The specific diagnosis and treatment of gliomas is a primary challenge in clinic due to their high invasiveness and blood-brain barrier (BBB) obstruction. It is highly desirable to find a multifunctional agent with good BBB penetration for precise theranostics. Herein, we design and construct a core-shell structured nanotheranostic agent (YVO4:Nd3+-HMME@MnO2-LF, marked as YHM) with YVO4:Nd3+ particles as the core and MnO2 nanosheets as the shell. Sonosensitizer hematoporphyrinmonomethyl ether (HMME) and lactoferrin (LF) were further loaded and modified on the surface, giving it a good ability to cross the BBB, near-infrared fluorescence imaging in the second window (NIR-II)/magnetic resonance imaging (MRI) bimodality, and highly efficient sonodynamic therapy (SDT) of orthotopic gliomas. The YVO4:Nd3+ (25%) core exhibited good NIR-II fluorescence properties, enabling YHM to act as promising probes for NIR-II fluorescence imaging of vessels and orthotopic gliomas. MnO2 shell can not only provide O2 in the tumor microenvironments (TME) to significantly improve the healing efficacy of SDT, but also release Mn2+ ions to achieve T1-weight MRI in situ. Non-invasive SDT can effectively restrain tumor growth. This work not only demonstrates that multifunctional YHM is promising for diagnosis and treatment of orthotopic glioma, but also provides insights into exploring the theranostic agents based on rare earth-doped yttrium vanadate nanoparticles.

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The unsatisfactory therapeutic effect and long-term adverse effect markedly prevent inorganic nanomaterials from clinical transformation. In light of this, we developed a novel biodegradable theranostic agent (MnCO 3 :Ho 3+ @DOX/Ca 3 (PO 4 ) 2 @BSA, HMCDB) based on the sonosensitizer manganese carbonate (MnCO 3 ) coating with calcium phosphate (Ca 3 (PO 4 ) 2 ) and simultaneously loaded it with the chemotherapeutic drug doxorubicin (DOX). Due to the mild acidity of the tumor microenvironment (TME), the Ca 3 (PO 4 ) 2 shell degraded first, releasing substantial quantities of calcium ions (Ca 2+ ) and DOX. Meanwhile, with the ultrasound (US) irradiation, MnCO 3 produced enough reactive oxygen species (ROS) to cause oxidative stress in the cells, resulting in accumulation of Ca 2+ . Consequently, the cascade effect significantly amplified the therapeutic effect. Importantly, the nanocomposite can be completely degraded and cleared from the body, demonstrating that it was a promising theranostic agent for tumor therapy. Furthermore, the doped holmium ions (Ho 3+ ) and in situ generation of manganese ions (Mn 2+ ) in TME endow the nanoagent with the ability for tumor-specific bimodality T 1 /T 2 -weighted magnetic resonance imaging (MRI). This novel nanoplatform with low toxicity and biodegradability holds great potential for cancer diagnosis and treatment.

Ferroptosis, characterized by iron accumulation and lipid peroxidation (LPO), can avoid the intrinsic apoptotic resistance of tumor cells and have been explored for glioblastoma (GBM) therapy. However, the direct delivery of iron species may trigger severe adverse side effects. Using nonferrous species to induce LPO‐mediated ferroptosis maybe a promising strategy for GBM treatment, but there is still no report till now. Therefore, in this study, first an intelligent blood–brain barrier (BBB)‐permeable nanoplatform (PCN‐224@Au/CeO2‐Lf) is constructed for efficient nonferrous ferroptosis‐involved orthotopic GBM therapy. Porous coordination network‐224 nanoparticles (PCN‐224 NPs) are served as sonosensitizers for sonodynamic therapy (SDT). In situ growth of small Au NPs with glucose oxidase (GOx)‐mimic activity and CeO2 NPs with peroxidase (POD)‐ and catalase (CAT)‐mimic abilities are applied for H2O2 self‐supplement, more acidic microenvironment, and generation of cytotoxic hydroxyl radical (·OH) and O2, which improves the efficacy of SDT. Besides, Ce4+‐mediated glutathione (GSH) depletion further promotes ferroptosis and apoptosis. Reactive oxygen species (ROS) burst and GSH consumption‐related glutathione peroxidase 4 (GPX4) deactivation promote the accumulation of LPO, leading to significant nonferrous ferroptosis, which can effectively shrink the orthotopic GBM. These findings first demonstrate the nonferrous ferroptosis strategy for efficient GBM treatment.

Despite the fact that chemotherapy has been widely used in the clinical treatment of breast cancer, the toxicity of chemotherapeutics to normal tissues cannot be ignored due to the low specificity. Therefore, due to the non-negligible toxicity of chemotherapeutic agents to normal tissues, tumor microenvironment (TME)-responsive cancer therapy has attracted a great deal of attention. Here, we report a TME-responsive theranostic nanoagent

Accurate diagnosis and highly effective treatment of glioblastoma are still challenges in clinic. Near-infrared (NIR) light triggered fluorescence imaging and photodynamic therapy (PDT) showed the potential for theranostics of glioblastoma, but the presence of blood-brain barrier (BBB) and hypoxia limited treatment effect. Herein, the novel theranostic nanoagents with YOF:Nd3+ as core, MnO2 as shell, and further loading photosensitizer (indocyanine green, ICG) and glucose oxidase (GOx) were successfully constructed, and further modified with lactoferrin to endow them with BBB penetration and target abilities (YOF:Nd3+@MnO2–ICG-GOx-LF, YMIGL). The YOF:Nd3+ core with good fluorescence performances makes YMIGL act as promising probes for fluorescence imaging in the second biowindow (NIR-II FL). The combination of GOx and MnO2 shell significantly increased the O2 generation from the cascade reactions and consumed glucose, improving the treatment effect of PDT and achieving starvation treatment (ST). These theranostic nanoagents exhibit a highly efficient inhibition effect on orthotopic gliomas by cascade reactions, which improved PDT and ST.

The metabolic reprogramming of glioblastoma (GBM) poses a tremendous obstacle to effective immunotherapy due to its impact on the immunosuppressive microenvironment. Here, we develop a hydrogen‐bonded organic frameworks (HOF) specifically designed for GBM immunotherapy, taking advantage of the relatively isolated cholesterol metabolism microenvironment in the central nervous system (CNS). The HOF‐based biotuner regulates extra/intracellular cholesterol metabolism, effectively blocking the programmed cell death protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) pathway and reducing 2B4 expression. This metabolically disrupts the immunosuppressive microenvironment of GBM and rejuvenates CD8+ T cells. Moreover, cholesterol metabolism regulation offers additional benefits in treating GBM invasion. Furthermore, in response to the tumor microenvironment (TEM)‐initiated chemiexcited photodynamic therapy (PDT), which was enhanced during the regulation of cholesterol metabolism, the biotuner could effectively trigger immunogenic cell death (ICD) and increase the infiltration of cytotoxic T lymphocytes (CTLs) in GBM. By reversing immunosuppressive microenvironment and bolstering chemiexcited‐PDT, our approach invigorates efficient antibody non‐dependent immunotherapy for GBM. This study provides a model for enhancing immunotherapy through cholesterol metabolism regulation and explores the feasibility of a “metabolic checkpoint” strategy in GBM treatment.This article is protected by copyright. All rights reserved

Although photodynamic therapy (PDT) have exhibited good potential in therapy of glioma, the limited penetration depth of light and the obstacle of blood-brain barrier (BBB) lead to the unsatisfactory treatment...