Boost Infiltration and Activity of T Cells via Inhibiting Ecto-5'-nucleotidase (CD73) Immune Checkpoint to Enhance Glioblastoma Immunotherapy.

The currently available immune checkpoint therapy shows a disappointing therapeutic efficacy for glioblastoma multiforme (GBM), and it is of great importance to discover better immune checkpoints and develop innovative targeting strategies. The discovered metabolic immune checkpoint ecto-5-nucleotidase (CD73) in a tumor contributes to its immune evasion due to the dysregulation of extracellular adenosine (ADO), which significantly inhibits the function of antitumor T cells and increases the activity of immunosuppressive cells. Herein, we drastically inhibit the expression of CD73 to reduce the production of ADO by using versatile Au@Cu2-xSe nanoparticles (ACS NPs). ACS NPs can decrease the expression of CD73 by alleviating the tumor hypoxia through their Fenton-like reaction to weaken the ADO-driven immunosuppression for enhancing antitumor T cell infiltration and activity of GBM. The copper ions (Cu2+) released from ACS NPs can chelate with disulfide, leading to the formation of cytotoxic bis(N,N-diethyldithiocarbamate)-copper complex (CuET), which can be combined with radiotherapy to recruit more antitumor T cells to infiltrate into the tumor site. Based on the inhibition of CD73 to promote the infiltration and activity of antitumor T cells, a cascade of enhancing GBM immunotherapy effects can be achieved. The significant increase in CD8+ T and CD4+ T cells within the tumor and the memory T cells in the spleen effectively reduces tumor size by 92%, which demonstrates the excellent efficacy of immunotherapy achieved by a combination of metabolic immune checkpoint CD73 inhibition with chemoradiotherapy. This work demonstrates that modulation of CD73-mediated tumor immunosuppression is an important strategy of improving the outcome of GBM immunotherapy.

Antigen Self-Presented Personalized Nanovaccines Boost the Immunotherapy of Highly Invasive and Metastatic Tumors.

Dendritic cell (DC)-based vaccines have shown promise in adoptive cell therapy for enhancing the antigen-specific response of antitumor immunity. However, their clinical efficacy is limited by the less-presented tumor-associated antigens (TAAs) through MHC I and low lymph node homing efficiency. Herein, to address these issues, we rationally design and fabricate DC-based nanovaccines by coating Cu2-xSe nanoparticles (CS NPs) with the membrane of matured DCs (named as DCNV(CSD) nanovaccines). We reveal the important roles of CS NPs in the DCNV(CSD) nanovaccines from three aspects: (1) inducing the immunogenic cell death of tumor cells to expose abundant TAAs; (2) promoting the escape of TAAs from the lysosomes of DCs during the antigen presenting process through MHC I; (3) sustainably releasing traces of copper ions to promote the proliferation of T cells. Our DCNV(CSD) nanovaccines are characterized with high expressions of MHC I, CD80, CD86, CCR7, and ICAM-1 proteins, which not only endow them with abundantly processed specific TAAs, but also a strong capability of homing to the lymph nodes. The homing capability of our small DCNV(CSD) nanovaccines is better than that of matured DCs. More importantly, they can elicit the strong response of potent antispecific CD8+ T cells for antitumor immunotherapy, as tested in the treatment of highly invasive glioblastoma and highly metastatic melanoma. Additionally, DCNV(CSD) nanovaccines can generate memory T cells (TEM) in the spleen of mice to effectively prevent the recurrence of treated tumors. This work demonstrates a universal approach to fabricate high-performance DC-based nanovaccines for tumor immunotherapy by using versatile CS NPs.

Ultrasmall Nanoparticles Regulate Immune Microenvironment by Activating IL-33/ST2 to Alleviate Renal Ischemia-Reperfusion Injury.

