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.

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.

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.

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.

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.

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.

Ferroptosis-Strengthened Metabolic and Inflammatory Regulation of Tumor-Associated Macrophages Provokes Potent Tumoricidal Activities.

Modulation of tumor-associated macrophages (TAMs) holds promise for cancer treatment, mainly relying on M1 signaling activation and pro-inflammatory promotion. Nevertheless, the antitumor activity is often limited by the anti-inflammatory factors in the tumor microenvironment. Moreover, the metabolic function of TAMs is also critical to tumor progression. However, there are a few strategies that can simultaneously regulate both inflammatory and metabolic functions to achieve safe and potent antitumor activation of TAMs. Herein, we demonstrate that an iron-based metal organic framework nanoparticle and a ferroptosis-inducing agent synergistically induce mitochondrial alternation in TAMs, resulting in a radical metabolic switch from mitochondrial oxidative phosphorylation to glycolysis, which is resistant to anti-inflammatory stimuli challenge. The ferroptosis stress strengthened by the nanoformulation also drives multiple pro-inflammatory signaling pathways, enabling macrophage activation with potent tumoricidal activities. The ferroptosis-strengthened macrophage regulation strategy present in this study paves the way for TAM-centered antitumoral treatment to overcome the limitations of conventional methods.

Physical and Chemical Cues at the Nano-Bio Interface for Immunomodulation.

Immunomodulation has made remarkable progress in fighting infectious disease and cancer. Conventionally, immunomodulation largely relies on chemical/biochemical agents, which, unfortunately, suffer from sever off-target adverse effects. Recent insights into nano-bio interactions suggest that nanomaterials can directly participate in immunomodulation. A range of physical and chemical cues at the nano-bio interface have been harnessed to regulate diverse immuno-signaling for disease control and treatment. In this Minireview, we summarize recent studies on the physical and chemical cues enabled by intrinsic nanomaterials to trigger immunological signaling. First, we discuss physical cues mediated by surface topography, hydrophobicity, charge, and heat at the nano-bio interface for immunomodulation. Then, various nanomaterials enabled chemical cues, such as metal species and oxidative species are outlined. Finally, our perspectives on challenges and possible future directions are provided.

Silica-Based Nanoparticles for Biomedical Applications: From Nanocarriers to Biomodulators.

Silica-based nanoparticles (SNPs) are a classic type of material employed in biomedical applications because of their excellent biocompatibility and tailorable physiochemical properties. Typically, SNPs are designed as nanocarriers for therapeutics delivery, which can address a number of intrinsic drawbacks of therapeutics, including limited bioavailability, short circulation lifetime, and unfavorable biodistribution. To improve the delivery efficiency and spatiotemporal precision, tremendous efforts have been devoted to engineering the physiochemical properties of SNPs, including particle size, morphology, and mesostructure, as well as conjugating targeting ligands and/or "gatekeepers" to endow improved cell selectivity and on demand release profiles. Despite significant progress, the biologically inert nature of the bare silica framework has largely restricted the functionalities of SNPs, rendering conventional SNPs mainly as nanocarriers for targeted delivery and controlled release. To meet the requirements of next generation nanomedicines with improved efficacy and precision, new insights on the relationship between the physiochemical properties of SNPs and their biological behavior are highly valuable. Meanwhile, a conceptual shift from a simple spatiotemporal control mechanism to a more sophisticated biochemistry and signaling pathway modulation would be of great importance.In this Account, an overview of our recent contribution to the field is presented, wherein SNPs with rationally designed nanostructures and nanochemistry are applied as nanocarriers (defined as "nanomaterials being used as a transport module for another substance" according to Wikipedia) and/or biomodulators (defined as "any material that modifies a biological response" according to Wiktionary). This Account encompasses two main sections. In the first section, we focus on the conventional nanocarriers concept with new insights on the design principles of the nanostructures. We present examples to demonstrate the engineering of pore geometry, surface topology, and asymmetry of nanoparticles to achieve enhanced drug, gene, and protein delivery efficiency. The contribution of surface roughness of SNPs on improving the cellular uptake efficiency, adhesion property, and DNA transfection capacity is particularly highlighted. In the second section, we discuss novel SNPs designed as biomodulators to regulate intracellular microenvironment and cell signaling, such as the oxidative stress and glutathione levels for improving the anticancer efficacy of therapeutics and mRNA transfection in specific cell lines. The interplay between the nanoparticles, biological system, and drugs is discussed. We further discuss how to engineer the composition of SNPs to modulate metal hemostasis to realize inherent anticancer activity. Two typical examples, including modulating copper signaling for tumor vasculature targeted therapy and controlling iron signaling for macrophage polarization based immunotherapy, are presented to highlight the unique advantages of SNPs as nanosized therapeutics in comparison to molecular drugs. Moreover, utilizing these two examples, we showcase the possibility of designing SNPs with intrinsic pharmaceutical activity to indirectly control tumor growth without inducing significant cytotoxicity, thus alleviating the biosafety concerns of nanomedicines. At the end of this Account, we discuss our personal perspectives on the promises, opportunities, and issues in engineered SNPs as nanocarriers as well as their transition toward biomodulators. With a major focus on the latter scenario, the current status and possible future directions are outlined.

