Sulfate Radical Based In Situ Vaccine Boosts Systemic Antitumor Immunity via Concurrent Activation of Necroptosis and STING Pathway.

In situ vaccine (ISV) can provoke systemic anti-tumor immunity through the induction of immunogenic cell death (ICD). The development of ISV technology has been restricted by the limited and suboptimal ICD driven tumor antigen production which are currently relying on chemo-drugs, photo-/radio-sensitizers, oncolytic-virus and immunostimulatory agents. Herein, a sulfate radical (SO4 ·-) based ISV is reported that accomplishes superior tumor immunotherapy dispense from conventional approaches. The ISV denoted as P-Mn-LDH is constructed by intercalating peroxydisulfate (PDS, a precursor of SO4 ·-) into manganese layered double hydroxide nanoparticles (Mn-LDH). This design allows the stabilization of PDS under ambient condition, but triggers a Mn2+ mediated PDS decomposition in acidic tumor microenvironment (TME) to generate in situ SO4 ·-. Importantly, it is found that the SO4 ·- radicals not only effectively kill cancer cells, but also induce a necroptotic cell death pathway, leading to robust ICD signaling for eliciting adaptive immunity. Further, the P-Mn-LDH can activate the stimulator of interferon genes (STING) pathway to further boost anti-tumor immunity. Collectively, the P-Mn-LDH based ISV exhibited potent activity in inhibiting tumor growth and lung metastasis. When combined with immune checkpoint inhibitor, significant inhibition of distant tumors is achieved. This study underpins the promise of SO4 ·- based vaccine technology for cancer immunotherapy.

Tadpole-Like Carbon Nanotube with Fe Nanoparticle Encapsulated at the Head and Zn Single-Atom Anchored on the Body: One-Pot Carbonization for Tetramodal Synergistic Cancer Therapy.

Precise integration of diverse therapeutic approaches into nanomaterials is the key to the development of multimodal synergistic cancer therapy. In this work, tadpole-like carbon nanotubes with Fe nanoparticle encapsulated at the head and Zn single-atom anchored on the body (Fe@CNT-Zn) is precisely designed and facilely prepared via one-pot carbonization. In vitro studies revealed the integration of chemotherapy (CT), chemodynamic therapy (CDT), photothermal therapy (PTT), and photodynamic therapy (PDT) in Fe@CNT-Zn as well as the near-infrared light (NIR)-responsive cascade therapeutic efficacy. Furthermore, in vivo studies demonstrated the NIR-triggered cascade-amplifying synergistic cancer therapy in a B16 tumor-bearing mouse model. The results not only showcased the Fe@CNT-Zn as a potential tetramodal therapeutic platform, but also demonstrated a proof-of-concept on metal-organic framework-based "one stone for multiple birds" strategy for in situ functionalization of carbon materials.

Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.

Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.

Improved Vth Stability and Gate Reliability of GaN-Based MIS-HEMTs by Employing Alternating O2 Plasma Treatment.

The Vth stability and gate reliability of AlGaN/GaN metal-insulator-semiconductor high-electron-mobility transistors (MIS-HEMTs) with alternating O2 plasma treatment were systematically investigated in this article. It was found that the conduction band offset at the Al2O3/AlGaN interface was elevated to 2.4 eV, which contributed to the suppressed gate leakage current. The time-dependent dielectric breakdown (TDDB) test results showed that the ALD-Al2O3 with the alternating O2 plasma treatment had better quality and reliability. The AlGaN/GaN MIS-HEMT with the alternating O2 plasma treatment demonstrated remarkable advantages in higher Vth stability under high-temperature and long-term gate bias stress.

Mesoporous nanoperforators as membranolytic agents via nano- and molecular-scale multi-patterning.

