Cyclo(RGD)‐Decorated Reduction‐Responsive Nanogels Mediate Targeted Chemotherapy of Integrin Overexpressing Human Glioblastoma In Vivo

Cyclo(Arg‐Gly‐Asp) peptide (cRGD) decorated disulfide (SS) containing poly(vinyl alcohol) nanogels (cRGD‐SS‐NGs) with an average diameter of 142 nm prepared by inverse nanoprecipitation, “click” reaction, and cRGD conjugation are developed for targeted treatment of integrin overexpressing human glioblastoma in vivo. Doxorubicin (DOX) release from cRGD‐SS‐NGs is highly inhibited under physiological conditions, while accelerated at endosomal pH and in response to cytoplasmic concentration of glutathione. Confocal microscopy shows that cRGD‐SS‐NGs facilitate the cellular uptake and intracellular DOX release in α_vβ₃ integrin overexpressing human glioblastoma U87‐MG cells. DOX‐loaded cRGD‐SS‐NGs present much better killing activity toward U87‐MG cells than that for nontargeted nanogels determined by MTT assay. The in vivo imaging and biodistribution studies reveal that DOX‐loaded cRGD‐SS‐NGs have a much better tumor targetability toward human U87‐MG glioblastoma xenograft in nude mice. Also the tumor growth is effectively inhibited by treatment with DOX‐loaded cRGD‐SS‐NGs, while continuous tumor growth is observed for mice treated with nondecorated nanogels as well as free DOX. Furthermore, the treatment with DOX‐loaded cRGD‐SS‐NGs has much fewer side effects, rendering these nanogels as a new platform for cancer chemotherapy in vivo.     

Virus‐Mimicking Chimaeric Polymersomes Boost Targeted Cancer siRNA Therapy In Vivo

Small interfering RNA (siRNA) offers a highly selective and effective pharmaceutical for various life‐threatening diseases, including cancers. The clinical translation of siRNA is, however, challenged by its short plasma life, poor cell uptake, and cumbersome intracellular trafficking. Here, cNGQGEQc peptide‐functionalized reversibly crosslinked chimaeric polymersomes (cNGQ/RCCPs) is shown to mediate high‐efficiency targeted delivery of Polo‐like kinase1 specific siRNA (siPLK1) to orthotopic human lung cancer in nude mice. Strikingly, siRNA is completely and tightly loaded into the aqueous lumen of the polymersomes at an unprecedentedly low N/P ratio of 0.45. cNGQ/RCCPs loaded with firefly luciferase specific siRNA (siGL3) or siPLK1 are efficiently taken up by α₃β₁‐integrin‐overexpressing A549 lung cancer cells and quickly release the payloads to the cytoplasm, inducing highly potent and sequence‐specific gene silencing in vitro. The in vivo studies using nude mice bearing orthotopic A549 human lung tumors reveal that siPLK1‐loaded cNGQ/RCCPs boost long circulation, superb tumor accumulation and selectivity, effective suppression of tumor growth, and significantly improved survival time. These virus‐mimicking chimaeric polymersomes provide a robust and potent platform for targeted cancer siRNA therapy.     

Intelligent Nanocomposites with Intrinsic Blood–Brain‐Barrier Crossing Ability Designed for Highly Specific MR Imaging and Sonodynamic Therapy of Glioblastoma

The blood–brain barrier (BBB) is the most important obstacle to improving the clinical outcomes of diagnosis and therapy of glioblastoma. Thus, the development of a novel nanoplatform that can efficiently traverse the BBB and achieve both precise diagnosis and therapy is of great importance. Herein, an intelligent nanoplatform based on holo‐transferrin (holo‐Tf) with in situ growth of MnO₂ nanocrystals is constructed via a reformative mild biomineralization process. Furthermore, protoporphyrin (ppIX), acting as a sonosensitizer, is then conjugated into holo‐Tf to obtain MnO₂@Tf‐ppIX nanoparticles (TMP). Because of the functional inheritance of holo‐Tf during fabrication, TMP can effectively traverse the BBB for highly specific magnetic resonance (MR) imaging of orthotopic glioblastoma. Clear suppression of tumor growth in a C6 tumor xenograft model is achieved via sonodynamic therapy. Importantly, the experiments also indicate that the TMP nanoplatform has satisfactory biocompatibility and biosafety, which favors potential clinical translation.     

