An endogenous oxygen self-supplied nanoplatform with GSH-depleted and NIR-II triggered electron-hole separation for enhanced photocatalytic anti-tumor therapy.

The use of artificial enzymes and light energy in photocatalytic therapy, a developing drug-free therapeutic approach, can treat malignant tumors in vivo. However, the relatively deficient oxygen concentration in the tumor microenvironment (TME) restrains their further tumor treatment capability. Herein, a novel nanoplatform with Cu7S4@Au nanocatalyst coated by MnO2 was successfully designed. After 1064 nm light irradiation, the designed nanocatalyst can promote the separation of light generated electron-hole pairs, resulting in ROS generation and tumor cell apoptosis. The MnO2 shelled nanoplatform can function as a TME-responsive oxygen self-supplied producer to improve photocatalyst treatment and GSH depletion. In summary, the designed novel nanoplatform shows efficient inhibition of tumor growth via GSH depletion and synergistic photocatalytic therapy, which is of great significance for improving the clinical tumor treatment effect.

Axial O Atom-Modulated Fe(III)-N4 Sites for Enhanced Cascade Catalytic 1O2-Induced Tumor Therapy.

The rational construction of efficient hypoxia-tolerant nanocatalysts capable of generating singlet oxygen (1O2) without external stimuli is of great importance for tumor therapy. Herein, uniformly dispersed and favorable biosafety profile graphitic carbon nitride quantum dots immobilized with Fe-N4 moieties modulated by axial O atom (denoted as O-Fe-N4) are developed for converting H2O2 into 1O2 via Russell reaction, without introducing external energy. Notably, O-Fe-N4 performs two interconnected catalytic properties: glutathione oxidase-mimic activity to provide substrate for subsequent 1O2 generation, avoiding the blunting anticancer efficacy by glutathione. The O-Fe-N4 catalyst demonstrates a specific activity of 79.58 U mg-1 at pH 6.2, outperforming the most reported Fe-N4 catalysts. Density functional theory calculations demonstrate that the axial O atom can effectively modulate the relative position and electron affinity between Fe and N, lowering the activation energy, strengthening the selectivity, and thus facilitating the Russell-type reaction. The gratifying enzymatic activity stemming from the well-defined Fe-N/O structure can inhibit tumor proliferation by efficiently downregulating glutathione peroxidase 4 activity and inducing lipid peroxidation. Altogether, the O-Fe-N4 catalyst not only represents an efficient platform for self-cascaded catalysis to address the limitations of 1O2-involved cancer treatment but also provides a paradigm to enhance the performance of the Fe-N4 catalyst.

Nickel atom-clusters nanozyme for boosting ferroptosis tumor therapy.

The translation of Fe-based agents for ferroptosis tumor therapy is restricted by the unstable iron valence state, the harsh catalytic environment, and the complex tumor self-protection mechanism. Herein, we developed a stable nickel-based single-atom-metal-clusters (NSAMCs) biocatalyst for efficient tumor ferroptosis therapy. NSAMCs with a nanowire-like nanostructure and hydrophilic functional groups exhibit good water-solubility, colloidal stability, negligible systemic toxicity, and target specificity. In particular, NSAMCs possess excellent peroxidase-like and glutathione oxidase-like activities through the synergistic influence between metal clusters and single atoms. The dual-enzymatic performance enables NSAMCs to synergistically promote efficient ferroptosis of cancer cells through lipid peroxidization aggregation and glutathione peroxidase 4 inactivation. Importantly, NSAMCs highlight the boost of ferroptosis tumor therapy via the synergistic effect between single-atoms and metal clusters, providing a practical and feasible paradigm for further improving the efficiency of ferroptosis tumor treatment.

Lanthanide Inorganic Nanoparticles Enhance Semiconducting Polymer Nanoparticles Afterglow Luminescence for In Vivo Afterglow/Magnetic Resonance Imaging.

