Immunological nanomaterials to combat cancer metastasis.

Metastasis causes greater than 90% of cancer-associated deaths, presenting huge challenges for detection and efficient treatment of cancer due to its high heterogeneity and widespread dissemination to various organs. Therefore, it is imperative to combat cancer metastasis, which is the key to achieving complete cancer eradication. Immunotherapy as a systemic approach has shown promising potential to combat metastasis. However, current clinical immunotherapies are not effective for all patients or all types of cancer metastases owing to insufficient immune responses. In recent years, immunological nanomaterials with intrinsic immunogenicity or immunomodulatory agents with efficient loading have been shown to enhance immune responses to eliminate metastasis. In this review, we would like to summarize various types of immunological nanomaterials against metastasis. Moreover, this review will summarize a series of immunological nanomaterial-mediated immunotherapy strategies to combat metastasis, including immunogenic cell death, regulation of chemokines and cytokines, improving the immunosuppressive tumour microenvironment, activation of the STING pathway, enhancing cytotoxic natural killer cell activity, enhancing antigen presentation of dendritic cells, and enhancing chimeric antigen receptor T cell therapy. Furthermore, the synergistic anti-metastasis strategies based on the combinational use of immunotherapy and other therapeutic modalities will also be introduced. In addition, the nanomaterial-mediated imaging techniques (e.g., optical imaging, magnetic resonance imaging, computed tomography, photoacoustic imaging, surface-enhanced Raman scattering, radionuclide imaging, etc.) for detecting metastasis and monitoring anti-metastasis efficacy are also summarized. Finally, the current challenges and future prospects of immunological nanomaterial-based anti-metastasis are also elucidated with the intention to accelerate its clinical translation.

Advancing nanotechnology for neoantigen-based cancer theranostics.

Neoantigens play a pivotal role in the field of tumour therapy, encompassing the stimulation of anti-tumour immune response and the enhancement of tumour targeting capability. Nonetheless, numerous factors directly influence the effectiveness of neoantigens in bolstering anti-tumour immune responses, including neoantigen quantity and specificity, uptake rates by antigen-presenting cells (APCs), residence duration within the tumour microenvironment (TME), and their ability to facilitate the maturation of APCs for immune response activation. Nanotechnology assumes a significant role in several aspects, including facilitating neoantigen release, promoting neoantigen delivery to antigen-presenting cells, augmenting neoantigen uptake by dendritic cells, shielding neoantigens from protease degradation, and optimizing interactions between neoantigens and the immune system. Consequently, the development of nanotechnology synergistically enhances the efficacy of neoantigens in cancer theranostics. In this review, we provide an overview of neoantigen sources, the mechanisms of neoantigen-induced immune responses, and the evolution of precision neoantigen-based nanomedicine. This encompasses various therapeutic modalities, such as neoantigen-based immunotherapy, phototherapy, radiotherapy, chemotherapy, chemodynamic therapy, and other strategies tailored to augment precision in cancer therapeutics. We also discuss the current challenges and prospects in the application of neoantigen-based precision nanomedicine, aiming to expedite its clinical translation.

A D-Y Shaped Neuropeptide Y Mimetic Peptide-Dye Self-Assembly with Maximal Emission Beyond 1300 nm and Glioma Mitochondrial Activity Modulation.

Neuropeptide Y (NPY), as one of the most abundant neuropeptides known, is widely distributed in the central and peripheral nervous system. However, most of the reported NPY-mimetic peptides are hard to cross the blood-brain barrier, target glioma mitochondria, and achieve self-assembly nanostructure in situ. Here, based on the α-helix structure of the novel chiral NPY-mimetic peptides D/LNPY(14), a Y-shaped peptide is designed with the sequences that can be recognized by enterokinase and achieved nanofibers conversion in glioma cell mitochondria. Coupling the Y-shaped NPY-mimetic peptide with the NIR-II fluorophore IR1048, a red-shifting of the fluorescence spectrum beyond 1300 nm is achieved through self-assembly. After the self-assembly in glioma mitochondria, the formed nanofibers can promote intracellular mitochondrial ROS production and extend the NIR-II fluorescence imaging time to at least 7 days in vivo. This work for the first time endows the self-assembly of α-helical-based chiral NPY-mimetic peptides, providing a novel strategy for glioma subcellular regulation enhanced antitumor treatment guided by NIR-II fluorescence imaging.