Renal ischemia-reperfusion injury (IRI) is a common disease with high morbidity and mortality. Renal IRI can cause the disorder of immune microenvironment and reprograming the immune microenvironment to alleviate excessive inflammatory response is crucial for its treatment. Cytokine IL-33 can improve the immune inflammatory microenvironment by modulating both innate and adaptive immune cells, and serve as an important target for modulating immune microenvironment of renal IRI. Herein, we report that bilobetin-functionalized ultrasmall Cu2- xSe nanoparticles (i.e., CSPB NPs) can activate the PKA/p-CREB/IL-33/ST2 signaling pathway to regulate innate and adaptive immune cells for reprograming the immune microenvironment of IRI-induced acute kidney injury. The biocompatible CSPB NPs can promote the polarization of M1-like macrophages into M2-like macrophages, and the expansion of ILC2 and Treg cells by activating IL-33/ST2 to modulate the excessive immune inflammatory response of renal IRI. More importantly, they can rapidly accumulate at the injured kidney to significantly alleviate IRI. This work demonstrates that modulating the expression of cytokines to reprogram immune microenvironment has great potential in the treatment of renal IRI and other ischemic diseases.

Boosting Microglial Lipid Metabolism via TREM2 Signaling by Biomimetic Nanoparticles to Attenuate the Sevoflurane-Induced Developmental Neurotoxicity.

Lipid metabolism has been considered as a potential therapeutic target in sevoflurane-induced neurotoxicity that can potentially affect the learning and memory function in the developmental brain. Recently, triggering receptor expressed on myeloid cells 2 (TREM2) is identified as a crucial step in regulating lipid metabolism and associated with the pathogenesis of neurodegenerative diseases. Herein, it is reported that quercetin modified Cu2- x Se (abbreviated as CSPQ) nanoparticles can ameliorate sevoflurane-induced neurotoxicity by tuning the microglial lipid metabolism and promoting microglial M2-like polarization via TREM2 signaling pathway, in which the apolipoprotein E (ApoE), and adenosine triphosphate-binding cassette transporters (ABCA1 and ABCG1) levels are upregulated. Furthermore, the protective effects of CSPQ nanoparticles against sevoflurane-induced neurotoxicity via TREM2 are further demonstrated by the small interfering RNA (siRNA)-TREM2 transfected BV2 cells, which are obviously not influenced by CSPQ nanoparticles. The cell membrane coated CSPQ (referred as CSPQ@CM) nanoparticles can significantly reduce sevoflurane-induced learning and memory deficits, improve lipid metabolism dysfunction, and promote the remyelination in the hippocampus of mice. The study shows great potential of targeting microglial lipid metabolism in promoting remyelination of neurons for treatment of neurotoxicity and neurodegenerative diseases.

Boosting the therapy of glutamine-addiction glioblastoma by combining glutamine metabolism therapy with photo-enhanced chemodynamic therapy.

The complete treatment of high grade invasive glioblastoma (GBM) remains to be a great challenge, and it is of great importance to develop innovative therapeutic approaches. Herein, we found that GBM derived from U87 MG cells is a glutamine-addiction tumor, and jointly using glutamine-starvation therapy and photo-enhanced chemodynamic therapy (CDT) can significantly boost its therapy. We rationally fabricated tumor cell membrane coated Cu2-xSe nanoparticles (CS NPs) and an inhibitor of glutamine metabolism (Purpurin) for combined therapy, because glutamine rather than glucose plays a crucial role in the proliferation and growth of GBM cells, and serves as a precursor for the synthesis of glutathione (GSH). The resultant CS-P@CM NPs can be specifically delivered to the tumor site to inhibit glutamine metabolism in tumor cells, suppress tumor intracellular GSH, and increase H2O2 content, which benefit the CDT catalyzed by CS NPs. The cascade reaction can be further enhanced by irradiation with the second near-infrared (NIR-II) light at the maximum concentration of H2O2, which can be monitored by photoacoustic imaging. The NIR-II light irradiation can generate a large amount of reactive oxygen species (ROS) within a short time to kill tumor cells and enhance the CDT efficacy. This is the first work on the treatment of orthotopic malignant GBM through combined glutamine metabolism therapy and photo-enhanced CDT, and provides insights into the treatment of other solid tumors by modulating the metabolism of tumor cells.

