Abstract Metallic nanoparticles due to their small size and unique physico-chemical characteristics have found excellent applications in various branches of industry and medicine. Therefore, for many years a growing interest has been observed among the scientific community in the improvement of our understanding of the impact of nanoparticles on the living organisms, especially on humans. Considering the delicate structure of the central nervous systemit is one of the organs most vulnerable to the adverse effects of metallic nanoparticles. For that reason, it is important to identify the modes of exposure and understand the mechanisms of the effect of nanoparticles on neuronal tissue. In this review, an attempt is undertaken to present current knowledge about metallic nanoparticles neurotoxicity based on the selected scientific publications. The route of entry of nanoparticles is described, as well as their distribution, penetration through the cell membrane and the blood-brain barrier. In addition, a study on the neurotoxicity in vitro and in vivo is presented, as well as some of the mechanisms that may be responsible for the negative effects of metallic nanoparticles on the central nervous system. Graphical abstract: This review summarizes the current knowledge on the toxicity of metallic NPs in the brain and central nervous system of the higher vertebrates.

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Toxicity of metallic nanoparticles in the central nervous system

Cuproptosis, a newly identified form of regulated cell death that is copper‐dependent, offers great opportunities for exploring the use of copper‐based nanomaterials inducing cuproptosis for cancer treatment. Here, a glucose oxidase (GOx)‐engineered nonporous copper(I) 1,2,4‐triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], for starvation‐augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be “turned on” for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@[Cu(tz)]‐mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper‐induced toxicity. The increased intracellular hydrogen peroxide (H2O2) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@[Cu(tz)]. The in vivo experimental results indicate that GOx@[Cu(tz)] produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis‐based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis.

An Enzyme‐Engineered Nonporous Copper(I) Coordination Polymer Nanoplatform for Cuproptosis‐Based Synergistic Cancer Therapy

Widespread biomedical applications of nanomaterials (NMs) bring about increased human exposure risk due to their unique physicochemical properties. Autophagy, which is of great importance for regulating the physiological or pathological activities of the body, has been reported to play a key role in NM-driven biological effects both in vivo and in vitro. The coexisting hazard and health benefits of NM-mediated autophagy in biomedicine are nonnegligible and require our particular concerns. We collected research on the toxic effects related to NM-mediated autophagy both in vivo and in vitro. Generally, NMs can be delivered into animal models through different administration routes, or internalized by cells through different uptake pathways, exerting varying degrees of damage in tissues, organs, cells, and organelles, eventually being deposited in or excreted from the body. In addition, other biological effects of NMs, such as oxidative stress, inflammation, necroptosis, pyroptosis, and ferroptosis, have been associated with autophagy and cooperate to regulate body activities. We therefore highlight that NM-mediated autophagy serves as a double-edged sword, which could be utilized in the treatment of certain diseases related to autophagy dysfunction, such as cancer, neurodegenerative disease, and cardiovascular disease. Challenges and suggestions for further investigations of NM-mediated autophagy are proposed with the purpose to improve their biosafety evaluation and facilitate their wide application. Databases such as PubMed and Web of Science were utilized to search for relevant literature, which included all published, Epub ahead of print, in-process, and non-indexed citations. In this review, we focus on the dual effect of NM-mediated autophagy in the biomedical field. It has become a trend to use the benefits of NM-mediated autophagy to treat clinical diseases such as cancer and neurodegenerative diseases. Understanding the regulatory mechanism of NM-mediated autophagy in biomedicine is also helpful for reducing the toxic effects of NMs as much as possible.

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Nanomaterial-mediated autophagy: coexisting hazard and health benefits in biomedicine.

Immunotherapy has revolutionized cancer treatment, dramatically improving survival rates of melanoma and lung cancer patients. Nevertheless, immunotherapy is almost ineffective against ovarian cancer (OC) due to its cold tumor immune microenvironment (TIM). Many traditional medications aimed at remodeling TIM are often associated with severe systemic toxicity, require frequent dosing, and show only modest clinical efficacy. In recent years, emerging nanomedicines have demonstrated extraordinary immunotherapeutic effects for OC by reversing the TIM because the physical and biochemical features of nanomedicines can all be harnessed to obtain optimal and expected tissue distribution and cellular uptake. However, nanomedicines are far from being widely explored in the field of OC immunotherapy due to the lack of appreciation for the professional barriers of nanomedicine and pathology, limiting the horizons of biomedical researchers and materials scientists. Herein, a typical cold tumor‐OC is adopted as a paradigm to introduce the classification of TIM, the TIM characteristics of OC, and the advantages of nanomedicines for immunotherapy. Subsequently, current nanomedicines are comprehensively summarized through five general strategies to substantially enhance the efficacy of immunotherapy by heating the cold OC. Finally, the challenges and perspectives of this expanding field for improved development of clinical applications are also discussed.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202202797

Nanomedicine Strategies for Heating “Cold” Ovarian Cancer (OC): Next Evolution in Immunotherapy of OC