Plasma membrane lysis is an effective anticancer strategy, which mostly relying on soluble molecular membranolytic agents. However, nanomaterial-based membranolytic agents has been largely unexplored. Herein, we introduce a mesoporous membranolytic nanoperforators (MLNPs) via a nano- and molecular-scale multi-patterning strategy, featuring a spiky surface topography (nanoscale patterning) and molecular-level periodicity in the spikes with a benzene-bridged organosilica composition (molecular-scale patterning), which cooperatively endow an intrinsic membranolytic activity. Computational modelling reveals a nanospike-mediated multivalent perforation behaviour, i.e., multiple spikes induce nonlinearly enlarged membrane pores compared to a single spike, and that benzene groups aligned parallelly to a phospholipid molecule show considerably higher binding energy than other alignments, underpinning the importance of molecular ordering in phospholipid extraction for membranolysis. Finally, the antitumour activity of MLNPs is demonstrated in female Balb/c mouse models. This work demonstrates assembly of organosilica based bioactive nanostructures, enabling new understandings on nano-/molecular patterns co-governed nano-bio interaction.

Transcriptome Sequencing Unveils a Molecular-Stratification-Predicting Prognosis of Sarcoma Associated with Lipid Metabolism.

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.

Engineered Silica Nanoparticles for Nucleic Acid Delivery.

The development of nucleic acid-based drugs holds great promise for therapeutic applications, but their effective delivery into cells is hindered by poor cellular membrane permeability and inherent instability. To overcome these challenges, delivery vehicles are required to protect and deliver nucleic acids efficiently. Silica nanoparticles (SiNPs) have emerged as promising nanovectors and recently bioregulators for gene delivery due to their unique advantages. In this review, a summary of recent advancements in the design of SiNPs for nucleic acid delivery and their applications is provided, mainly according to the specific type of nucleic acids. First, the structural characteristics and working mechanisms of various types of nucleic acids are introduced and classified according to their functions. Subsequently, for each nucleic acid type, the use of SiNPs for enhancing delivery performance and their biomedical applications are summarized. The tailored design of SiNPs for selected type of nucleic acid delivery will be highlighted considering the characteristics of nucleic acids. Lastly, the limitations in current research and personal perspectives on future directions in this field are presented. It is expected this opportune review will provide insights into a burgeoning research area for the development of next-generation SiNP-based nucleic acid delivery systems.

Mesoporous carbon hemispheres integrated with Fe-Gd nanoparticles for potential MR/PA imaging-guided photothermal therapy.

Asymmetric carbon has emerged as an important material to enrich morphologies as well as enhance functions for bioapplications. Here, asymmetric mesoporous carbon hemispheres (CHS) integrated with γ-Fe2O3 and GdPO4 (Fe-Gd) nanoparticles are proposed and prepared for potential imaging-guided photothermal therapy (PTT). Interestingly, Fe-Gd/CHS contributes to an almost 1.5 times enhancement in light harvesting and photothermal conversion efficiency as compared with its corresponding spherical analogue. The possible underlying mechanism is discussed in view of the unique asymmetric structure-featured carbon. Further identification of the inherited photoacoustic (PA) and magnetic resonance (MR) imaging properties leads to the consequent in vivo evaluation of its imaging and PTT performances, which demonstrates its capability as a function-integrated system for potential theranostics.

Engineering Crystallinity Gradients for Tailored CaO2 Nanostructures: Enabling Alkalinity-Reinforced Anticancer Activity with Minimized Ca2+/H2O2 Production.

CaO2 nanoparticles (CNPs) can produce toxic Ca2+ and H2O2 under acidic pH, which accounts for their intrinsic anticancer activity but at the same time raises safety concerns upon systemic exposure. Simultaneously realizing minimized Ca2+/H2O2 production and enhanced anticancer activity poses a dilemma. Herein, we introduce a "crystallinity gradient-based selective etching" (CGSE) strategy, which is realized by creating a crystallinity gradient in a CNP formed by self-assembled nanocrystals. The nanocrystals distributed in the outer layer have a higher crystallinity and thus are chemically more robust than those distributed in the inner layer, which can be selectively etched. CGSE not only leads to CNPs with tailored single- and double-shell hollow structures and metal-doped compositions but more surprisingly enables significantly enhanced anticancer activity as well as tumor growth inhibition under limited Ca2+/H2O2 production, which is attributed to an alkalinity-reinforced lysosome-dependent cell death pathway.