Single siRNA Nanocapsules for Effective siRNA Brain Delivery and Glioblastoma Treatment

Small interfering RNA (siRNA) has been considered as a highly promising therapeutic agent for human cancer treatment including glioblastoma (GBM), which is a fatal disease without effective therapy methods. However, siRNA-based GBM therapy is seriously hampered by a number of challenges in siRNA brain delivery including poor stability, short blood circulation, low blood–brain barrier (BBB) penetration, and tumor accumulation, as well as inefficient siRNA intracellular release. Herein, an Angiopep-2 (Ang) functionalized intracellular-environment-responsive siRNA nanocapsule (Ang-NC_ss(siRNA)) is successfully developed as a safe and efficient RNAi agent to boost siRNA-based GBM therapy. The experimental results demonstrate that the developed Ang-NC_ss(siRNA) displays long circulation in plasma, efficient BBB penetration capability, and GBM accumulation and retention, as well as responsive intracellular siRNA release due to the unique design of small size (25 nm) with polymeric shell for siRNA protection, Ang functionalization for BBB crossing and GBM targeting, and disulfide bond as a linker for intracellular-environment-responsive siRNA release. Such superior properties of Ang-NC_ss(siRNA) result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. The developed siRNA nanocapsules provide a new strategy for RNAi therapy of GBM and beyond.     

Enhanced In Vivo Tumor Detection by Active Tumor Cell Targeting Using Multiple Tumor Receptor‐Binding Peptides Presented on Genetically Engineered Human Ferritin Nanoparticles

Human ferritin heavy‐chain nanoparticle (hFTH) is genetically engineered to present tumor receptor‐binding peptides (affibody and/or RGD‐derived cyclic peptides, named 4CRGD here) on its surface. The affibody and 4CRGD specifically and strongly binds to human epidermal growth factor receptor I (EGFR) and human integrin αvβ3, respectively, which are overexpressed on various tumor cells. Through in vitro culture of EGFR‐overexpressing adenocarcinoma (MDA‐MB‐468) and integrin‐overexpressing glioblastoma cells (U87MG), it is clarified that specific interactions between receptors on tumor cells and receptor‐binding peptides on engineered hFTH is critical in active tumor cell targeting. After labeling with the near‐infrared fluorescence dye (Cy5.5) and intravenouse injection into MDA‐MB‐468 or U87MG tumor‐bearing mice, the recombinant hFTHs presenting either peptide or both of affibody and 4CRGD are successfully delivered to and retained in the tumor for a prolonged period of time. In particular, the recombinant hFTH presenting both affibody and 4CRGD notably enhances in vivo detection of U87MG tumors that express heterogeneous receptors, integrin and EGFR, compared to the other recombinant hFTHs presenting either affibody or 4CRGD only. Like affibody and 4CRGD used in this study, other multiple tumor receptor‐binding peptides can be also genetically introduced to the hFTH surface for actively targeting of in vivo tumors with heterogenous receptors.     

A 3D Real‐Scale,Biomimetic, and Biohybrid Model of the Blood‐Brain Barrier Fabricated through Two‐Photon Lithography

The investigation of the crossing of exogenous substances through the blood‐brain barrier (BBB) is object of intensive research in biomedicine, and one of the main obstacles for reliable in vitro evaluations is represented by the difficulties at the base of developing realistic models of the barrier, which could resemble as most accurately as possible the in vivo environment. Here, for the first time, a 1:1 scale, biomimetic, and biohybrid BBB model is proposed. Microtubes inspired to the brain capillaries were fabricated through two‐photon lithography and used as scaffolds for the co‐culturing of endothelial‐like bEnd.3 and U87 glioblastoma cells. The constructs show the maturation of tight junctions, good performances in terms of hindering dextran diffusion through the barrier, and a satisfactory trans‐endothelial electrical resistance. Moreover, a mathematical model is developed, which assists in both the design of the 3D microfluidic chip and its characterization. Overall, these results show the effective formation of a bioinspired cellular barrier based on microtubes reproducing brain microcapillaries to scale. This system will be exploited as a realistic in vitro model for the investigation of BBB crossing of nanomaterials and drugs, envisaging therapeutic and diagnostic applications for several brain pathologies, including brain cancer.     