Ameliorating Mitochondrial Dysfunction of Neurons by Biomimetic Targeting Nanoparticles Mediated Mitochondrial Biogenesis to Boost the Therapy of Parkinson's Disease.

Mitochondrial dysfunction of neurons is the core pathogenesis of incurable Parkinson's disease (PD). It is crucial to ameliorate the mitochondrial dysfunction of neurons for boosting the therapy of PD. Herein, the remarkable promotion of mitochondrial biogenesis to ameliorate mitochondrial dysfunction of neurons and improve the treatment of PD by using mitochondria-targeted biomimetic nanoparticles, which are Cu2- x Se-based nanoparticles functionalized with curcumin and wrapped with DSPE-PEG2000 -TPP-modified macrophage membrane (denoted as CSCCT NPs), is reported. These nanoparticles can efficiently target mitochondria of damaged neurons in an inflammatory environment, and mediate the signaling pathway of NAD+ /SIRT1/PGC-1α/PPARγ/NRF1/TFAM to alleviate 1-methyl-4-phenylpyridinium (MPP+ )-induced neuronal toxicity. They can reduce the mitochondrial reactive oxygen species, restore mitochondrial membrane potential (MMP), protect the integrity of mitochondrial respiratory chain, and ameliorate mitochondrial dysfunction via promoting mitochondrial biogenesis, which synergistically improve the motor disorders and anxiety behavior of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. This study demonstrates that targeting mitochondrial biogenesis to ameliorate mitochondrial dysfunction has a great potential in the treatment of PD and mitochondria-related diseases.

Simultaneous Elimination of Reactive Oxygen Species and Activation of Nrf2 by Ultrasmall Nanoparticles to Relieve Acute Kidney Injury.

Excess reactive oxygen species (ROS) can induce serious acute kidney injury (AKI) to result in numerous deaths annually in clinical practice. Elimination of excess ROS by advanced nanotechnology is a very promising AKI therapy. In this Article, we report that PVP-stabilized and quercetin-functionalized ultrasmall Cu2-xSe nanoparticles (abbreviated as CSPQ NPs) can efficiently scavenge ROS and increase the expression of intracellular antioxidative enzymes by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein, which drastically alleviates the cellular oxidative stress. Our ultrasmall nanoparticles exhibit excellent biocompatibility. They can be rapidly accumulated into the injured kidney to simultaneously eliminate ROS and activate Nrf2 to improve the renal function. This work demonstrates the great potential of simultaneous elimination of ROS and activation of intracellular Nrf2 in treatment of AKI. It also highlights the potential of CSPQ NPs in protection and prevention of AKI.

Reversing T Cell Dysfunction to Boost Glioblastoma Immunotherapy by Paroxetine-Mediated GRK2 Inhibition and Blockade of Multiple Checkpoints through Biomimetic Nanoparticles.

T cell dysfunction-induced tumor immune escape is particularly severe in glioblastoma (GBM), and significantly affects the efficacy of immunotherapy. It is crucial to innovatively reverse the T cell dysfunction for improving GBM immunotherapy. Herein, T cell dysfunction is remarkably reversed and immunotherapy of GBM is boosted by repurposing the U. S. Food and Drug Administration-approved antidepressant paroxetine (PX) with biomimetic nanoparticles (CS-J@CM/6 NPs). The PX is successfully applied to abrogate T cell sequestration in the bone marrow of GBM-bearing mice and increase their infiltration in tumor. The biomimetic NPs are composed of ultrasmall Cu2- x Se NPs, JQ1, and tumor cell membrane modified with CD6, and are efficiently delivered into tumor through the specific interactions between CD6 and activated leukocyte cell adhesion molecule. They ameliorate the T cell dysfunction through the double roles of loaded JQ1, which simultaneously decreases the expression of PD-1 and TIM-3 on T cells, and the expression of PD-L1 on tumor cells. The NP also induces the immunogenic cell death of tumor cells to activate immune response. The synergistic roles of PX and biomimetic CS-J@CM/6 NPs notably enhance the survival of GBM-bearing mice. This work provides new insights into tumor immunotherapy by repurposing "old drugs" with advanced NPs.

