Harnessing bioactive nanomaterials in modulating tumor glycolysis-associated metabolism.

Glycolytic reprogramming is emerging as a hallmark of various cancers and a promising therapeutic target. Nanotechnology is revolutionizing the anti-tumor therapeutic approaches associated with glycolysis. Finely controlled chemical composition and nanostructure provide nanomaterials unique advantages, enabling an excellent platform for integrated drug delivery, biochemical modulation and combination therapy. Recent studies have shown promising potential of nanotherapeutic strategies in modulating tumor glycolytic metabolism alone or in combination with other treatments such as chemotherapy, radiotherapy and immunotherapy. To foster more innovation in this cutting-edge and interdisciplinary field, this review summarizes recent understandings of the origin and development of tumor glycolysis, then provides the latest advances in how nanomaterials modulate tumor glycolysis-related metabolism. The interplay of nanochemistry, metabolism and immunity is highlighted. Ultimately, the challenges and opportunities are presented.

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.

Benzene-Bridged Organosilica Modified Mesoporous Silica Nanoparticles via an Acid-Catalysis Approach.

Surface functionalization of mesoporous silica nanoparticles is important for their applications but fairly challenging using benzene-bridged organosilane as the precursor through the postsynthesis approach. Herein, we report an acid-catalysis approach for the postmodification of benzene-bridged organosilica onto the surface of large-pore mesoporous silica nanoparticles. By using HCl (∼1 M) as the acid catalyst in a tetrahydrofuran solvent, the self-assembly of the bridged organosilica precursor is avoided, while surface modification of mesoporous silica nanoparticles is promoted with controllable organic contents and retained large pore sizes. This strategy can also be applied to the postmodification of organosilica with end benzene groups. The strategy developed in this study is expected to be applied for the postmodification of other organosilica precursors with various functions.

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.

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.

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.

Hybrid Nanoreactors: Enabling an Off-the-Shelf Strategy for Concurrently Enhanced Chemo-immunotherapy.

Immunosuppressive tumors generally exhibit poor response to immune checkpoint blockade based cancer immunotherapy. Rationally designed hybrid nanoreactors are now presented that have integrated functions as Fenton catalysts and glutathione depletion agents for amplifying the immunogenic cell death and activating immune cells. A simple physical mixture of nanoreactors and chemodrugs in combination with immune checkpoint blockades show synergistically and concurrently enhanced chemo-immunotherapy efficacy, inhibiting the growth of both treated primary immunosuppressive tumors and untreated distant tumors. The off-the-shelf strategy uses tumor antigens generated in situ and avoids cargo loading, and is thus a substantial advance in personalized nanomedicine for clinical translation.

Plasmid DNA Delivery: Nanotopography Matters.

Plasmid DNA molecules with unique loop structures have widespread bioapplications, in many cases relying heavily on delivery vehicles to introduce them into cells and achieve their functions. Herein, we demonstrate that control over delicate nanotopography of silica nanoparticles as plasmid DNA vectors has significant impact on the transfection efficacy. For silica nanoparticles with rambutan-, raspberry-, and flower-like morphologies composed of spike-, hemisphere-, and bowl-type subunit nanotopographies, respectively, the rambutan-like nanoparticles with spiky surfaces demonstrate the highest plasmid DNA binding capability and transfection efficacy of 88%, higher than those reported for silica-based nanovectors. Moreover, it is shown that the surface spikes of rambutan nanoparticles provide a continuous open space to bind DNA chains via multivalent interactions and protect the gene molecules sheltered in the spiky layer against nuclease degradation, exhibiting no significant transfection decay. This unique protection feature is in great contrast to a commercial transfection agent with similar transfection performance but poor protection capability against enzymatic cleavage. Our study provides new understandings in the rational design of nonviral vectors for efficient gene delivery.

A nanoparticle-assisted signal-enhancement technique for lateral flow immunoassays.

Lateral flow immunoassay (LFIA), an affordable and rapid paper-based detection technology, is employed extensively in clinical diagnosis, environmental monitoring, and food safety analysis. The COVID-19 pandemic underscored the validity and adoption of LFIA in performing large-scale clinical and public health testing. The unprecedented demand for prompt diagnostic responses and advances in nanotechnology have fueled the rise of next-generation LFIA technologies. The utilization of nanoparticles to amplify signals represents an innovative approach aimed at augmenting LFIA sensitivity. This review probes the nanoparticle-assisted amplification strategies in LFIA applications to secure low detection limits and expedited response rates. Emphasis is placed on comprehending the correlation between the physicochemical properties of nanoparticles and LFIA performance. Lastly, we shed light on the challenges and opportunities in this prolific field.