Improved Stable Indocyanine Green (ICG)‐Mediated Cancer Optotheranostics with Naturalized Hepatitis B Core Particles

In recent years, hepatitis B core protein virus‐like particle (HBc VLP) is an impressive biomaterial, which has attracted considerable attention due to favorable properties such as structural stability, high uptake efficiency, and biocompatibility in biomedical applications. Heretofore, only a few attempts have been made to apply it in physical, chemical, and biological therapy for cancer. In this study, a tumor‐targeting RGD‐HBc VLP is first fabricated through genetic engineering. For image‐guided cancer phototherapy, indocyanine green (ICG) is loaded into RGD‐HBc VLP via a disassembly/reassembly pathway and electrostatic attraction with high efficiency. The self‐assembled stable RGD‐HBc VLP significantly improves body retention (fourfold longer), aqueous stability, and target specificity of ICG. Remarkably, these positive reformations promote more accurate and sensitive imaging of U87MG tumor, as well as prolonged tumor destruction in comparison with free ICG. Moreover, the photothermal and photodynamic effect on tumors are quantitatively differentiated by multiple linear regression analysis. Overall, less‐potent medicinal ICG can be perfectly rescued by bioengineered HBc VLP to realize enhanced cancer optotheranostics.     

Graphene Nanomesh Promises Extremely Efficient In Vivo Photothermal Therapy

Reduced graphene oxide nanomesh (rGONM), as one of the recent structures of graphene with a surprisingly strong near‐infrared (NIR) absorption, is used for achieving ultraefficient photothermal therapy. First, by using TiO₂ nanoparticles, graphene oxide nanoplatelets (GONPs) are transformed into GONMs through photocatalytic degradation. Then rGONMs functionalized by polyethylene glycol (PEG), arginine–glycine–aspartic acid (RGD)‐based peptide, and cyanine 7 (Cy7) are utilized for in vivo tumor targeting and fluorescence imaging of human glioblastoma U87MG tumors having α_νβ₃ integrin receptors, in mouse models. The rGONM‐PEG suspension (1 μg mL^?1) exhibits about 4.2‐ and 22.4‐fold higher NIR absorption at 808 nm than rGONP‐PEG and graphene oxide (GO) with lateral dimensions of ≈60 nm and ≈2 μm. In vivo fluorescence imaging demonstrates high selective tumor uptake of rGONM‐PEG‐Cy7‐RGD in mice bearing U87MG cells. The excellent NIR absorbance and tumor targeting of rGONM‐PEG‐Cy7‐RGD results in an ultraefficient photothermal therapy (100% tumor elimination 48 h after intravenous injection of an ultralow concentration (10 μg mL^?1) of rGONM‐PEG‐Cy7‐RGD followed by irradiation with an ultralow laser power (0.1 W cm^?2) for 7 min), whereas the corresponding rGO‐ and rGONP‐based composites do not present remarkable treatments under the same conditions. All the mice treated by rGONM‐PEG‐Cy7‐RGD survived over 100 days, whereas the mice treated by other usual rGO‐based composites were dead before 38 days. The results introduce rGONM as one of the most promising nanomaterials in developing highly desired ultraefficient photothermal therapy.     

WO3 Nanofiber‐Based Biomarker Detectors Enabled by Protein‐Encapsulated Catalyst Self‐Assembled on Polystyrene Colloid Templates

A novel catalyst functionalization method, based on protein‐encapsulated metallic nanoparticles (NPs) and their self‐assembly on polystyrene (PS) colloid templates, is used to form catalyst‐loaded porous WO₃ nanofibers (NFs). The metallic NPs, composed of Au, Pd, or Pt, are encapsulated within a protein cage, i.e., apoferritin, to form unagglomerated monodispersed particles with diameters of less than 5 nm. The catalytic NPs maintain their nanoscale size, even following high‐temperature heat‐treatment during synthesis, which is attributed to the discrete self‐assembly of NPs on PS colloid templates. In addition, the PS templates generate open pores on the electrospun WO₃ NFs, facilitating gas molecule transport into the sensing layers and promoting active surface reactions. As a result, the Au and Pd NP‐loaded porous WO₃ NFs show superior sensitivity toward hydrogen sulfide, as evidenced by responses (R_air/R_gas) of 11.1 and 43.5 at 350 °C, respectively. These responses represent 1.8‐ and 7.1‐fold improvements compared to that of dense WO₃ NFs (R_air/R_gas = 6.1). Moreover, Pt NP‐loaded porous WO₃ NFs exhibit high acetone sensitivity with response of 28.9. These results demonstrate a novel catalyst loading method, in which small NPs are well‐dispersed within the pores of WO₃ NFs, that is applicable to high sensitivity breath sensors.     