Dual/multimodal imaging strategies are increasingly recognized for their potential to provide comprehensive diagnostic insights in cancer imaging by harnessing complementary data. This study presents an innovative probe that capitalizes on the synergistic benefits of afterglow luminescence and magnetic resonance imaging (MRI), effectively eliminating autofluorescence interference and delivering a superior signal-to-noise ratio. Additionally, it facilitates deep tissue penetration and enables noninvasive imaging. Despite the advantages, only a limited number of probes have demonstrated the capability to simultaneously enhance afterglow luminescence and achieve high-resolution MRI and afterglow imaging. Herein, we introduce a cutting-edge imaging platform based on semiconducting polymer nanoparticles (PFODBT) integrated with NaYF4@NaGdF4 (Y@Gd@PFO-SPNs), which can directly amplify afterglow luminescence and generate MRI and afterglow signals in tumor tissues. The proposed mechanism involves lanthanide nanoparticles producing singlet oxygen (1O2) upon white light irradiation, which subsequently oxidizes PFODBT, thereby intensifying afterglow luminescence. This innovative platform paves the way for the development of high signal-to-background ratio imaging modalities, promising noninvasive diagnostics for cancer.

Nanoparticles for cancer therapy: a review of influencing factors and evaluation methods for biosafety.

Nanoparticles are widely used in the biomedical field for diagnostic and therapeutic purposes due to their small size, high carrier capacity, and ease of modification, which enable selective targeting and as contrast agents. Over the past decades, more and more nanoparticles have received regulatory approval to enter the clinic, more nanoparticles have shown potential for clinical translation, and humans have increasing access to them. However, nanoparticles have a high potential to cause unpredictable adverse effects on human organs, tissues, and cells due to their unique physicochemical properties and interactions with DNA, lipids, cells, tissues, proteins, and biological fluids. Currently, issues, such as nanoparticle side effects and toxicity, remain controversial, and these pitfalls must be fully considered prior to their application to body systems. Therefore, it is particularly urgent and important to assess the safety of nanoparticles acting in living organisms. In this paper, we review the important factors influencing the biosafety of nanoparticles in terms of their properties, and introduce common methods to summarize the biosafety evaluation of nanoparticles through in vitro and in body systems.

An electrochemical immunosensor for the detection of Glypican-3 based on enzymatic ferrocene-tyramine deposition reaction.

An ultrasensitive electrochemical immunosensor based on signal amplification of the deposition of the electroactive ferrocene-tyramine (Fc-Tyr) molecule, catalyzed by horseradish peroxidase (HRP), was constructed for the detection of the liver cancer marker Glypican-3 (GPC3). Functional electroactive molecule Fc-Tyr is reported to exhibit both the enzymatic cascade catalytic activity of tyramine signal amplification (TSA) and the excellent redox properties of ferrocene. In terms of design, the low matrix effects inherent in using the magnetic bead platforms, a quasi-homogeneous system, allowed capturing the target protein GPC3 without sample pretreatment, and loading HRP to trigger the TSA, which induced a large amount of Fc-Tyr deposited on the electrode surface layer by layer as a signal probe for the detection of GPC3. The concept of Fc-Tyr as an electroactive label was validated, GPC3 biosensor exhibited high selectivity and sensitivity to GPC3 in the range of 0.1 ng mL-1-1 µg mL-1. Finally, the sensor was used simultaneously with ELISA to assess GPC3 levels in the serum of clinical liver cancer patients, and the results showed consistency, with a recovery of 98.33-105.35% and a relative standard deviation (RSD) of 4.38-8.18%, providing a theoretical basis for achieving portable, rapid and point of care testing (POCT) of tumor markers.

NIR-II Responsive Upconversion Nanoprobe with Simultaneously Enhanced Single-Band Red Luminescence and Phase/Size Control for Bioimaging and Photodynamic Therapy.