Reducing Chemo-/Radioresistance to Boost the Therapeutic Efficacy against Temozolomide-Resistant Glioblastoma.

Chemo-/radioresistance is the most important reason for the failure of glioblastoma (GBM) treatment. Reversing the chemo-/radioresistance of GBM for boosting therapeutic efficacy is very challenging. Herein, we report a significant decrease in the chemo-/radioresistance of GBM by the in situ generation of SO2 within a tumor, which was released on demand from the prodrug 5-amino-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (ATD) loaded on rare-earth-based scintillator nanoparticles (i.e., NaYF4:Ce@NaLuF4:Nd@ATD@DSPE-PEG5000, ScNPs) under X-ray irradiation. Our novel X-ray-responsive ScNPs efficiently converted highly penetrating X-rays into ultraviolet rays for controlling the decomposition of ATD to generate SO2, which effectively damaged the mitochondria of temozolomide-resistant U87 cells to lower the production of ATP and inhibit P-glycoprotein (P-gp) expression to reduce drug efflux. Meanwhile, the O6-methylguanine-DNA methyltransferase (MGMT) of drug-resistant tumor cells was also reduced to prevent the repair of damaged DNA and enhance cell apoptosis and the efficacy of chemo-/radiotherapy. The tumor growth was obviously suppressed, and the mice survived significantly longer than untreated temozolomide-resistant GBM-bearing mice. Our work demonstrates the potential of SO2 in reducing chemo-/radioresistance to improve the therapeutic effect against resistant tumors if it can be well controlled and in situ generated in tumor cells. It also provides insights into the rational design of stimuli-responsive drug delivery systems for the controlled release of drugs.

Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy.

Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-x Se nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Harnessing anti-tumor and tumor-tropism functions of macrophages via nanotechnology for tumor immunotherapy.

Reprogramming the immunosuppressive tumor microenvironment by modulating macrophages holds great promise in tumor immunotherapy. As a class of professional phagocytes and antigen-presenting cells in the innate immune system, macrophages can not only directly engulf and clear tumor cells, but also play roles in presenting tumor-specific antigen to initiate adaptive immunity. However, the tumor-associated macrophages (TAMs) usually display tumor-supportive M2 phenotype rather than anti-tumor M1 phenotype. They can support tumor cells to escape immunological surveillance, aggravate tumor progression, and impede tumor-specific T cell immunity. Although many TAMs-modulating agents have shown great success in therapy of multiple tumors, they face enormous challenges including poor tumor accumulation and off-target side effects. An alternative solution is the use of advanced nanostructures, which not only can deliver TAMs-modulating agents to augment therapeutic efficacy, but also can directly serve as modulators of TAMs. Another important strategy is the exploitation of macrophages and macrophage-derived components as tumor-targeting delivery vehicles. Herein, we summarize the recent advances in targeting and engineering macrophages for tumor immunotherapy, including (1) direct and indirect effects of macrophages on the augmentation of immunotherapy and (2) strategies for engineering macrophage-based drug carriers. The existing perspectives and challenges of macrophage-based tumor immunotherapies are also highlighted.

Dye-Sensitized Rare Earth Nanoparticles with Up/Down Conversion Luminescence for On-Demand Gas Therapy of Glioblastoma Guided by NIR-II Fluorescence Imaging.