Engineering Single-Atom Nanozymes for Catalytic Biomedical Applications.

Nanomaterials with enzyme-mimicking properties, coined as nanozymes, are a promising alternative to natural enzymes owing to their remarkable advantages, such as high stability, easy preparation, and favorable catalytic performance. Recently, with the rapid development of nanotechnology and characterization techniques, single atom nanozymes (SAzymes) with atomically dispersed active sites, well-defined electronic and geometric structures, tunable coordination environment, and maximum metal atom utilization are developed and exploited. With superior catalytic performance and selectivity, SAzymes have made impressive progress in biomedical applications and are expected to bridge the gap between artificial nanozymes and natural enzymes. Herein, the recent advances in SAzyme preparation methods, catalytic mechanisms, and biomedical applications are systematically summarized. Their biomedical applications in cancer therapy, oxidative stress cytoprotection, antibacterial therapy, and biosensing are discussed in depth. Furthermore, to appreciate these advances, the main challenges, and prospects for the future development of SAzymes are also outlined and highlighted in this review.

EGFR-Targeted Liposomes Combined with Ginsenoside Rh2 Inhibit Triple-Negative Breast Cancer Growth and Metastasis.

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype due to its lack of targeted therapies and poor prognosis. In order to treat patients with these tumors, efforts have been made to explore feasible targets. Epidermal growth factor receptor (EGFR)-targeted therapy is currently in clinical trials and regarded to be a promising treatment strategy. In this study, an EGFR-targeting nanoliposome (LTL@Rh2@Lipo-GE11) using ginsenoside Rh2 as a wall material was developed, in which GE11 was used as the EGFR-binding peptide to deliver more ginsenoside Rh2 and luteolin into TNBC. In comparison to non-targeted liposomes (Rh2@Lipo and LTL@Rh2@Lipo), the nanoliposomes LTL@Rh2@Lipo-GE11 demonstrated a high specificity to MDA-MB-231 cells that expressed a high level of EGFR both in vitro and in vivo, contributing to the strong inhibitory effects on the growth and migration of TNBC. These results suggest that LTL@Rh2@Lipo-GE11 is a prospective candidate for targeted therapy of TNBC, with a remarkable capability to inhibit tumor development and metastasis.

Development of nanotechnology-mediated precision radiotherapy for anti-metastasis and radioprotection.

Radiotherapy (RT), including external beam RT and internal radiation therapy, uses high-energy ionizing radiation to kill tumor cells. However, ionizing radiation inevitably damages the surrounding normal tissues. Therefore, it is imperative to develop precision RT for improving the treatment outcome and reducing the adverse effects. Recent breakthroughs in nanotechnology have provided a variety of strategies by which RT can precisely and efficiently eradicate local tumors. In this review, we would like to summarize a series of nanotechnology-mediated strategies to achieve precision RT, including tumor-targeted delivery, image-guided precision radiotherapy, and exo/endogenous stimuli-responsive nanomedicines for enhanced tumor accumulation/penetration. In addition, this review will also discuss two representative featured applications of precision RT: RT-induced immunotherapy against cancer metastasis and radioprotection of the surrounding healthy tissues. Since RT is usually thought to be only effective for treating local tumors, this review will interpret the unusual mechanisms of RT-mediated systemic antitumor immunity for eliminating distant cancer metastasis as well as the abscopal effects of RT in combination with other treatments (e.g., photodynamic therapy (PDT), chemodynamic therapy (CDT), etc.). Furthermore, this review will discuss nanotechnology-mediated radioprotection strategies for shielding healthy tissues from radiation damage. Finally, the current challenges and future prospects of precision RT are also elucidated with the intention to accelerate its clinical translation.