Lanthanide based upconversion (UC) nanoprobes have emerged as promising agents for biological applications. Extending the excitation light to the second near-infrared (NIR-II), instead of the traditional 980/808 nm light, and realizing NIR-II responsive single-band red UC emission is highly demanded for bioimaging application, which has not yet been explored. Here, a new type of NIR-II (1532 nm) light responsive UC nanoparticles (UCNPs) with enhanced single-band red UC emission and controllable phase and size is designed by introducing Er3+ as sensitizer and utilizing Mn2+ as energy manipulator. Through tuning the content of Mn2+ in NaLnF4 :Er/Mn, the crystal phase, size, and emitting color are readily controlled, and the red-to-green (R/G) ratio is significantly increased from ≈20 to ≈300, leading to NIR-II responsive single band red emission via efficient energy transfer between Er3+ and Mn2+ . In addition, the single band red emitting intensity can be further improved by coating shell to avoid the surface quenching effect. More importantly, NIR-II light activated red UC bioimaging and photodynamic therapy through loading photosensitizer of zinc phthalocyanine are successfully achieved for the first time. These findings provide a new strategy of designing NIR-II light responsive single-band red emissive UCNPs for biomedical applications.

Recyclable Endogenous H2 S Activation of Self-Assembled Nanoprobe with Controllable Biodegradation for Synergistically Enhanced Colon Cancer-Specific Therapy.

Excessive production of hydrogen sulfide (H2 S) plays a crucial role in the progress of colon cancer. Construction of tumor-specific H2 S-activated smart nanoplatform with controllable biodegradation is of great significance for precise and sustainable treatment of colon cancer. Herein, an endogenous H2 S triggered Co-doped polyoxometalate (POM-Co) cluster with self-adjustable size, controlled biodegradation, and sustainable cyclic depletion of H2 S/glutathione (GSH) is designed for synergistic enhanced tumor-specific photothermal and chemodynamic therapy. The designed POM-Co nanocluster holds H2 S responsive "turn-on" photothermal property in colon cancer via self-assembling to form large-sized POM-CoS, enhancing the accumulation at tumor sites. Furthermore, the formed POM-CoS can gradually biodegrade, resulting in release of Co2+ and Mo6+ for Co(II)-catalyzed •OH production and Russell mechanism-enabled 1 O2 generation with GSH consumption, respectively. More importantly, the degraded POM-CoS is reactivated by endogenous H2 S for recyclable and sustainable consumption of H2 S and GSH, resulting in tumor-specific photothermal/chemodynamic continuous therapy. Therefore, this study provides an opportunity of designing tumor microenvironment-driven nanoprobes with controllable biodegradation for precise and sustainable anti-tumor therapy.

In Situ Silver-Based Electrochemical Oncolytic Bioreactor.

In this study, it is shown for the first time that a reduced graphene oxide (rGO) carrier has a 20-fold higher catalysis rate than graphene oxide in Ag+ reduction. Based on this, a tumor microenvironment-enabled in situ silver-based electrochemical oncolytic bioreactor (SEOB) which switched Ag+ prodrugs into in situ therapeutic silver nanoparticles with and above 95% transition rate is constructed to inhibit the growths of various tumors. In this SEOB-enabled intratumoral nanosynthetic medicine, intratumoral H2 O2 and rGO act as the reductant and the catalyst, respectively. Chelation of aptamers to the SEOB-unlocked prodrugs increases the production of silver nanoparticles in tumor cells, especially in the presence of Vitamin C, which is broken down in tumor cells to supply massive amounts of H2 O2 . Consequently, apoptosis and pyroptosis are induced to cooperatively contribute to the considerably-elevated anti-tumor effects on subcutaneous HepG2 and A549 tumors and orthotopic implanted HepG2 tumors in livers of nude mice. The specific aptamer targeting and intratumoral silver nanoparticle production guarantee excellent biosafety since it fails to elicit tissue damages in monkeys, which greatly increases the clinical translation potential of the SEOB system.

In Vivo High-Resolution Bioimaging of Bone Marrow and Fracture Diagnosis Using Lanthanide Nanoprobes with 1525 nm Emission.

Bones play vital roles in human health. Noninvasive visualization of the full extent of bones is highly demanded to evaluate many bone-related diseases. Herein, we report poly (acrylic acid) (PAA)-modified NaLuF4:Yb/Er/Gd/Ce@NaYF4 nanoparticles (PAA-Er) with second near-infrared emission beyond 1500 nm (also referred as NIR-IIb) for high-resolution bone/bone marrow imaging and bone fracture diagnosis. The NIR-IIb optical-guided bone marrow imaging presents a high signal to noise ratio, which is superior to that for imaging in the NIR-II window (1000-1400 nm, NIR-IIa). Importantly, we also investigated the size-dependent accumulation of the nanoparticles and the possible accumulation mechanism of the designed PAA-Er nanoprobes in bone marrow. Due to the high affinity capability of the PAA-Er nanoprobes, a highly sensitive NIR-IIb optical-guided bone fracture diagnosis was successfully achieved. This novel technology paves the way to design lanthanide nanoprobes for NIR-IIb optical-guided high-resolution bone marrow imaging and bone-related disease diagnosis.