Non-Buffer Epi-AlGaN/GaN on SiC for High-Performance Depletion-Mode MIS-HEMTs Fabrication.

A systematic study of epi-AlGaN/GaN on a SiC substrate was conducted through a comprehensive analysis of material properties and device performance. In this novel epitaxial design, an AlGaN/GaN channel layer was grown directly on the AlN nucleation layer, without the conventional doped thick buffer layer. Compared to the conventional epi-structures on the SiC and Si substrates, the non-buffer epi-AlGaN/GaN structure had a better crystalline quality and surface morphology, with reliable control of growth stress. Hall measurements showed that the novel structure exhibited comparable transport properties to the conventional epi-structure on the SiC substrate, regardless of the buffer layer. Furthermore, almost unchanged carrier distribution from room temperature to 150 °C indicated excellent two-dimensional electron gas (2DEG) confinement due to the pulling effect of the conduction band from the nucleation layer as a back-barrier. High-performance depletion-mode MIS-HEMTs were demonstrated with on-resistance of 5.84 Ω·mm and an output current of 1002 mA/mm. The dynamic characteristics showed a much smaller decrease in the saturation current (only ~7%), with a quiescent drain bias of 40 V, which was strong evidence of less electron trapping owing to the high-quality non-buffer AlGaN/GaN epitaxial growth.

A Novel Atomic-Level Post-Etch-Surface-Reinforcement Process for High-Performance p-GaN Gate HEMTs Fabrication.

A novel atomic-level post-etch-surface-reinforcement (PESR) process is developed to recover the p-GaN etching induced damage region for high performance p-GaN gate HEMTs fabrication. This process is composed of a self-limited surface modification step with O2 plasma, following by an oxide removal step with BCl3 plasma. With PESR process, the AlGaN surface morphology after p-GaN etching was comparable to the as-epitaxial level by AFM characterization, and the AlGaN lattice crystallization was also recovered which was measured in a confocal Raman system. The electrical measurement further confirmed the significant improvement of AlGaN surface quality, with one-order of magnitude lower surface leakage in a metal-semiconductor (MS) Schottky-diode and 6 times lower interface density of states (Dit) in a MIS C-V characterization. The XPS analysis of Al2O3/AlGaN showed that the p-GaN etching induced F-byproduct and Ga-oxide was well removed and suppressed by PESR process. Finally, the developed PESR process was successfully integrated in p-GaN gate HEMTs fabrication, and the device performance was significantly enhanced with ~20% lower of on-resistance and ~25% less of current collapse at Vds,Q bias of 40 V, showing great potential of leverage p-GaN gate HEMTs reliability.

In Situ H-Radical Surface Treatment on Aluminum Gallium Nitride for High-Performance Aluminum Gallium Nitride/Gallium Nitride MIS-HEMTs Fabrication.

In this work, we demonstrated a low current collapse normally on Al2O3/AlGaN/GaN MIS-HEMT with in situ H-radical surface treatment on AlGaN. The in situ atomic pretreatment was performed in a specially designed chamber prior to the thermal ALD-Al2O3 deposition, which improved the Al2O3/AlGaN interface with Dit of ~2 × 1012 cm-2 eV-1, and thus effectively reduced the current collapse and the dynamic Ron degradation. The devices showed good electrical performance with low Vth hysteresis and peak trans-conductance of 107 mS/mm. Additionally, when the devices operated under 25 °C pulse-mode stress measurement with VDS,Q = 40 V (period of 1 ms, pulse width of 1 µs), the dynamic Ron increase of ~14.1% was achieved.