Hippocampal Lnx1-NMDAR multiprotein complex mediates initial social memory.

Social interaction and communication are evolutionary conserved behaviours that are developed in mammals to establish partner cognition. Deficit in sociability has been represented in human patients and animal models of neurodevelopmental disorders, which are connected with genetic variants of synaptic glutamate receptors and associated PDZ-binding proteins. However, it remains elusive how these key proteins are specialized in the cellular level for the initial social behaviour during postnatal developmental stage. Here we identify a hippocampal CA3 specifically expressed PDZ scaffold protein Lnx1 required for initial social behaviour. Through gene targeting we find that Lnx1 deficiency led to a hippocampal subregional disorder in neuronal activity and social memory impairments for partner discrimination observed in juvenile mice which also show cognitive defects in adult stage. We further demonstrate that Lnx1 deletion causes NMDA receptor (NMDAR) hypofunction and this is attributable to decreased GluN2B expression in PSD compartment and disruption of the Lnx1-NMDAR-EphB2 complex. Specific restoration of Lnx1 or EphB2 protein in the CA3 area of Lnx1-/- mice rescues the defective synaptic function and social memory. These findings thus reveal crucial roles of postsynaptic NMDAR multiprotein complex that regulates the formation of initial social memory during the adolescent period.

Construction of competitive endogenous RNA network reveals regulatory role of long non-coding RNAs in intracranial aneurysm.

BACKGROUND: Rupture of intracranial aneurysm (IA) is the main cause of devastating subarachnoid hemorrhage, which urges our understanding of the pathogenesis and regulatory mechanisms of IA. However, the regulatory roles of long non-coding RNAs (lncRNAs) in IA is less known. RESULTS: We processed the raw SRR files of 12 superficial temporal artery (STA) samples and 6 IA samples to count files. Then the differentially expressed (DE) mRNAs, miRNAs, and lncRNAs between STAs and IAs were identified. The enrichment analyses were performed using DEmRNAs. Next, a lncRNA-miRNA-mRNA regulatory network was constructed using integrated bioinformatics analysis. In summary, 341 DElncRNAs, 234 DEmiRNAs, and 2914 DEmRNAs between the STA and IA. The lncRNA-miRNA-mRNA regulatory network of IA contains 91 nodes and 146 edges. The subnetwork of hub lncRNA PVT1 was extracted. The expression level of PVT1 was positively correlated with a majority of the mRNAs in its subnetwork. Moreover, we found that several mRNAs (CCND1, HIF1A, E2F1, CDKN1A, VEGFA, COL1A1 and COL5A2) in the PVT1 subnetwork served as essential components in the PI3K-Akt signaling pathway, and that some of the non-coding RNAs (ncRNAs) (PVT1, HOTAIR, hsa-miR-17, hsa-miR-142, hsa-miR-383 and hsa-miR-193b) interacted with these mRNAs. CONCLUSION: Our annotations noting ncRNA's role in the pathway may uncover novel regulatory mechanisms of ncRNAs and mRNAs in IA. These findings provide significant insights into the lncRNA regulatory network in IA.

Transcriptome analyses reveal molecular mechanisms underlying phenotypic differences among transcriptional subtypes of glioblastoma.

