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.

High Intensity Focused Ultrasound-Driven Nanomotor for Effective Ferroptosis-Immunotherapy of TNBC.

The heterogeneity of triple-negative breast cancers (TNBC) remains challenging for various treatments. Ferroptosis, a recently identified form of cell death resulting from the unrestrained peroxidation of phospholipids, represents a potential vulnerability in TNBC. In this study, a high intensity focused ultrasound (HIFU)-driven nanomotor is developed for effective therapy of TNBC through induction of ferroptosis. Through bioinformatics analysis of typical ferroptosis-associated genes in the FUSCCTNBC dataset, gambogic acid is identified as a promising ferroptosis drug and loaded it into the nanomotor. It is found that the rapid motion of nanomotors propelled by HIFU significantly enhanced tumor accumulation and penetration. More importantly, HIFU not only actuated nanomotors to trigger effective ferroptosis of TNBC cells, but also drove nanomotors to activate ferroptosis-mediated antitumor immunity in primary and metastatic TNBC models, resulting in effective tumor regression and prevention of metastases. Overall, HIFU-driven nanomotors show great potential for ferroptosis-immunotherapy of TNBC.

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.

Fluoropolymer Coated DNA Nanoclews for Volumetric Visualization of Oligonucleotides Delivery and Near Infrared Light Activated Anti-Angiogenic Oncotherapy.

The potential of microRNA regulation in oncotherapy is limited by the lack of delivery vehicles. Herein, it is shown that fluoropolymer coated DNA nanoclews (FNCs) provide outstanding ability to deliver oligonucleotide through circulation and realize near infrared (NIR) light activated angiogenesis suppression to abrogate tumors. Oligonucleotides are loaded in DNA nanoclews through sequence specific bindings and then a fluorinated zwitterionic polymer is coated onto the surface of nanoclews. Further incorporating quantum dots in the polymer coating endows the vectors with NIR-IIb (1500-1700 nm) fluorescence and NIR light triggered release ability. The FNC vector can deliver oligonucleotides to cancer cells systemically and realize on-demand cytosolic release of the cargo with high transfection efficiency. Taking advantage of the NIR-IIb emission, the whole delivery process of FNCs is visualized volumetrically in vivo with a NIR light sheet microscope. Loaded by FNCs, an oligonucleotide can effectively silence the target miRNA when activated with NIR light, and inhibit angiogenesis inside tumor, leading to complete ablation of cancer. These findings suggest FNCs can be used as an efficient oligonucleotide delivery platform to modulate the expression of endogenous microRNA in gene therapy of cancer.

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.

Defect self-assembly of metal-organic framework triggers ferroptosis to overcome resistance.

The emergence of multidrug treatment resistance presents a hurdle for the successful chemotherapy of tumours. Ferroptosis, resulting from the iron-dependent accumulation of lipid peroxides, has the potential to reverse multidrug resistance. However, simultaneous delivery of the iron sources, ferroptosis inducers, drugs, and enhanced circulation carriers within matrices remains a significant challenge. Herein, we designed and fabricated a defect self-assembly of metal-organic framework (MOF)-red blood cell (RBC) membrane-camouflaged multi-drug-delivery nanoplatform for combined ferroptosis-apoptosis treatment of multidrug-resistant cancer. Ferroptosis and chemotherapeutic drugs are embedded in the centre of the iron (III)-based MOF at defect sites by coordination with metal clusters during a one-pot solvothermal synthesis process. The RBC membrane could camouflage the nanoplatform for longer circulation. Our results demonstrate that this defect self-assembly-enabled MOF-membrane-camouflaged nanoplatform could deplete the glutathione, amplify the reactive oxidative species oxidative stress, and enable remarkable anticancer properties. Our work provides an alternative strategy for overcoming multidrug resistance, which could regulate the fluidity and permeability of the cell membrane by ferroptosis to downregulate of P-glycoprotein protein expression by ferroptosis. This defect self-assembly-enabled MOF-membrane-camouflaged multi-drug-delivery nanoplatform has great therapeutic potential.