Kidney Podocytes as Specific Targets for cyclo(RGDfC)‐Modified Nanoparticles

Renal nanoparticle passage opens the door for targeting new cells like podocytes, which constitute the exterior part of the renal filter. When cyclo(RGDfC)‐modified Qdots are tested on isolated primary podocytes for selective binding to the αvβ3 integrin receptor a highly cell‐ and receptor‐specific binding can be observed. In displacement experiments with free cyclo(RGDfC) IC₅₀ values of 150 nM for αvβ3 integrin over‐expressing U87‐MG cells and 60 nM for podocytes are measured. Confocal microscopy shows a cellular Qdot uptake into vesicle‐like structures. Our ex vivo study gives clear evidence that, after renal filtration, nanoparticles can be targeted to podocyte integrin receptors in the future. This could be a highly promising approach for future therapy and diagnostics of podocyte‐associated diseases.     

ROS‐Responsive Polymeric siRNA Nanomedicine Stabilized by Triple Interactions for the Robust Glioblastoma Combinational RNAi Therapy

Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at‐site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I‐NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I‐NM@siRNA nanomedicine demonstrates effective at‐site siRNA release resulting from tumoral reactive oxygen species (ROS)‐triggered sequential destabilization. Furthermore, the utility of 3I‐NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I‐NM@siRNA nanomedicine with angiopep‐2 peptide is enhanced. The targeted Ang‐3I‐NM@siRNA exhibits superb blood–brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo‐like kinase 1 and vascular endothelial growth factor receptor‐2, Ang‐3I‐NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple‐interaction stabilization together with inbuilt self‐destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.     

Co-delivery of pemetrexed and miR-21 antisense oligonucleotide by lipid-polymer hybrid nanoparticles and effects on glioblastoma cells

Abstract

Combination therapy using anticancer drugs and nucleic acid is a more promising strategy to overcome multidrug resistance in cancer and to enhance apoptosis. In this study, lipid-polymer hybrid nanoparticles (LPNs), which contain both pemetrexed and miR-21 antisense oligonucleotide (anti-miR-21), have been developed for treatment of glioblastoma, the most aggressive type of brain tumor. Prepared LPNs have been well characterized by particle size distribution and zeta potential measurements, determination of encapsulation efficiency, and in vitro release experiments. Morphology of LPNs was determined by transmission electron microscopy. LPNs had a hydrodynamic size below 100?nm and exhibited sustained release of pemetrexed up to 10?h. Encapsulation of pemetrexed in LPNs increased cellular uptake from 6% to 78%. Results of confocal microscopy analysis have shown that co-delivery of anti-miR-21 significantly improved accumulation of LPNs in the nucleus of U87MG cells. Nevertheless, more effective cytotoxicity results could not be obtained due to low concentration of anti-miR-21, loaded in LPNs. We expect that the effective drug delivery systems can be obtained with higher concentration of anti-miR-21 for the treatment of glioblastoma.     

CD44‐Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma

Chemotherapy is widely used in the clinic though its benefits are controversial owing to low cancer specificity. Nanovehicles capable of selectively transporting drugs to cancer cells have been energetically pursued to remodel cancer treatment. However, no active targeting nanomedicines have succeeded in clinical translation to date, partly due to either modest targetability or complex fabrication. CD44‐specific A6 short peptide (KPSSPPEE) functionalized polymersomal epirubicin (A6‐PS‐EPI), which boosts targetability and anticancer efficacy toward human multiple myeloma (MM) in vivo, is described. A6‐PS‐EPI encapsulating 11 wt% EPI is small (≈55 nm), robust, reduction‐responsive, and easy to fabricate. Of note, A6 decoration markedly augments the uptake and anticancer activity of PS‐EPI in CD44‐overexpressing LP‐1 MM cells. A6‐PS‐EPI displays remarkable targeting ability to orthotopic LP‐1 MM, causing depleted bone damage and striking survival benefits compared to nontargeted PS‐EPI. Overall, A6‐PS‐EPI, as a simple and intelligent nanotherapeutic, demonstrates high potential for clinical translation.     