Near-infrared-II (NIR-II, 1000-1700 nm) light-triggered photothermal therapy (PTT) has been regarded as a promising candidate for cancer treatment, but PTT alone often fails to achieve satisfactory curative outcomes. Hollow nanoplatforms prove to be attractive in the biomedical field owing to the merits including good biocompatibility, intrinsic physical-chemical nature and unique hollow structures, etc. On one hand, hollow nanoplatforms themselves can be NIR-II photothermal agents (PTAs), the cavities of which are able to carry diverse therapeutic units to realize multi-modal therapies. On the other hand, NIR-II PTAs are capable of decorating on the surface to combine with the functions of components encapsulated inside the hollow nanoplatforms for synergistic cancer treatment. Notably, PTAs generally can serve as good photoacoustic imaging (PAI) contrast agents (CAs), which means such kind of hollow nanoplatforms are also expected to be multifunctional all-in-one nanotheranostics. In this review, the recent advances of NIR-II hollow nanoplatforms for single-modal PTT, dual-modal PTT/photodynamic therapy (PDT), PTT/chemotherapy, PTT/catalytic therapy and PTT/gas therapy as well as multi-modal PTT/chemodynamic therapy (CDT)/chemotherapy, PTT/chemo/gene therapy and PTT/PDT/CDT/starvation therapy (ST)/immunotherapy are summarized for the first time. Before these, the typical synthetic strategies for hollow structures are presented, and lastly, potential challenges and perspectives related to these novel paradigms for future research and clinical translation are discussed. 

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Recent advances in near-infrared-II hollow nanoplatforms for photothermal-based cancer treatment

A therapeutic tumor vaccine is a promising approach to cancer treatment. One of its strategies is to treat patient-derived tumor cells in vitro and then administer them in vivo to induce an adaptive immune response and achieve cancer treatment. Here, we want to explore the possibility of converting cancer tissue into a therapeutic tumor vaccine through induced immunogenic cell death (ICD) in situ. We loaded indocyanine green (ICG) into liposomes (ICG-Lipo) and modified it with the pardaxin peptide to realize an endoplasmic reticulum (ER)-targeting function (Par-ICG-Lipo). A microfluidic technique was developed for loading ICG, a water-soluble molecule, into liposomes with a high encapsulation efficiency (greater than 90%). Under near-infrared (NIR) irradiation, ER-targeting photodynamic therapy (PDT) induced by Par-ICG-Lipo could promote the release of danger-signaling molecules (DAMPs) and tumor antigens (TAAs) in vivo, which significantly enhanced the immunogenicity in vivo and thus stimulates a strong antitumor immune response. This process would be further amplified by adopting dendritic cells. In general, our strategy transformed in situ tumor cells into therapeutic vaccines by ER-targeting PDT, which could provide a clinically applicable and effective approach for cancer treatment.

ER-Targeting PDT Converts Tumors into In Situ Therapeutic Tumor Vaccines.

HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma.

Biomimetic mesoporous polydopamine nanoparticles for MRI-guided photothermal-enhanced synergistic cascade chemodynamic cancer therapy

Reactivation of dysfunctional dendritic cells by a stress-relieving nanosystem resets anti-tumor immune landscape

Existing ferroptosis as an iron‐dependent form of regulated cell death primarily relies on importing exogenous iron. However, the excessive employment of toxic materials may cause potential adverse effects on human health. Herein, a ferritin‐hijacking nanoparticle (Ce6‐PEG‐HKN15) is fabricated, by conjugating the ferritin‐homing peptide HKN15 with the photosensitizer chlorin e6 (Ce6) for endogenous ferroptosis without introducing Fenton‐reactive metals. Once internalized, the designed Ce6‐PEG‐HKN15 NPs can specifically accumulate around ferritin. With laser irradiation, the activated Ce6 in nanoparticles potently generates reactive oxygen species (ROS) surrounding ferritin. Abundant ROS not only helps to destroy the iron storage protein and activate endogenous ferroptosis but also directly kill tumor cells. In turn, the released iron partially interacts with intracellular excess H2O2 to produce O2, thereby enhancing photodynamic therapy and further amplifying oxidative stress. Overall, this work highlights the possibility of endogenous ferroptosis via spatiotemporally destroying ferritin, offering a paradigm for synergistic ferroptosis–photodynamic antitumor therapy.

Yongzhong Du

Papers

ER-Targeting PDT Converts Tumors into In Situ Therapeutic Tumor Vaccines.

HIF-2α-targeted interventional chemoembolization multifunctional microspheres for effective elimination of hepatocellular carcinoma.

Biomimetic mesoporous polydopamine nanoparticles for MRI-guided photothermal-enhanced synergistic cascade chemodynamic cancer therapy

Reactivation of dysfunctional dendritic cells by a stress-relieving nanosystem resets anti-tumor immune landscape

Ferritin‐Hijacking Nanoparticles Spatiotemporally Directing Endogenous Ferroptosis for Synergistic Anticancer Therapy