Using molecular signatures, previous studies have defined glioblastoma (GBM) subtypes with different phenotypes, such as the proneural (PN), neural (NL), mesenchymal (MES) and classical (CL) subtypes. However, the gene programmes underlying the phenotypes of these subtypes were less known. We applied weighted gene co-expression network analysis to establish gene modules corresponding to various subtypes. RNA-seq and immunohistochemical data were used to validate the expression of identified genes. We identified seven molecular subtype-specific modules and several candidate signature genes for different subtypes. Next, we revealed, for the first time, that radioresistant/chemoresistant gene signatures exist only in the PN subtype, as described by Verhaak et al, but do not exist in the PN subtype described by Phillips et al PN subtype. Moreover, we revealed that the tumour cells in the MES subtype GBMs are under ER stress and that angiogenesis and the immune inflammatory response are both significantly elevated in this subtype. The molecular basis of these biological processes was also uncovered. Genes associated with alternative RNA splicing are up-regulated in the CL subtype GBMs, and genes pertaining to energy synthesis are elevated in the NL subtype GBMs. In addition, we identified several survival-associated genes that positively correlated with glioma grades. The identified intrinsic characteristics of different GBM subtypes can offer a potential clue to the pathogenesis and possible therapeutic targets for various subtypes.

Effect of α7nAChR on learning and memory dysfunction in a rat model of diffuse axonal injury.

Diffuse axonal injury (DAI) is the predominant effect of severe traumatic brain injury and significantly contributes to cognitive deficits. The mechanisms that underlie these cognitive deficits are often associated with complex molecular alterations. α7nAChR, one of the abundant and widespread nicotinic acetylcholine receptors (nAChRs) in the brain, plays important physiological functions in the central nervous system. However, the relationship between temporospatial alterations in the α7nAChR and DAI-related learning and memory dysfunction are not completely understood. Our study detected temporospatial alterations of α7nAChR in vulnerable areas (hippocampus, internal capsule, corpus callosum and brain stem) of DAI rats and evaluated the development and progression of learning and memory dysfunction via the Morris water maze (MWM). We determined that α7nAChR expression in vulnerable areas was mainly reduced at the recovery of DAI in rats. Moreover, the escape latency of the injured group increased significantly and the percentages of the distance travelled and time spent in the target quadrant were significantly decreased after DAI. Furthermore, α7nAChR expression in the vulnerable area was significantly positively correlated with MWM performance after DAI according to regression analysis. In addition, we determined that a selective α7nAChR agonist significantly improved learning and memory dysfunction. Rats in the α7nAChR agonist group showed better learning and memory performance than those in the antagonist group. These results demonstrate that microstructural injury-induced alterations of α7nAChR in the vulnerable area are significantly correlated with learning and memory dysfunctions after DAI and that augmentation of the α7nAChR level by its agonist contributes to the improvement of learning and memory function.

Inhibition of miRNA-21 promotes retinal ganglion cell survival and visual function by modulating Müller cell gliosis after optic nerve crush.

BACKGROUND: Müller cell gliosis not only plays an important physiological role by maintaining retinal neuronal homeostasis but is also associated with multiple pathological events in the retina, including optic nerve crush (ONC) injury. Modulating Müller cell gliosis contributes to the creation of a permissive environment for neuronal survival. However, the underlying mechanism of Müller cell gliosis has remained elusive. OBJECTIVE: To investigate the underlying mechanism of Müller cell gliosis after ONC. METHODS: Rats with ONC injury were transfected with miRNA-21 (miR-21) agomir (overexpressing miR-21) or antagomir (inhibiting miR-21) via intravitreous injection. Immunofluorescence and western blotting were performed to confirm the effects of miR-21 on Müller cell gliosis. The retinal nerve fiber layer (RNFL) thickness was measured using optical coherence tomography and the positive scotopic threshold response (pSTR) was recorded using electroretinogram. RESULTS: In the acute phase (14 days) after ONC, compared with the crushed group, inhibiting miR-21 promoted Müller cell gliosis, exhibiting thicker processes and increased GFAP expression. In the chronic phase (35 days), inhibiting miR-21 ameliorated Müller cell gliosis, which exhibited thicker and denser processes and increased GFAP expression. Retinal ganglion cell (RGC) counts in retinas showed that the number of surviving RGCs increased significantly in the antagomir group. The thickness of the RNFL increased significantly, and pSTR showed significant preservation of the amplitudes in the antagomir group. CONCLUSIONS: Inhibition of miR-21 promotes RGC survival, RNFL thickness and the recovery of RGC function by modulating Müller cell gliosis after ONC.