Development and characterization of cationic solid lipid nanoparticles for co-delivery of pemetrexed and miR-21 antisense oligonucleotide to glioblastoma cells

The practical use of solid lipid nanoparticles (SLNs) in research has been highlighted in the literature, but few reports have combined SLNs with miRNA-based therapy and chemotherapy. We aimed to prepare cationic SLNs (cSLNs) to load anti-miR-21 oligonucleotide and pemetrexed for glioblastoma therapy in vitro. cSLNs were employed to encapsulate both pemetrexed and anti-miR-21 by a high-pressure homogenization method, and then the properties of cSLNs were characterized. We studied cellular uptake and cytotoxicity properties of cSLNs in U87MG cells. cSLNs were 124.9?±?1.6?nm in size and 27.3?±?1.6?mV in zeta potential with spherical morphology in the TEM image. cSLNs uptake by U87MG cells was increased significantly higher and more effective than free pemetrexed. These findings suggest that cSLNs represent a potential new approach for carrying both pemetrexed and anti-miR-21 for glioblastoma therapy.     

Cancer-targeted optical imaging with fluorescent zinc oxide nanowires

Herein we demonstrate that intrinsically fluorescent zinc oxide (ZnO) nanowires (NWs) can be adopted for molecularly targeted imaging of cancer cells, after they are functionalized to render water solubility, biocompatibility, and low cellular toxicity. Optical imaging of integrin α(v)β(3) on U87MG human glioblastoma cells was achieved with RGD peptide-conjugated green fluorescent ZnO NWs, which opened up new avenues of research for investigating ZnO NW-based agents in tumor vasculature-targeted molecular imaging and drug delivery.     

Low‐Density Lipoprotein‐Mimicking Nanoparticles for Tumor‐Targeted Theranostic Applications

This study introduces multifunctional lipid nanoparticles (LNPs), mimicking the structure and compositions of low‐density lipoproteins, for the tumor‐targeted co‐delivery of anti‐cancer drugs and superparamagnetic nanocrystals. Paclitaxel (4.7 wt%) and iron oxide nanocrystals (6.8 wt%, 11 nm in diameter) are co‐encapsulated within folate‐functionalized LNPs, which contain a cluster of nanocrystals with an overall diameter of about 170 nm and a zeta potential of about ‐40 mV. The folate‐functionalized LNPs enable the targeted detection of MCF‐7, human breast adenocarcinoma expressing folate receptors, in T₂‐weighted magnetic resonance images as well as the efficient intracellular delivery of paclitaxel. Paclitaxel‐free LNPs show no significant cytotoxicity up to 0.2 mg mL^?1, indicating the excellent biocompatibility of the LNPs for intracellular drug delivery applications. The targeted anti‐tumor activities of the LNPs in a mouse tumor model suggest that the low‐density lipoprotein‐mimetic LNPs can be an effective theranostic platform with excellent biocompatibility for the tumor‐targeted co‐delivery of various anti‐cancer agents.     

A Novel Pseudo‐Protein‐Based Biodegradable Nanomicellar Platform for the Delivery of Anticancer Drugs

Amino acid‐based poly(ester amide)s are a new family of biodegradable polymers that exhibit “pseudo‐protein” characteristics and the structural varieties of poly(ester amide)s make them hold great potential in multiple biomedical applications. In this study, a lysine‐phenylalanine‐based pseudo‐protein is developed as the self‐assembled nanomicellar carrier for efficient delivery of doxorubicin. The lysine moieties from the pseudo‐protein provide available sites for further functionalization, and methylcoumarin is introduced for easy and photocontrollable crosslinking, to effectively improve the micellar stability in serum containing environment and against dilution. However, photocrosslinks do not bring in any barrier for the intracellular release of doxoubicin. Doxorubicin release is significantly accelerated by proteolytic enzyme, due to the biodegradability of pseudo‐protein micelles. In addition, pseudo‐protein delivery system exhibits unique interactions with HCT116 human colon cancer cells. Doxorubicin loaded in pseudo‐protein micelles colocalizes with mitochondria and endolysosomes, while free doxorubicin is distributed only in the nuclei. Doxorubicin‐loaded pseudo‐protein micelles stimulate increased level of intracellular reactive oxygen species and mitochondrial damage. Free doxorubicin induces conditional apoptosis in HCT116 cells between 0.5× 10^?6 and 2 × 10^?6 m , while DOX loaded in pseudo‐protein micelles induces apoptosis over a higher/broader concentration range (2 × 10^?6–10 × 10^?6 m ).     