Switchable supermode emission in a doubly-coupled-ring system for multifunctional integrated photonic devices.

Effective integration of optical modes within chip-scale devices is critical to realize functional light emission, as it offers abundant physics and a versatile ability to control the mode evolution. Here, we present an efficient approach to achieve switchable emission by flexibly controlling supermode states in a doubly-coupled-ring system with four guided modes. The lasing conditions, which rely on the system's Hamiltonian, are revealed to yield multiple supermode states, including an exceptional-point state, a (quasi-)dark state, and a bright state. By freely engineering the coupling rate via phase-change material, the proposed system allows the generation of any desired states, enabling switchable and multifunctional emissions in fixed on-chip structures. Beyond the manipulation of various supermode emission states, our work presents a promising path toward the development of multifunctional integrated photonic devices, which may have applications in light storage, optical isolation, sensing, and so on.

Advanced Oxidation Nanoprocessing Boosts Immunogenicity of Whole Tumor Cells.

Whole tumor cells expressing a wide array of tumor antigens are considered as a highly promising source of antigens for cancer vaccines. However, simultaneously preserving the antigen diversity, improving immunogenicity, and eliminating the potential tumorigenic risk of whole tumor cells are highly challenging. Inspired by the recent progress in sulfate radical-based environmental technology, herein, an advanced oxidation nanoprocessing (AONP) strategy is developed for boosting the immunogenicity of whole tumor cells. The AONP is based on the activation of peroxymonosulfate by ZIF-67 nanocatalysts to produce SO4 -∙ radicals continuously, leading to sustained oxidative damage to tumor cells and consequently extensive cell death. Importantly, AONP causes immunogenic apoptosis as evidenced by the release of a series of characteristic damage associated molecular patterns and at the same time maintains the integrity of cancer cells, which is critical to preserve the cellular components and thus maximize the diversity of antigens. Finally, the immunogenicity of AONP-treated whole tumor cells is evaluated in a prophylactic vaccination model, demonstrating significantly delayed tumor growth and increased survival rate of live tumor-cell-challenged mice. It is expected that the developed AONP strategy would pave the way to develop effective personalized whole tumor cell vaccines in future.

Gelothermal Synthesis of Monodisperse MIL-88A Nanoparticles with Tunable Sizes and Metal Centers for Potential Bioapplications.

Developing novel synthetic strategies to downsize metal-organic frameworks (MOFs) from polydisperse crystals to monodisperse nanoparticles is of great importance for their potential bioapplications. In this work, a novel synthetic strategy termed gelothermal synthesis is proposed, in which coordination polymer gel is first prepared and followed by a thermal reaction to give the monodisperse MOF nanoparticles. This novel synthetic strategy successfully leads to the isolation of Materials of Institute Lavoisier (MIL-88), Cu(II)-fumarate MOFs (CufumDMF), and Zeolitic Imidazolate Frameworks (ZIF-8) nanoparticles. Focused on MIL-88A, the studies reveal that the size can be well-tuned from nanoscale to microscale without significant changes in polydispersity index (PDI) even in the case of in situ metal substitution. A possible mechanism is consequently proposed based on extensive studies on the gelothermal condition including sol-gel chemistry, thermal condition, kinds of solvents, and so on. The unique advantages of monodisperse MIL-88A nanoparticles over polydisperse ones are further demonstrated in terms of in vitro magnetic resonance imaging (MRI), cellular uptake, and drug-carrying properties.

Cuproptosis: mechanisms and links with cancers.