Eliciting Immunogenic Cell Death via a Unitized Nanoinducer.

Utilizing chemotherapeutics to induce immunogenic cell death (ICD) is a promising strategy to sensitize tumor cells and induce anticancer immunity. However, the application of traditional ICD inducers, such as chemodrugs, is largely hindered by their low tumor selectivity and severe side effects. Here, a new unitized ICD nanoinducer with high potency and cancer cell specificity is reported to achieve effective cancer immunotherapy. This nanoinducer is composed of disulfide-bond-incorporated organosilica nanoparticles, curcumin (CUR), and iron oxide nanoparticles, which can deplete intracellular glutathione, produce hydroxyl radicals, and induce cancer-cell-specific Ca2+ depletion as well as thioredoxin reductase inhibition. While the components are unable to induce ICD individually, their complementary pharmaceutical activities significantly elevate intracellular oxidative stress and endoplasmic reticulum stress in parallel. Consequently, ICD and systemic antitumor immunity can be elicited. Compared to the conventional ICD inducer doxorubicin, the unitized nanoinducer exhibits significantly improved ICD-inducing activity and cancer cell selectivity.

Designer Anticancer Nanoprodrugs with Self-Toxification Activity Realized by Acid-triggered Biodegradation and In†Situ Fragment Complexation.

Prodrugs that allow in situ chemical conversion of less toxic precursors into active drugs in response to certain stimuli are promising anticancer candidates. Herein, we present a novel design of nanoprodrugs with a "degradation-mediated self-toxification" strategy, which realizes intracellular synthesis of anticancer agents using the nanoparticles' own degradation fragments as the precursors. To fulfill this concept, a metal complexing dicyclohexylphosphine (DCP) organosilane is carefully screened out from various ligands to conjugate onto Pd(OH)2 nanodots confined hollow silica nanospheres (PD-HSN). This constructed nanoprodrug shows acid-triggered degradation in lysosomes and neutralizes protons to induce lysosomes rupturing, generating predesigned less toxic fragments (Pd2+ and DCP-silicates) that complex into DCP/Pd complex in situ for inducing DNA damage, leading to enhanced anticancer activity against various cancer cell lines as well as in a xenograft tumour model.

Responsively Aggregatable Sub-6 nm Nanochelators Induce Simultaneous Antiangiogenesis and Vascular Obstruction for Enhanced Tumor Vasculature Targeted Therapy.