As the primary malignant tumor in the brain, glioblastoma exhibits a high mortality due to the challenges for complete treatment by conventional therapeutic methods. It is of great importance to develop innovative therapeutic agents and methods for treatment of glioblastoma. In this work, the imaging and therapy of glioblastoma are reported by using dye sensitized core-shell NaYF4 :Yb/Tm@NaYF4 :Nd nanoparticles with strong up/down-conversion luminescence, of which the ultraviolet up-conversion emissions at 348 and 365 nm are significantly enhanced by nearly 28 times and used to control the release of SO2 from 5-Amino-1,3-dihydrobenzo[c]thiophene 2,2-dioxide prodrug for gas therapy, and the second near-infrared (NIR-II) down conversion emission at 1340 nm is increased five times and applied for imaging. It is revealed that the released SO2 molecules not only cause oxidative stress damage of tumor cells, but also induce their pro-death autophagy by down-regulating the expression of p62 and up-regulating the ratio of LC3-II/LC3-I, ultimately inhibiting tumor growth. The work demonstrates the great potential of rare earth nano-platform with functions of NIR-II imaging and photo-controlled gas therapy in the diagnosis and treatment of orthotopic glioblastoma.

Inhibiting autophagy flux and DNA repair of tumor cells to boost radiotherapy of orthotopic glioblastoma.

Radio-resistance of glioblastoma (GBM) remains a leading cause of radiotherapy failure because of the protective autophagy induced by X-Ray irradiation and tumor cells' strong capability of repairing damaged DNA. It is of great importance to overcome the radio-resistance for improving the efficacy of radiotherapy. Herein, we report the novel mechanism of core-shell copper selenide coated gold nanoparticles (Au@Cu2-xSe NPs) inhibiting the protective autophagy and DNA repair of tumor cells to drastically boost the radiotherapy efficacy of glioblastoma. We reveal that the core-shell Au@Cu2-xSe NPs can inhibit the autophagy flux by effectively alkalizing lysosomes. They can increase the SQSTM1/p62 protein levels of tumor cells without influencing their mRNA. We also reveal that Au@Cu2-xSe NPs can increase the ubiquitination of DNA repair protein Rad51, and promote the degradation of Rad51 by proteasomes to prevent the DNA repair. The simultaneous inhibition of protective autophagy and DNA repair significantly suppress the growth of orthotopic GBM by using radiotherapy and our novel Au@Cu2-xSe NPs. Our work provides a new insight and paradigm to significantly improve the efficacy of radiotherapy by rationally designing theranostic nano-agents to simultaneously inhibit protective autophagy and DNA repair of tumor cells.

Highly Tumor-Specific and Long-Acting Iodine-131 Microbeads for Enhanced Treatment of Hepatocellular Carcinoma with Low-Dose Radio-Chemoembolization.

Transarterial radioembolization (TARE) is considered the standard treatment for intermediate-stage hepatocellular carcinoma (HCC). Iodine-131 (131I)-labeled lipiodol TARE is an effective treatment for HCC but has been withdrawn due to its poor retention in tumor lesions and significant distribution in normal tissues with severe side effects. In this work, a highly tumor-specific 131I-TARE agent with long-time retention is developed by simply introducing tyrosine to poly(vinyl alcohol) (PVA) drug-eluting microbeads (Tyr-PVA-DEBs). The labeling efficiency of 131I-labeled microbeads remains above 85% in 50% serum for 31 days. Micro-single-photon emission computed tomography/computed tomography (µSPECT/CT) evidences that the 131I-labeled microbeads accumulate in the orthotopic N1S1 hepatoma of rats for 31 days following intra-arterial injection. The cumulative radiation dose per cubic centimeter of the tumor is at least 13 678-fold higher than that of normal tissues. The highly tumor-selective radiation of the 131I-labeled microbeads allows localized delivery of 345.04 ± 139.16 Gy to the tumor following a single injection dose as low as 0.2 mCi of 131I. Moreover, the 131I-labeled microbeads are loaded with doxorubicin hydrochloride (DOX) through the carboxy groups on tyrosine of the polymer. The 131I-DOX-loaded microbeads present a synergetic antitumor effect without recurrence in comparison with the microbeads labeled with 131I or loading DOX alone, attributed to the sensitization of DOX to 131I-induced ionizing radiation damage to DNA under the embolization-induced hypoxia. Our results demonstrate a high tumor retention of 131I-labeled embolic agent for low-dose transarterial radio-chemoembolization (TARCE) with a synergetic therapeutic effect on treating HCC, showing potential for clinical application.