Transforming growth factor beta induced (TGFBI) is a potential signature gene for mesenchymal subtype high-grade glioma.

Previous study revealed that higher expression of transforming growth factor beta induced (TGFBI) is correlated to poorer cancer-specific survival and higher proportion of tumor necrosis and Fuhrman grades III and IV in clear cell renal cell carcinomas. However, the relationships between TGFBI expression and malignant phenotypes of gliomas remain unclear. We downloaded and analyzed data from seven GEO datasets (GSE68848, GSE4290, GSE13041, GSE4271, GSE83300, GSE34824 and GSE84010), the TCGA database and the REMBRANDT database to investigate whether TGFBI could be a biomarker of glioma. From microarray data (GSE68848, GSE4290) and RNA-seq data (TCGA), TGFBI expression levels were observed to correlate positively with pathological grade, and TGFBI expression levels were significantly higher in gliomas than in normal brain tissues. Furthermore, in GSE13041, GSE4271 and the TCGA cohort, TGFBI expression in the mesenchymal (Mes) subtype high-grade glioma (HGG) was significantly higher than that in the proneural subtype. Kaplan-Meier survival analysis of GBM patients in the GSE83300 dataset, REMBRANDT and TCGA cohort revealed that patients in the top 50% TGFBI expression group survived for markedly shorter periods than those in the bottom 50%. Analysis of grade III gliomas showed that the median survival time was significantly shorter in the TGFBI high expression group than in the TGFBI low expression group. In addition, we found that TGFBI expression levels might relate to several classical molecular characterizations of glioma, such as, IDH mutation, TP53 mutation, EGFR amplification, etc. These results suggest that TGFBI expression positively correlates with glioma pathological grades and that TGFBI is a potential signature gene for Mes subtype HGG and a potential prognostic molecule.

Carrier-Free Self-Assembly Nano-Sonosensitizers for Sonodynamic-Amplified Cuproptosis-Ferroptosis in Glioblastoma Therapy.

Cuproptosis is a newly discovered form of programmed cell death significantly depending on the transport efficacy of copper (Cu) ionophores. However, existing Cu ionophores, primarily small molecules with a short blood half-life, face challenges in transporting enough amounts of Cu ions into tumor cells. This work describes the construction of carrier-free nanoparticles (Ce6@Cu NPs), which self-assembled by the coordination of Cu2+ with the sonosensitizer chlorin e6 (Ce6), facilitating sonodynamic-triggered combination of cuproptosis and ferroptosis. Ce6@Cu NPs internalized by U87MG cells induce a sonodynamic effect and glutathione (GSH) depletion capability, promoting lipid peroxidation and eventually inducing ferroptosis. Furthermore, Cu+ concentration in tumor cells significantly increases as Cu2+ reacts with reductive GSH, resulting in the downregulation of ferredoxin-1 and lipoyl synthase. This induces the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase, causing proteotoxic stress and irreversible cuproptosis. Ce6@Cu NPs possess a satisfactory ability to penetrate the blood-brain barrier, resulting in significant accumulation in orthotopic U87MG-Luc glioblastoma. The sonodynamic-triggered combination of ferroptosis and cuproptosis in the tumor by Ce6@Cu NPs is evidenced both in vitro and in vivo with minimal side effects. This work represents a promising tumor therapeutic strategy combining ferroptosis and cuproptosis, potentially inspiring further research in developing logical and effective cancer therapies based on cuproptosis.

Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist ß-amyloid peptides (Aß) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Comparative metabarcoding analysis of phytoplankton community composition and diversity in aquaculture water and the stomach contents of Tegillarca granosa during months of growth.