Inhibiting the formation of new tumor blood vessels (so-called antiangiogenesis) and obstructing the established ones are two primary strategies in tumor vasculature targeted therapy. However, the therapeutic outcome of conventional methodologies relying on only one mechanism is rather limited. Herein, the first example of ultrasmall responsively aggregatable nanochelators that can intrinsically fulfill both antivasculature functions as well as high renal clearable efficiency is introduced. The nanochelators with sub-6 nm sizes exhibit not only systemic copper depletion activity for tumor antiangiogenesis but also, more surprisingly, the capability to transform from a "dispersed" state to an "aggregated" state to form large secondary particles in response to tumor microenvironment with elevated copper and phosphate levels for blood vessel obstruction. Compared to a benchmark antiangiogenic agent that can only inhibit the formation of tumor blood vessels, the nanochelators with unprecedented synergistic functions demonstrate significantly enhanced tumor inhibition activity in both breast cancer and colon cancer tumor models. Moreover, these ultrasmall nanochelators are noncytotoxic and renal clearable, ensuring superior biocompatibility. It is envisaged that the design of nanomaterials with ground-breaking properties and the synergistic antivasculature functions would offer a substantial conceptual advance for tumor vasculature targeted therapy and may provide vast opportunities for developing advanced nanomedicines.

Functional Nanoparticles with a Reducible Tetrasulfide Motif to Upregulate mRNA Translation and Enhance Transfection in Hard-to-Transfect Cells.

Effective messenger RNA (mRNA) transfection in hard-to-transfect cells delivered by vectors is a long-standing challenge. Now it is hypothesized that the high intracellular glutathione level is associated with suppressed mRNA translation. This theory leads to a new design principle of next-generation mRNA vectors: nanoparticles with glutathione depletion chemistry upregulate mRNA translation and enhance transfection, which is beneficial for mRNA delivery in hard-to-transfect cells in vitro and in vivo.

Dendritic Mesoporous Silica Nanoparticle Adjuvants Modified with Binuclear Aluminum Complex: Coordination Chemistry Dictates Adjuvanticity.

Aluminum-containing adjuvants used in vaccine formulations suffer from low cellular immunity, severe aggregation, and accumulation in the brain. Conventional aluminosilicates widely used in the chemical industry focus mainly on acidic sites for catalytic applications, but they are rarely used as adjuvants. Reported here is an innovative "ligand-assisted steric hindrance" strategy to create a high density of six-coordinate VI Al-OH groups with basicity on dendritic mesoporous silica nanoparticles as new nanoadjuvants. Compared to four-coordinate IV Al-modified counterparts, VI Al-OH-rich aluminosilicate nanoadjuvants enhance cellular delivery of antigens and provoke stronger cellular immunity. Moreover, the aluminum accumulation in the brain is more reduced than that with a commercial adjuvant. These results show that coordination chemistry can be used to control the adjuvanticity, providing new understanding in the development of next-generation vaccine adjuvants.

Openwork@Dendritic Mesoporous Silica Nanoparticles for Lactate Depletion and Tumor Microenvironment Regulation.

The direct depletion of lactate accumulated in the tumor microenvironment holds promise for cancer therapy but remains challenging. Herein, we report a one-pot synthesis of openwork@ dendritic mesoporous silica nanoparticles (ODMSNs) to address this problem. ODMSNs self-assembled through a time-resolved lamellar growth mechanism feature an openworked core and a dendritic shell, both constructed by silica nanosheets of ≈3 nm. With a large pore size, high surface area and pore volume, ODMSNs exhibited a high loading capacity (>0.7 g g-1 ) of lactate oxidase (LOX) and enabled intratumoral lactate depletion by >99.9 %, leading to anti-angiogenesis, down-regulation of vascular endothelial growth factor, and increased tumor hypoxia. The latter event facilitates the activation of a co-delivered prodrug for enhancing anti-tumor and anti-metastasis efficacy. This study provides an innovative nano-delivery system and demonstrates the first example of direct lactate-depletion-enabled chemotherapy.

FeOOH@Metal-Organic Framework Core-Satellite Nanocomposites for the Serum Metabolic Fingerprinting of Gynecological Cancers.