Zwitterionic polymer coated sorafenib-loaded Fe3O4 composite nanoparticles induced ferroptosis for cancer therapy.

Ferroptosis, as a form of cell death different from apoptosis, is very promising for the treatment of cancer in nonapoptotic systems. Since iron is a key component in the induction of ferroptosis in cells, the use of iron-based nanomaterials in treating cancer through ferroptosis is of great significance. Therefore, in this study, magnetic nanoparticles (MNP) were coated with the zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), and then loaded with sorafenib (SRF) to obtain drug-loaded composite nanoparticles MNP@PMPC-SRF. Fe3O4 provided a large number of ferric/ferrous ions as an iron source, releasing Fe2+ for the regulation of the ferroptosis process and enhancing the effect of the induced cellular ferroptosis on the treatment of colon cancer with SRF. The zwitterionic polymer PMPC effectively extended the blood circulation time, resulting in an enhanced tumor accumulation of the nanodrug. MNP@PMPC-SRF exhibited good biocompatibility for in vivo application and showed an excellent tumor inhibitory effect on HCT116 tumor-bearing nude mice.

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.

Covalent Organic Frameworks Enabling Site Isolation of Viologen-Derived Electron-Transfer Mediators for Stable Photocatalytic Hydrogen Evolution.

Electron transfer is the rate-limiting step in photocatalytic water splitting. Viologen and its derivatives are able to act as electron-transfer mediators (ETMs) to facilitate the rapid electron transfer from photosensitizers to active sites. Nevertheless, the electron-transfer ability often suffers from the formation of a stable dipole structure through the coupling between cationic-radical-containing viologen-derived ETMs, by which the electron-transfer process becomes restricted. Herein, cyclic diquats, a kind of viologen-derived ETM, are integrated into a 2,2'-bipyridine-based covalent organic framework (COF) through a post-quaternization reaction. The content and distribution of embedded diquat-ETMs are elaborately controlled, leading to the favorable site-isolated arrangement. The resulting materials integrate the photosensitizing units and ETMs into one system, exhibiting the enhanced hydrogen evolution rate (34600 µmol h-1 g-1 ) and sustained performances when compared to a single-module COF and a COF/ETM mixture. The integration strategy applied in a 2D COF platform promotes the consecutive electron transfer in photochemical processes through the multi-component cooperation.

Highly biosafe biomimetic stem cell membrane-disguised nanovehicles for cartilage regeneration.

Cartilage injury is very common and results in considerable pain and osteoarthritis. Owing to its low self-renewal capability, cartilage regeneration is still a great challenge for clinicians. Stem cell therapy has been treated as the most promising treatment for cartilage regeneration in recent decades. However, increasing concerns about the potential biosafety of stem cell products such as immune rejection and neoplastic transformation restrict their further application in clinic. Herein, biomimetic stem cell membrane-disguised nanovehicles without biosafety risks are designed and prepared for cartilage regeneration. In this study, based on the disguise of the natural bone marrow mesenchymal stem cell (BMSC) membrane, Kartogenin (KGN) as a drug for cartilage regeneration was encapsulated into Fe3O4 nanoparticles as the core of biomimetic stem cell nanovehicles. In the core-shell structure of biomimetic stem cell nanovehicles, the fabricated KGN-loaded BMSC membrane-disguised Fe3O4 nanoparticles (KGN-MNPs) showed a stable hybrid structure with a uniform size and morphology in the physiological environments. Moreover, the prepared KGN-MNPs exhibited excellent biocompatibility when disguised with the natural membrane of BMSCs and good biosafety by eliminating the nuclei of BMSCs. In a cartilage defect rat model, compared with pure KGN, the intra-articularly injected KGN-MNPs were capable of regenerating an integrated organized structure with a layer of hyaline-like cartilage in a shorter time due to the retained natural activities of the BMSC membrane. In a word, KGN-MNPs as one kind of our designed biomimetic stem cell nanovehicles enable rapid and high quality cartilage regeneration, and provide a novel and standardized strategy for stem cell therapy in the future.

