Search

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.

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 H2O2content, 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.

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. 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 ischemia‐reperfusion injury‐induced acute kidney injury (AKI) and alleviating AKI damage.

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.

In this article number 20200128, Zhen Li and co‐workers have summarized the recent advances of the NIR‐II fluorescence imaging technique, and addressed its significance in the early prevention and treatment of cerebral diseases inclusive of traumatic brain injury (TBI), stroke, and cerebroma. The advanced NIR‐II fluorescence imaging system and nano‐fluorophores enable the dynamic and visible evaluation of cerebral lesions from tissue, cellular and molecular levels.

As the major pipeline for transporting oxygen and nutrients to living tissues, well‐ordered and functional vasculature is vital to maintain the function of organisms. The cerebrovascular disorders induced by acute or chronic diseases, including traumatic brain injury (TBI), stroke, and brain tumors, could cause vascular cognitive impairment and even mortality. Due to the complication of these cerebrovascular diseases, early diagnosis and monitoring their pathological processes in real time in animal models could enlighten us with insights into early prevention and effective treatment. Over the last decade, the NIR‐II fluorescence imaging technology has been well developed in both nanofluorophores and imaging systems. For cerebrovascular disorders, the collaborative use of wide‐field imaging setup with NIR‐II nanoprobes enable arteriovenous staging, and calculation of blood flow velocity to distinguish ischemic area in TBI and stroke. The changes in molecular and cellular levels of TBI provide the guidance on the design of targeted and activatable NIR‐II nanoprobes for evaluating and monitoring the microenvironment variations. For the brain tumors, both targeted strategy and focus ultrasound sonication are efficient approaches for overcoming the blood‐brain‐barrier and brain‐tumor‐barrier for delivery of nanoprobes. Therefore, NIR‐II fluorescence imaging‐guided surgical navigation of brain tumors and resected lesions biopsy intraoperatively ensure the accuracy of surgery based on the precise definition of tumor margins. This review summarizes the recent advances in NIR‐II fluorescence imaging technology, which is mainly inclusive of well‐developed NIR‐II nanofluorophores and their applications in cerebrovascular diseases with address of its challenges and great potential in these aspects. Recent advances in the NIR‐II fluorescence imaging of cerebral diseases inclusive of stroke, TBI, cerebroma at multilevels of tissue, cell, and molecule by using inorganic and organic nanoprobes are comprehensively reviewed.