Intelligent Nanotransducer for Deep-Tumor Hypoxia Modulation and Enhanced Dual-Photosensitizer Photodynamic Therapy.

Upconversion nanoparticles (UCNPs) emerged as promising near-infrared (NIR) light-triggered nanotransducers for photodynamic therapy (PDT). However, the traditionally used 980 nm excitation source could cause an overheating effect on biological tissues, and the single photosensitizer (PS) loading could not efficiently utilize multiradiation UC luminescence, resulting in a limited efficiency of PDT in tumor tissues with hypoxia characteristics. Herein, 808 nm light-responsive Nd-sensitized UCNPs@mSiO2@MnO2 core-shell NPs were designed as light nanotransducers with efficient UC emission at 550 and 650 nm for PDT and downshifting luminescence at 1525 nm for second NIR (NIR-II) imaging. UC emission was fully utilized by loading dual PSs, rose bengal (RB), and zinc phthalocyanine (ZnPc), thus significantly improving the reactive oxide species (ROS) generation efficiency. Moreover, a manganese dioxide (MnO2) shell with ultrasensitive biodegradability in an acidic tumor microenvironment (TME) can generate an amount of oxygen molecules, alleviating the symptoms of hypoxia and then improving the efficacy of PDT. Meanwhile, the biodegraded Mn2+ ions can further strengthen T1-weighted magnetic resonance imaging (MRI). This work presented a new multifunctional theranostic agent for combining NIR-II/MRI imaging and 808 nm light-triggered PDT to combat the limitations of cancer therapy.

A H2S-Triggered Dual-Modal Second Near-Infrared/Photoacoustic Intelligent Nanoprobe for Highly Specific Imaging of Colorectal Cancer.

An endogenous H2S-triggered intelligent optical nanoprobe combining second near-infrared (NIR-II) fluorescence with photoacoustic (PA) imaging can provide more comprehensive information to further improve the sensitivity and reliability of diagnosis for colorectal tumor, which is rarely explored. Herein, an endogenous H2S-triggered SiO2@Ag nanoprobe was designed for in situ dual-modal NIR-II/PA imaging of colorectal cancer. The designed dual-modal nanoprobe can be converted to SiO2@Ag2S after in situ biosynthesis via a sulfuration reaction with the over-expressed endogenous H2S in the colorectal tumor. More importantly, the designed SiO2@Ag nanoprobe exhibits high sensitivity and specificity for diagnosing colorectal cancer in vivo via dual-modal NIR-II/PA imaging. These results provide a new NIR-II/PA dual-modal imaging strategy for noninvasive intelligent detection of colorectal cancer.

Soft X-Ray Stimulated Lanthanide@MOF Nanoprobe for Amplifying Deep Tissue Synergistic Photodynamic and Antitumor Immunotherapy.

Combining photodynamic therapy (PDT) and immunotherapy has shown profound impact for synergistic treatment of malignant tumors. However, the shallow penetration depth of the traditional visible light activated PDT, immunosuppressive tumor microenvironment (TME), and poor immunogenicity of deep-seated solid tumors have significantly impeded the therapeutic efficiency. Herein, a soft X-ray activated nanoprobe is rationally engineered via integrating porphyrin Zr-based metal-organic framework with lanthanide NaYF4 :Gd,Tb@NaYF4 scintillator nanoparticles (SNPs) by a new in situ growth strategy for synergistic PDT and immunotherapy of tumor. The nanoprobe possesses remarkably enhanced reactive oxygen species (ROS) generation triggered by soft X-ray via further covalently grafting rose bengal on the nanoprobe, even at tissue depths of 3 cm. Moreover, the soft X-ray induced ROS can act as potential immunogenic cell death (ICD) trigger, subsequently leading to the activation of the adaptive antitumor immune-response. Significantly, the boosted ROS generation can further modulate the immunosuppressive TME. This work provides new strategy of designing antitumor nanoprobes for soft X-ray triggered deep-tissue PDT and immune response, breaking the depth barriers suffered by the traditional photoactivated PDT or ICD using visible and near infrared light.

