitudes increased linearly with nanoparticle concentration at the excitation wavelength ranged from 680 nm to 800 nm, which could be used for quantification of Melanin@RBC-M in vivo. Looking forward, coating hybrid membrane onto nanoparticles could add flexibility and controllability in enhancing nanoparticles functionality and offer new opportunities for biomedical applications.

Metal-Organic Framework/Graphene Quantum Dot Nanoparticles Used for Synergistic Chemo- and Photothermal Therapy.

In this study, a simple one-pot method was used to prepare a multifunctional platform for synergistic chemo- and photothermal therapy,, which is composed of zeolitic imidazolate framework-8 (ZIF-8) as drug nanocarriers and the embedded graphene quantum dots (GQDs) as local photothermal seeds. The structure, drug release behavior, photothermal effect, and synergistic therapeutic efficiency of the ZIF-8/GQD nanoparticles were systematically investigated. Using doxorubicin (DOX) as a model anticancer drug, the results showed that monodisperse ZIF-8/GQD nanoparticles with a particle size of 50-100 nm could encapsulate DOX during the synthesis procedure and trigger DOX release under acidic conditions. The DOX-loaded ZIF-8/GQD nanoparticles could efficiently convert near-infrared (NIR) irradiation into heat and thereby increase the temperature. More importantly, with breast cancer 4T1 cells as a model cellular system, the results indicated that the combined chemo- and photothermal therapy with DOX-ZIF-8/GQD nanoparticles exhibited a significant synergistic effect, resulting in a higher efficacy to kill cancer cells compared with chemotherapy and photothermal therapy alone. Hence, ZIF-8/GQD nanoparticles would be promising as versatile nanocarriers for synergistic cancer therapy.

Mesoporous Silica Nanoparticles Capped with Graphene Quantum Dots for Potential Chemo-Photothermal Synergistic Cancer Therapy.

In this study, mesoporous silica nanoparticles (MSNs) have been successfully capped with graphene quantum dots (GQDs) to form multifunctional GQD-MSNs with the potential for synergistic chemo-photothermal therapy. The structure, drug-release behavior, photothermal effect, and synergistic therapeutic efficiency of GQD-MSNs to 4T1 breast cancer cells were investigated. The results showed that GQD-MSNs were monodisperse and had a particle size of 50-60 nm. Using doxorubicin hydrochloride (DOX) as a model drug, the DOX-loaded GQD-MSNs (DOX-GQD-MSNs) not only exhibited pH- and temperature-responsive drug-release behavior, but using near-infrared irradiation, they efficiently generated heat to kill cancer cells. Furthermore, GQD-MSNs were biocompatible and were internalized by 4T1 cells. Compared with chemotherapy and photothermal therapy alone, DOX-GQD-MSNs were much more effective in killing the 4T1 cells owing to a synergistic chemo-photothermal effect. Therefore, GQD-MSNs may have promising applications in cancer therapy.

Graphene Quantum Dots-Capped Magnetic Mesoporous Silica Nanoparticles as a Multifunctional Platform for Controlled Drug Delivery, Magnetic Hyperthermia, and Photothermal Therapy.

A multifunctional platform is reported for synergistic therapy with controlled drug release, magnetic hyperthermia, and photothermal therapy, which is composed of graphene quantum dots (GQDs) as caps and local photothermal generators and magnetic mesoporous silica nanoparticles (MMSN) as drug carriers and magnetic thermoseeds. The structure, drug release behavior, magnetic hyperthermia capacity, photothermal effect, and synergistic therapeutic efficiency of the MMSN/GQDs nanoparticles are investigated. The results show that monodisperse MMSN/GQDs nanoparticles with the particle size of 100 nm can load doxorubicin (DOX) and trigger DOX release by low pH environment. Furthermore, the MMSN/GQDs nanoparticles can efficiently generate heat to the hyperthermia temperature under an alternating magnetic field or by near infrared irradiation. More importantly, breast cancer 4T1 cells as a model cellular system, the results indicate that compared with chemotherapy, magnetic hyperthermia or photothermal therapy alone, the combined chemo-magnetic hyperthermia therapy or chemo-photothermal therapy with the DOX-loaded MMSN/GQDs nanosystem exhibits a significant synergistic effect, resulting in a higher efficacy to kill cancer cells. Therefore, the MMSN/GQDs multifunctional platform has great potential in cancer therapy for enhancing the therapeutic efficiency.