Filter-feeder bivalves and phytoplankton are interdependent. Their interaction plays important role in estuarine and coastal ecosystem. The correlation between bivalve feeding and phytoplankton is highly species specificity and environment dependent. In the background of miniature and nondiatom trend of phytoplankton in coastal seawaters, how bivalve respond and how the response play roles in the phytoplankton community are poorly known. In the present study, by applying DNA metabarcoding approach based on plastid 23S rDNA, this question was addressed by comparing the phytoplankton composition in the seston and the stomach content of blood clam Tegillarca granosa sampled during the growth period from March to November 2020 in an experimental farm on tidal flat in Xiangshan Bay, East China Sea. The result showed that, a total of seven phyla, 55 genera and 73 species of phytoplankton were identified for all samples. Chlorophyta, Bacillariophyta, and Cyanobacteria were found to be three dominant phyla both in the stomach contents and seston. High diversity of pico-sized phytoplankton, which was easy overlooked by microscopy, was revealed both in seston and stomach contents. This result indicated that the clam was able to feed on the pico-sized algae. At the genus level, the most abundant genera were the pico-sized green alga Ostreococcus (6.12 %-67.88 %) in seston and Picochlorum (4.07 %-35.33 %) in the stomach contents. In addition, microalgae of high nutritional value showed trend of higher proportion in stomach contents than that in seston, especially in July and September when significant growth of T. granosa was observed during this period (the body size increased 155 %). Biodiversity of phytoplankton in the seston was totally higher than that in stomach content, however, the changes among the months showed respective trend. Especially in July when the biodiversity was the lowest in seston, that in the stomach content showed the highest. The results indicated that blood clam farming might influence the phytoplankton composition, including those of pico-sized level, although the particular species in seston were mainly correlating with the dominant environmental factors such as temperature, salinity, pH respectively. These results extend the understanding of roles that bivalve aquaculture may play in the changing of coastal phytoplankton community.

Changes in biochemical metabolites in manila clam after a temporary culture with high-quality microalgal feed mixed with the dinoflagellate species Karlodinium veneficum and K. zhouanum.

Phytoplankton composition is an important factor affecting the growth and physiological biochemical characteristics of filter-feeding bivalves. With the increasing trend in dinoflagellate biomass and blooms in mariculture areas, how the physio-biochemical traits and seafood quality of the mariculture organism are affected by the dinoflagellates, especially those at nonfatal levels, is not well understood. Different densities of two Karlodinium species, namely K. veneficum (KV) and K. zhouanum (KZ), mixed with high quality microalgal food Isochrysis galbana was applied in feeding manila clam Ruditapes philippinarum in a 14-day temporary culture, to comparatively study how the critical biochemical metabolites such as glycogen, free amino acids (FAAs), fatty acids (FAs), volatile organic compounds (VOCs) in the clam were affected. The survival rate of the clam showed dinoflagellate density and species specificity. The high-density KV group inhibited survival to 32% lower than that of the pure I. galbana control, respectively, while KZ at low concentrations did not significantly affect the survival compared with the control. In the high-density KV group, the glycogen and FAA contents decreased (p < 0.05), indicating that energy and protein metabolism were significantly affected. Amount of carnosine (49.91 ± 14.64 to 84.74 ± 8.59 µg/g of muscle wet weight) was detected in all the dinoflagellate-mixed groups, while it was not present in the field samples or in the pure I. galbana control, showing that carnosine participated in the anti-stress activities when the clam was exposed to the dinoflagellates. The global composition of FAs did not significantly vary among the groups. However, contents of the endogenous C18 PUFA precursors linoleic acid and α-linolenic acid significantly decreased in the high-density KV group compared to all the other groups, indicating that high density of KV affected the metabolisms of fatty acids. From the results of the changed VOC composition, oxidation of fatty acids and degradation of free amino acids might occur in the clams exposed to dinoflagellates. The increased VOCs, such as aldehydes, and decreased 1-octen-3-ol probably produced a more fishy taste and reduced food flavor quality when the clam was exposed to the dinoflagellates. This present study demonstrated that the biochemical metabolism and seafood qulity of the clam were affected. However, KZ with moderate density in the feed seemed to be beneficial in aquaculture for increasing the content of carnosine, a high-valued substance with multiple bioactivities.