A Mechanoresponsive Phase‐Changing Electrolyte Enables Fabrication of High‐Output Solid‐State Photobioelectrochemical Devices from Pigment‐Protein Multilayers

Exploitation of natural photovoltaic reaction center pigment proteins in biohybrid architectures for solar energy harvesting is attractive due to their global abundance, environmental compatibility, and near‐unity quantum efficiencies. However, it is challenging to achieve high photocurrents in a device setup due to limitations imposed by low light absorbance by protein monolayers and/or slow long‐range diffusion of liquid‐phase charge carriers. In an attempt to enhance the photocurrent density achievable by pigment proteins, here, an alternative solid‐state device architecture enabled by a mechanoresponsive gel electrolyte that can be applied under nondenaturing conditions is demonstrated. The phase‐changing electrolyte gel provides a pervading biocompatible interface for charge conduction through highly absorbing protein multilayers that are fabricated in a simple fashion. Assembled devices exhibit enhanced current stability and a maximal photoresponse of ≈860 µA cm⁻², a fivefold improvement over the best previous comparable devices under standard illumination conditions. Photocurrent generation is enhanced by directional energy transfer through extended layers of light‐harvesting complexes, mimicking the modular antenna/transducer architecture of natural photosystems, and by metastable radical pair formation when photovoltaic reaction centers are embedded throughout light‐harvesting regions of the device.     

Core–Shell–Satellite Nanomaces as Remotely Controlled Self‐Fueling Fenton Reagents for Imaging‐Guided Triple‐Negative Breast Cancer‐Specific Therapy

Triple‐negative breast cancer (TNBC) is highly aggressive and insensitive to conventional targeted therapies, resulting in poor therapeutic outcomes. Recent studies have shown that abnormal iron metabolism is observed in TNBC, suggesting an opportunity for TNBC treatment via the iron‐dependent Fenton reaction. Nevertheless, the efficiency of current Fenton reagents is largely restricted by the lack of specificity and low intracellular H₂O₂ level of cancer cells. Herein, core–shell–satellite nanomaces (Au @ MSN@IONP) are fabricated, as near‐infrared (NIR) light‐triggered self‐fueling Fenton reagents for the amplified Fenton reaction inside TNBC cells. Specifically, the Au nanorod core can convert NIR light energy into heat to induce massive production of intracellular H₂O₂, thereby the surface‐decorated iron oxide nanoparticles (IONP) are being fueled for robust Fenton reaction. By exploiting the vulnerability of iron efflux in TNBC cells, such a self‐fueling Fenton reaction leads to highly specific anti‐TNBC efficacy with minimal cytotoxicity to normal cells. The PI3K/Akt/FoxO axis, intimately involved in the redox regulation and survival of TNBC, is demonstrated to be inhibited after the treatment. Consequently, precise in vivo orthotopic TNBC ablation is achieved under the guidance of IONP‐enhanced magnetic resonance imaging. The results demonstrate the proof‐of‐concept of NIR‐light‐triggered self‐fueling Fenton reagents against TNBC with low ferroportin levels.     

Low Dose of X‐Ray‐Excited Long‐Lasting Luminescent Concave Nanocubes in Highly Passive Targeting Deep‐Seated Hepatic Tumors

Chromium‐doped zinc gallate, ZnGa₂O₄:Cr³⁺ (ZGC), is viewed as a long‐lasting luminescence (LLL) phosphor that can avoid tissue autofluorescence interference for in vivo imaging detection. ZGC is a cubic spinel structure, a typical agglomerative or clustered morphology lacking a defined cubic shape, but a sphere‐like feature is commonly obtained for the nanometric ZGC. The substantial challenge remains achieving a well‐defined cubic feature in nanoscale. The process by which dispersed and well‐defined concave cubic ZGC is obtained is described, exhibiting much stronger LLL in UV and X‐ray excitation for the dispersed cubic ZGC compared with the agglomerative form that cannot be excited using X‐rays with a low dose of 0.5 Gy. The cubic ZGC reveals a specific accumulation in liver and 0.5 Gy used at the end of X‐ray excitation is sufficient for imaging of deep‐seated hepatic tumors. The ZGC nanocubes show highly passive targeting of orthotopic hepatic tumors.