Targeting Microglia for Therapy of Parkinson's Disease by Using Biomimetic Ultrasmall Nanoparticles.

Microglia as an important type of innate immune cell in the brain have been considered as an effective therapeutic target for the treatment of central nervous degenerative diseases. Herein, we report cell membrane coated novel biomimetic Cu2-xSe-PVP-Qe nanoparticles (denoted as CSPQ@CM nanoparticles, where PVP is poly(vinylpyrrolidone), Qe is quercetin, and CM is the cell membrane of neuron cells) for effectively targeting and modulating microglia to treat Parkinson's disease (PD). The CSPQ nanoparticles exhibit multienzyme activities and could effectively scavenge the reactive oxygen species and promote the polarization of microglia into the anti-inflammatory M2-like phenotype to relieve neuroinflammation. We reveal that biomimetic CSPQ@CM nanoparticles targeted microglia through the specific interactions between the membrane surface vascular cells adhering to molecule-1 and α4ß1 integrin expressed by microglia. They could significantly improve the symptoms of PD mice to result in an excellent therapeutic efficacy, as evidenced by the recovery of their dopamine level in cerebrospinal fluid, tyrosine hydroxylase, and ionized calcium binding adapter protein 1 to normal levels. Our work demonstrates the great potential of these robust biomimetic nanoparticles in the targeted treatment of PD and other central nervous degenerative diseases.

Overcoming Radioresistance in Tumor Therapy by Alleviating Hypoxia and Using the HIF-1 Inhibitor.

Radiotherapy has been extensively used to treat cancer patients because it can effectively damage most solid tumors without penetration limits. A hypoxic microenvironment in solid tumors leads to severe radioresistance and expression of hypoxic inducible factor-1 (HIF-1), which results in poor efficacy of radiotherapy alone. Herein, we report the excellent efficacy of radiotherapy achieved using a new type of yolk-shell Cu2-xSe@PtSe (CSP) nanosensitizer functionalized with the HIF-1α inhibitor acriflavine (ACF). We prepare the CSP nanosensitizer through the interfacial redox reactions between chloroplatinic acid and Cu2-xSe nanoparticles (CS) and then functionalize the nanosensitizer with ACF through their electrostatic interactions. We show that the synthesized CSP nanosensitizer can arrest the cell cycle (i.e., at the gap 2/mitosis (G2/M) phases) of tumor cells to enhance their sensitivity to X-rays and decompose endogenous H2O2 into O2 to reduce hypoxia and increase the production of reactive oxygen species, which leads to severe damage to DNA double strands and apoptosis of tumor cells. We also show that the ACF on the surface of CSP nanoparticles can effectively reduce the expression of HIF-1α. All these effects lead to a low vascular endothelial growth factor, low density of microvessels in tumor, decreased cell proliferation, and increased cell apoptosis, which synergistically and drastically enhance the efficacy of radiotherapy. This work provides insights and guidance for developing novel nanosensitizers to enhance the efficacy of radiotherapy.

The release and detection of copper ions from ultrasmall theranostic Cu2-xSe nanoparticles.