Low Dose Soft X-Ray Remotely Triggered Lanthanide Nanovaccine for Deep Tissue CO Gas Release and Activation of Systemic Anti-Tumor Immunoresponse.

Gas-based therapy has emerged as a new green therapy strategy for anti-tumor treatment. However, the therapeutic efficacy is still restricted by the deep tissue controlled release, poor lymphocytic infiltration, and inherent immunosuppressive tumor microenvironment (TME). Herein, a new type of nanovaccine is designed by integrating low dose soft X-ray-triggered CO releasing lanthanide scintillator nanoparticles (ScNPs: NaLuF4 :Gd,Tb@NaLuF4 ) with photo-responsive CO releasing moiety (PhotoCORM) for synergistic CO gas/immuno-therapy of tumors. The designed nanovaccine presents significantly boosted radioluminescence and enables deep tissue CO generation at unprecedented tissue depths of 5 cm under soft X-ray irradiation. Intriguingly, CO as a superior immunogenic cell death (ICD) inducer further reverses the deep tissue immunosuppressive TME and concurrently activates adaptive anti-tumor immunity through efficient reactive oxygen species (ROS) generation. More importantly, the designed nanovaccine presents efficient growth inhibition of both local and distant tumors via a soft X-ray activated systemic anti-tumor immunoresponse. This work provides a new strategy of designing anti-tumor nanovaccines for synergistic deep tissue gas-therapy and remote soft X-ray photoactivation of the immune response.

Human endoglin-CD3 bispecific T cell engager antibody induces anti-tumor effect in vivo.

Rationale: Endoglin, also known as CD105, is a homo-dimeric membrane glycoprotein required for angiogenesis and serves as a marker for cancer vasculature. In this study, we constructed a bispecific T-cell engager (BiTE) antibody that targets human endoglin and CD3 (hEND-CD3/BiTE). We examined BiTE binding to endoglin-expressing cells and its effects on the cytolytic activity of T cells and cancer development. Methods: The in vitro effects of hEND-CD3/BiTE, including binding to target cells, T-cell activation, proliferation, and cytotoxicity, were examined in endoglin-expressing 293T cells, human umbilical vascular endothelial cells, tumor-derived endothelial cells, and CD3+ T cells. An in vivo xenograft tumor model was established using A549 human lung cancer cells. The therapeutic efficacy of hEND-CD3/BiTE was assessed by monitoring tumor growth, angiogenesis, and mouse survival. Results: hEND-CD3/BiTE specifically bound to endoglin-expressing cells and CD3+ T cells in vitro and stimulated T-cell activation, proliferation, and Th1 cytokine secretion, and promoted T-cell-mediated cytolysis of endoglin-expressing cells. The hEND-CD3/BiTE in vivo caused minimal toxicity to major organs, reduced tumor neoangiogenesis, inhibited tumor growth, and significantly improved mouse survival. Conclusions: Our study demonstrated the therapeutic potential of hEND-CD3/BiTE and provided a novel approach to clinical cancer treatment.

The Tree Shrew as a Model for Cancer Research.

Animal disease models are necessary in medical research, and an appropriate animal model is of great importance for studies about the prevention or treatment of cancer. The most important thing in the selection of animal models is to consider the similarity between animals and humans. The tree shrew (Tupaia belangeri) is a squirrel-like mammal which placed in the order Scandentia. Whole-genome sequencing has revealed that tree shrews are extremely similar to primate and humans than to rodents, with many highly conserved genes, which makes the data from studies that use tree shrews as models more convincing and the research outcomes more easily translatable. In tumor research, tree shrews are often used as animal models for hepatic and mammary cancers. As research has progressed, other types of tree shrew tumor models have been developed and exhibit clinical manifestations similar to those of humans. Combining the advantages of both rodents and primates, the tree shrew is expected to be the most powerful animal model for studying tumors.