Cuproptosis was a copper-dependent and unique kind of cell death that was separate from existing other forms of cell death. The last decade has witnessed a considerable increase in investigations of programmed cell death, and whether copper induced cell death was an independent form of cell death has long been argued until mechanism of cuproptosis has been revealed. After that, increasing number of researchers attempted to identify the relationship between cuproptosis and the process of cancer. Thus, in this review, we systematically detailed the systemic and cellular metabolic processes of copper and the copper-related tumor signaling pathways. Moreover, we not only focus on the discovery process of cuproptosis and its mechanism, but also outline the association between cuproptosis and cancers. Finally, we further highlight the possible therapeutic direction of employing copper ion ionophores with cuproptosis-inducing functions in combination with small molecule drugs for targeted therapy to treat specific cancers.

Complement-related molecular classification and a gene signature for lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a major cause of cancer-related death worldwide, and the roles of complement-related genes in it have not been thoroughly investigated yet. In the study, we aimed to systemically examine the prognostic performance of complement-related genes, classify the patients into two different clusters and stratify the patients into different risk groups using a complement-related gene signature. METHODS: To achieve this, clustering analyses, Kaplan-Meier survival analyses, immune infiltration analyses were performed. LUAD patients from The Cancer Genome Atlas (TCGA) were classified into two subtypes (C1 and C2). A prognostic signature, consisting of four complement-related genes, was established using TCGA-LUAD cohort and validated in six Gene Expression Omnibus datasets and an independent cohort from our center. RESULTS: The prognosis of C2 patients is better than that of C1 patients and the prognosis of low risk patients is significantly better than high risk patients across the public datasets. In our cohort, the OS of patients in low risk group is better than that in high risk group but the difference is not significant. Patients with a lower risk score were characterized by a higher immune score, a higher level of BTLA, higher infiltration levels of T cells, B lineage, myeloid dendritic cells, neutrophils, endothelial cells, and a lower infiltration level of fibroblast. CONCLUSIONS: In summary, our study has established a new classification method and developed a prognostic signature for LUAD, while future studies are needed for further exploration of the underlying mechanism.

Hybrid Nanomaterials for Cancer Immunotherapy.

Nano-immunotherapy has been recognized as a highly promising strategy for cancer treatment in recent decades, which combines nanotechnology and immunotherapy to combat against tumors. Hybrid nanomaterials consisting of at least two constituents with distinct compositions and properties, usually organic and inorganic, have been engineered with integrated functions and enormous potential in boosting cancer immunotherapy. This review provides a summary of hybrid nanomaterials reported for cancer immunotherapy, including nanoscale metal-organic frameworks, metal-phenolic networks, mesoporous organosilica nanoparticles, metallofullerene nanomaterials, polymer-lipid, and biomacromolecule-based hybrid nanomaterials. The combination of immunotherapy with chemotherapy, chemodynamic therapy, radiotherapy, radiodynamic therapy, photothermal therapy, photodynamic therapy, and sonodynamic therapy based on hybrid nanomaterials is also discussed. Finally, the current challenges and the prospects for designing hybrid nanomaterials and their application in cancer immunotherapy are outlined.

Mesoporous sodium four-coordinate aluminosilicate nanoparticles modulate dendritic cell pyroptosis and activate innate and adaptive immunity.

Pyroptosis is a programmed cell death widely studied in cancer cells for tumour inhibition, but rarely in dendritic cell (DC) activation for vaccine development. Here, we report the synthesis of sodium stabilized mesoporous aluminosilicate nanoparticles as DC pyroptosis modulators and antigen carriers. By surface modification of sodium-stabilized four-coordinate aluminium species on dendritic mesoporous silica nanoparticles, the resultant Na-IVAl-DMSN significantly activated DC through caspase-1 dependent pyroptosis via pH responsive intracellular ion exchange. The released proinflammatory cellular contents further mediated DC hyperactivation with prolonged cytokine release. In vivo studies showed that Na-IVAl-DMSN induced enhanced cellular immunity mediated by natural killer (NK) cells, cytotoxic T cells, and memory T cells as well as humoral immune response. Our results provide a new principle for the design of next-generation nanoadjuvants for vaccine applications.