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.

Platelet Membrane-Camouflaged Magnetic Nanoparticles for Ferroptosis-Enhanced Cancer Immunotherapy.

Although cancer immunotherapy has emerged as a tremendously promising cancer therapy method, it remains effective only for several cancers. Photoimmunotherapy (e.g., photodynamic/photothermal therapy) could synergistically enhance the immune response of immunotherapy. However, excessively generated immunogenicity will cause serious inflammatory response syndrome. Herein, biomimetic magnetic nanoparticles, Fe3 O4 -SAS @ PLT, are reported as a novel approach to sensitize effective ferroptosis and generate mild immunogenicity, enhancing the response rate of non-inflamed tumors for cancer immunotherapy. Fe3 O4 -SAS@PLT are built from sulfasalazine (SAS)-loaded mesoporous magnetic nanoparticles (Fe3 O4 ) and platelet (PLT) membrane camouflage and triggered a ferroptotic cell death via inhibiting the glutamate-cystine antiporter system Xc- pathway. Fe3 O4 -SAS @ PLT-mediated ferroptosis significantly improves the efficacy of programmed cell death 1 immune checkpoint blockade therapy and achieves a continuous tumor elimination in a mouse model of 4T1 metastatic tumors. Proteomics studies reveal that Fe3 O4 -SAS @ PLT-mediated ferroptosis could not only induce tumor-specific immune response but also efficiently repolarize macrophages from immunosuppressive M2 phenotype to antitumor M1 phenotype. Therefore, the concomitant of Fe3 O4 -SAS @ PLT-mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of tumor metastasis.

Fixed-point "blasting" triggered by second near-infrared window light for augmented interventional photothermal therapy.

One of the major limitations of current cancer therapy is the inability to destroy tumors with high efficacy and minimal invasiveness. Herein, we developed a proof-of-concept fixed-point "blasting" strategy to destroy the "castle" of tumors and realized efficient interventional photothermal therapy. The "blasting" materials were composed of photothermal nanoparticles (ancient ink nanoparticles, AINP) and a low boiling point phase change agent (perfluoromethylcyclopentane, FMCP). An injectable in situ-forming thermal-responsive hydrogel composed of biodegradable and biocompatible polymers was employed as a carrier to load the AINP and FMCP. The obtained hydrogel system was a flowable aqueous solution at low or room temperature for facile injection; meanwhile, once administered, it rapidly transformed into a fixed gel at a body temperature of about 37 °C. This unique property could effectually fix the AINP and FMCP and thus restrict the destruction region inside the tumor. Subsequently, triggered by second window near-infrared light, the solid tumors were effectively destroyed by a mild photothermal effect and the subsequent gas mechanical damage. We envisage that this fixed-point "blasting" strategy will pave a new way for the next generation of cancer-interventional photothermal therapy.

Nanoparticles from Ancient Ink Endowing a Green and Effective Strategy for Cancer Photothermal Therapy in the Second Near-Infrared Window.

Photothermal therapy (PTT) in the second near-infrared window (NIR-II, 1000-1350 nm) has presented great superiority in cancer treatment recently. However, it is generally limited to a few photothermal agents and most of them often suffer from intricate design and complicated synthesis. Herein, by subtly extracting nanoparticles from ancient ink (AINPs), a versatile AINP dispersion with definite ingredients, good biosafety, and excellent photothermal effect in the NIR-II window was obtained. In vivo trials demonstrated that the obtained AINP dispersion provides a promising alternative for tumor sentinel lymph node (SLN) mapping. Besides, under the guidance of photoacoustic imaging, the metastatic SLNs could be accurately eliminated by NIR-II laser irradiation. The preliminary biosafety of AINP dispersion has also been systematically confirmed. Therefore, we believe this work would provide a green and effective strategy for PTT of tumor in the NIR-II window.

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.