Endogenous H2S-Activated Orthogonal Second Near-Infrared Emissive Nanoprobe for In Situ Ratiometric Fluorescence Imaging of Metformin-Induced Liver Injury.

Metformin as a hypoglycemic drug for antidiabetic treatment has emerged as a multipotential drug for many disease treatments such as cognitive disorders, cancers, promoting weight loss. However, overdose uptake may upregulate the hepatic H2S level, subsequently leading to serious liver injury and toxicity. Therefore, developing intelligent second near-infrared (NIR-II) emitting nanoprobes by using endogenous H2S as a smart trigger for noninvasive highly specific in situ monitoring of the metformin-induced hepatotoxicity is highly desirable, which is rarely explored. Herein, an endogenous H2S activated orthogonal NIR-II emitting myrica rubra-like nanoprobe based on NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2 coated with Ag nanodots was explored for highly specific in vivo ratiometrically monitoring of hepatotoxicity. The designed nanoprobes were mainly uptaken by the liver and subsequently converted to NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2@Ag2S via in situ sulfuration reaction triggered by the overexpressed endogenous H2S in the injured liver tissues, finally leading to a turn-on orthogonal emission centered at 1053 nm (irradiation by 808 nm laser) and 1525 nm (irradiation by 980 nm laser). The designed nanoprobe presents a high detection limit down to 0.7 nM of H2S. More importantly, the in situ highly specific ratiometric imaging of the metformin-induced hepatotoxicity was successfully achieved by using the activatable orthogonal NIR-II emitting probe. Our results provide an NIR-II ratiometric fluorescence imaging strategy for highly sensitive/specific diagnosis of hepatotoxicity levels induced by metformin.

Nanoparticle-delivered Therapeutic Agents Targeting the Tumor Microenvironment for Antitumor Therapy.

In recent years, nanotechnology has been widely used in the field of tumor treatment. Some nanomedicine applications have been approved for tumor treatment, but nanomedicine has not so far demonstrated the anticipated therapeutic effect. In this process, the tumor microenvironment plays a major role. The tumor microenvironment is an internal environment that supports tumor occurrence, development, and metastasis. It is composed of tumor cells and related cells, intercellular substances, capillaries, and biomolecules that pervade both the tumor mass itself and its surrounding area. The tumor microenvironment can be a potential target for tumor treatment. Therefore, nano-antitumor therapy targeting the tumor microenvironment has received widespread attention. This therapy is based on the physiological characteristics of tumors that differ from those of normal tissues. The tumor microenvironment is used as a therapeutic target, and drugs are delivered to the tumor site through nanoparticles-enabled targeting to achieve fast, controllable, and efficient tumor killing. This article reviews basic research such as design principles and applications of nano-antitumor therapeutic strategies targeting the tumor microenvironment, providing a theoretical basis and new research ideas for tumor treatment.

Antitumor Activity of Lipid-DNA Aptamer Modified T Lymphocytes in Carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with no current effective therapeutics. One of the main reasons for the low efficacy of PDAC immunotherapy is the limited CD8+ T cell infiltration, without neo antigen present in PDAC. Aptamers represent single-stranded oligonucleotides which bind to specific targets with high specificity. We developed DNA conjugates and prepared diacyl phospholipid-aptamer XQ-2d which has potential for the targeted therapy and diagnosis of PDAC. In this study, flow cytometry and fluorescence microscopy were employed to assess whether the Lipo-XQ-2d probe could anchor on activated T cells to constitute ligands specifically recognizing PDAC PL45 cells. Flow cytometry was employed to determine cytotoxicity in activated T cells. Results showed that the Lipo-XQ-2d probe could be inserted into T cells, and was specifically bound to both T cells and PL45 cells. In addition, the Lipo-XQ-2d probe redirected T cells to kill PL45 cells in vitro and was not toxic to cells. In conclusion, lipid-DNA-aptamer-modified T-lymphocytes might effectively kill PDAC in vitro, supporting the clinical application of T cell adoptive immunotherapy.