High-throughput metabolic analysis is of significance in diagnostics, while tedious sample pretreatment has largely hindered its clinic application. Herein, we designed FeOOH@ZIF-8 composites with enhanced ionization efficiency and size-exclusion effect for laser desorption/ionization mass spectrometry (LDI-MS)-based metabolic diagnosis of gynecological cancers. The FeOOH@ZIF-8-assisted LDI-MS achieved rapid, sensitive, and selective metabolic fingerprints of the native serum without any enrichment or purification. Further analysis of extracted serum metabolic fingerprints successfully discriminated patients with gynecological cancers (GCs) from healthy controls and also differentiated three major subtypes of GCs. Given the low cost, high-throughput, and easy operation, our approach brings a new dimension to disease analysis and classification.

Mechanism of Iron Oxide-Induced Macrophage Activation: The Impact of Composition and the Underlying Signaling Pathway.

Iron oxide nanoparticles (IONPs) have emerging anticancer applications via polarizing tumor-associated macrophages from tumor-promoting phenotype (M2) to tumor-suppressing phenotype (M1). However, the underlying mechanism and structure-function relationship remain unclear. We report magnetite IONPs are more effective compared to hematite in M1 polarization and tumor suppression. Moreover, magnetite IONPs specifically rely on interferon regulatory factor 5 signaling pathway for M1 polarization and down-regulate M2-assoicated arginase-1. This study provides new understandings and paves the way for designing advanced iron-based anticancer technologies.

Nano-resoles-Enabled Elegant Nanostructured Materials.

Since the extension of the Stöber method traditionally used in the synthesis of silica nanoparticles into the fabrication of resorcinol-formaldehyde nanospheres in 2011, significant progresses have been achieved in this exiting area of nano-resole-enabled synthesis of elegant nanostructures with versatile compositions and promising applications in various fields. To date, there are few reviews focused on this topic. In this minireview, we aim to provide an overview on recent developments, with the emphasis on nano-resoles as an enabling strategy in the synthesis of innovative materials. The history of nano-resoles and their distinct roles classified into four functions will be introduced. Clear understanding into this research field is vital for achieving rational design and controllable synthesis of a new generation of nano-resoles and their derived nanostructures.

A Concentration-Dependent Insulin Immobilization Behavior of Alkyl-Modified Silica Vesicles: The Impact of Alkyl Chain Length.

The insulin immobilization behaviors of silica vesicles (SV) before and after modification with hydrophobic alkyl -C8 and -C18 groups have been studied and correlated to the grafted alkyl chain length. In order to minimize the influence from the other structural parameters, monolayered -C8 or -C18 groups are grafted onto SV with controlled density. The insulin immobilization capacity of SV is dependent on the initial insulin concentrations (IIC). At high IIC (2.6-3.0 mg/mL), the trend of insulin immobilization capacity of SV is SV-OH > SV-C8 > SV-C18, which is determined mainly by the surface area of SV. At medium IIC (0.6-1.9 mg/mL), the trend changes to SV-C8 ≥ SV-C18 > SV-OH as both the surface area and alkyl chain length contribute to the insulin immobilization. At an extremely low IIC, the hydrophobic-hydrophobic interaction between the alkyl group and insulin molecules plays the most significant role. Consequently, SV-C18 with longer alkyl groups and the highest hydrophobicity show the best insulin enrichment performance compared to SV-C8 and SV-OH, as evidenced by an insulin detection limit of 0.001 ng/mL in phosphate buffered saline (PBS) and 0.05 ng/mL in artficial urine determined by mass spectrometry (MS).

Oxidative Dissolution of Resoles: A Versatile Approach to Intricate Nanostructures.

Resoles are resins obtained by base-catalyzed phenol-formaldehyde condensation with a three-dimensional cross-linked framework. They are considered as highly chemical-resistant, and calcination is thus generally used in the treatment of resole-type resins, which significantly limits the diversity of nanostructured materials that can be derived from resole-type resins. Herein, we report that selected metal nitrate solutions can be used to dissolve various types of nanostructured resoles through an oxidative dissolution process. This strategy not only enables the controlled dissolution of resoles, but more importantly provides a new approach to selectively etch resole-based nanocomposites to give rise to a variety of nanostructured materials with unprecedented architectures and great potential in bioapplications.