Enhancing Catalytic Activity of a Nickel Single Atom Enzyme by Polynary Heteroatom Doping for Ferroptosis-Based Tumor Therapy.

As a rising generation of nanozymes, single atom enzymes show significant promise for cancer therapy, due to their maximum atom utilization efficiency and well-defined electronic structures. However, it remains a tremendous challenge to precisely produce a heteroatom-doped single atom enzyme with an expected coordination environment. Herein, we develop an anion exchange strategy for precisely controlled production of an edge-rich sulfur (S)- and nitrogen (N)-decorated nickel single atom enzyme (S-N/Ni PSAE). In particular, sulfurized S-N/Ni PSAE exhibits stronger peroxidase-like and glutathione oxidase-like activities than the nitrogen-monodoped nickel single atom enzyme, which is attributed to the vacancies and defective sites of sulfurized nitrogen atoms. Moreover, both in vitro and in vivo results demonstrate that, compared with nitrogen-monodoped N/Ni PSAE, sulfurized S-N/Ni PSAE more effectively triggers ferroptosis of tumor cells via inactivating glutathione peroxidase 4 and inducing lipid peroxidation. This study highlights the enhanced catalytic efficacy of a polynary heteroatom-doped single atom enzyme for ferroptosis-based cancer therapy.

Photothermal Enhanced and Tumor Microenvironment Responsive Nanozyme for Amplified Cascade Enzyme Catalytic Therapy.

Nanocatalysts, a class of nanomaterials with intrinsic enzyme-like activities, have been widely investigated for cancer catalytic therapy in recent years. However, precise construction of nanocatalysts with excellent enzyme catalytic activity and biosafety for tumor therapy still remains challenging. Here, a biodegradable nanocatalyst, PEGylated Cux Mny Sz (PCMS), is reported that can promote cascade catalytic reactions in tumor microenvironment (TME) while confining off-target side effects on normal tissues. PCMS not only catalyzes the cascade conversion of endogenous hydrogen peroxide (H2 O2 ) to oxygen (O2 ) via catalase-like activity and then to superoxide radical (·O2 - ) via oxidase-like activity in the TME, but also effectively depletes intracellular glutathione via glutathione oxidase-like activity. The cascade catalytic reactions, by taking advantage of high H2 O2 level in tumor cells, result in an enhanced enzyme catalytic effect in generation of ·O2 - . More importantly, PCMS exhibits prominent photothermal effect under NIR-II 1064 nm laser irradiation that can further enhance chemodynamic therapy (CDT) efficacy in tumors. In addition, the biodegradation in TME and excellent photothermal effect of PCMS are beneficial to magnetic resonance imaging, photoacoustic imaging and infrared thermal imaging, resulting in tracing the fate of PCMS in vivo. This study provides a new tool for rational design of TME-responsive nanocatalysts with high biocompatibility for tumor catalytic therapy.

Platelet-Membrane-Coated Polydopamine Nanoparticles for Neuroprotection by Reducing Oxidative Stress and Repairing Damaged Vessels in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) has a high morbidity and mortality rate. Excessive reactive oxygen species (ROS) caused by primary and second brain injury can induce neuron death and inhibit neurological functional recovery after ICH. Therefore, exploring an effective way to noninvasively target hemorrhage sites to scavenge ROS is urgently needed. Inspired by the biological function of platelets to target injury vessel and repair injury blood vessels, platelet-membrane-modified polydopamine (Menp@PLT) nanoparticles are developed with targeting to hemorrhage sites of ICH. Results demonstrate that Menp@PLT nanoparticles can effectively achieve targeting to the location of intracranial hematoma. Furthermore, Menp@PLT with excellent anti-ROS properties can scavenge ROS and improve neuroinflammation microenvironment of ICH. In addition, Menp@PLT may play a role in decreasing hemorrhage volume by repairing injury blood vessels. Combining platelet membrane and anti-ROS nanoparticles for targeting brain hemorrhage sites provide a promising strategy for efficiently treating ICH.