Nanoscale copper chalcogenides have been widely used in nanomedicine, however, their pharmacokinetics, degradation, and biological effects of released copper ions are usually overlooked, which are crucial for their future clinical translation. Herein, we report the in vitro and in vivo release of copper ions from polyvinylpyrrolidone (PVP) functionalized ultrasmall copper selenide (Cu2-xSe) theranostic nanoparticles. We synthesized a Cu2+-specific fluorescent probe (NCM), which can quickly and specifically react with copper ions to exhibit very strong near infrared fluorescence. The in vitro study shows that copper ions can be slowly released from Cu2-xSe nanoparticles in aqueous solution with the progress of their oxidation. The release of copper ions from Cu2-xSe nanoparticles in RAW 264.7 murine macrophages is very fast, evidenced by the gradual increase of fluorescence intensity and the diffusion of fluorescence from cytoplasm into nuclei. We also demonstrate the distribution, degradation, and the metabolism of ultrasmall Cu2-xSe nanoparticles by the in vivo fluorescence imaging, the blood routine test, blood biochemistry and histology analysis, and the characterization of copper transport and binding proteins. The results show that ultrasmall Cu2-xSe nanoparticles were mainly eliminated through feces and urine from the body within 72 h after intravenous injection, and the released copper ions did not cause severe toxicity. Our research highlights the great potential of copper chalcogenide nanoparticles in nanomedicine.

Cholesterol-Modified Black Phosphorus Nanospheres for the First NIR-II Fluorescence Bioimaging.

Black phosphorus (BP) nanostructures with unique layer-dependent properties have been extensively applied in the fields of electronic devices, energy conversion and storage, and nanomedicine. As a narrow band gap semiconductor, they are expected to show strong second near-infrared (NIR-II) fluorescence. However, there is no report on the NIR-II fluorescence of free-standing BP nanostructures, which have great potential in the NIR-II fluorescence bioimaging because of their excellent biocompatibility and biodegradability. Here, for the first time, we report that the BP nanoparticles modified with cholesterol exhibit strong NIR-II fluorescence and can be encapsulated with the PEGylated lipid to form BP@lipid-PEG nanospheres for in vitro and in vivo NIR-II imaging. The resultant BP@lipid-PEG nanospheres exhibit broad emissions from 900 to 1650 nm under excitation by an 808 nm laser and have 8% quantum yield of that of standard dye IR-26. We also show that the NIR-II fluorescence image acquired with emission beyond 1400 nm has the sharpest contrast and can be used to in situ measure the diameter of blood vessels. In addition to NIR-II fluorescence imaging, we also show the potential of BP@lipid-PEG nanospheres in photoacoustic (PA) imaging. Both the long-wavelength NIR-II fluorescence imaging and PA imaging reveal that the as-fabricated BP@lipid-PEG nanospheres can be gradually metabolized by the liver in 48 h, thus making them promising for bioapplications.

Light-Enhanced O2-Evolving Nanoparticles Boost Photodynamic Therapy To Elicit Antitumor Immunity.

Breast cancer remains to show high mortality and poor prognosis in women despite of significant progress in recent diagnosis and treatment. Herein, we report the rational design of a highly efficient ultrasmall nanotheranostic agent with excellent photodynamic therapy (PDT) performance to against breast cancer and its metastasis by eliciting antitumor immunity. The ultrasmall nanoagent (3.1 ± 0.4 nm) was fabricated from polyethylene glycol modified Cu2- xSe nanoparticles, ß-cyclodextrin, and chlorin e6 under ambient conditions. The resultant nanoplatform (CS-CD-Ce6 NPs) can be passively accumulated into the tumor to exhibit dramatic antitumor efficacy through the excellent PDT effect under near-infrared irradiation. The excellent PDT performance of this nanoplatform is owing to its role as a Fenton-like Haber-Weiss catalyst for the efficient degradation of H2O2 within the tumor to release hydroxyl radicals (·OH) and very toxic singlet oxygen (1O2) under irradiation. The generated vast amounts of reactive oxygen species not only killed primary tumor cells but also elicited immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs) and induced proinflammatory M1-macrophages polarization. Thereby, antitumor immune responses against the metastasis of breast cancer were robustly evoked. Our work demonstrates that ultrasmall Cu2- xSe nanoparticle-based nanoplatform offers a promising way to prevent cancer metastasis via immunogenic effects through its excellent PDT performance.