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.

Designing Peptide-Based Nanoinhibitors of Programmed Cell Death Ligand 1 (PD-L1) for Enhanced Chemo-immunotherapy.

The combination of immune checkpoint blockade (ICB) and chemotherapy has shown significant potential in the clinical treatment of various cancers. However, circulating regeneration of PD-L1 within tumor cells greatly limits the efficiency of chemo-immunotherapy and consequent patient response rates. Herein, we report the synthesis of a nanoparticle-based PD-L1 inhibitor (FRS) with a rational design for effective endogenous PD-L1 suppression. The nanoinhibitor is achieved through self-assembly of fluoroalkylated competitive peptides that target PD-L1 palmitoylation. The FRS nanoparticles provide efficient protection and delivery of functional peptides to the cytoplasm of tumors, showing greater inhibition of PD-L1 than nonfluorinated peptidic inhibitors. Moreover, we demonstrate that FRS synergizes with chemotherapeutic doxorubicin (DOX) to boost the antitumor activities via simultaneous reduction of PD-L1 abundance and induction of immunogenic cell death in murine colon tumor models. The nano strategy of PD-L1 regulation present in this study is expected to advance the development of ICB inhibitors and overcome the limitations of conventional ICB-assisted chemo-immunotherapy.

Vertical Orientation Probability Matters for Enhancing Nanoparticle-Macrophage Interaction and Efficient Phagocytosis.

The geometry of nanoparticles has a profound effect on their interactions with macrophages. For an elongated geometry, the well-known curvature-dependent phagocytosis mechanism is still under debate, presumably because another important parameter, the probability of orientation, is overlooked. To verify this hypothesis, it is demonstrated that increasing the probability of the preferred vertical orientation is an efficient strategy to significantly enhance macrophage phagocytosis and uptake. This is achieved via a well-designed hexapod nanoparticle in comparison with a monopod counterpart. The hexapod nanoparticle can achieve ≈100% close-to-vertical orientation, thereby favoring phagocytosis. This discovery provides a new insight into the design of nanomaterials for macrophage-oriented bioapplications.

Tailoring head-tail mesoporous silica nanoparticles for enhanced gene transfection.

Plasmid DNA (pDNA) delivery has attracted extensive research interest due to its great potential in gene therapy. The design of efficient nano-vectors to promote cellular delivery and transfection of gene molecules is the key to success. Compared to conventional nanocarriers with spherical geometry, asymmetric nanoparticles have been well documented showing enhanced cellular uptake and drug delivery capability. However, the impact of asymmetric nanostructures on pDNA binding and following intracellular delivery performance has been less reported. Herein, asymmetric head-tail mesoporous silica nanoparticles (HTMSNs) with tailored tail lengths were synthesized and employed as nano-vectors for pDNA delivery. The nanostructures of HTMSNs were carefully characterized by electron tomography. The pDNA binding, cellular uptake and gene transfection capabilities of engineered asymmetric nanoparticles were compared with symmetric dendritic mesoporous silica nanoparticles (DMSNs). The results showed that the asymmetric morphology of nanoparticles promoted pDNA binding and cell internalization, where HTMSNs-66 with a specific tail length of 66 nm achieved the highest transfection efficiency. This study reveals the impact of asymmetric nanostructure on DNA interaction, and provides guidance in future designs of non-viral nano-vectors for efficient gene delivery.

Nanostructured Organosilica Nitric Oxide Donors Intrinsically Regulate Macrophage Polarization with Antitumor Effect.

Nitric oxide (NO) has many important biological functions; however, it has been a long-standing challenge to utilize the exogenous NO donor itself in the activation of macrophages for cancer immunotherapy. Herein, we report the synthesis of a nanoparticle-based NO delivery platform with a rational design for effective NO delivery and macrophage activation. S-Nitrosothiol (SNO) modified organosilica nanoparticles with a tetrasulfide-containing composition produced a higher level of intracellular NO than their bare silica counterparts in macrophages. Enhanced intracellular delivery of NO resulted in mitochondrial dysfunction and disruption of the tricarboxylic acid cycle, leading to macrophage activation and delayed tumor growth. This study provides insights on intracellularly delivered NO for regulating the polarization of macrophages and cancer immunotherapy.

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.

MnO2 Nanoflowers Induce Immunogenic Cell Death under Nutrient Deprivation: Enabling an Orchestrated Cancer Starvation-Immunotherapy.

MnO2 nanoparticles have been widely employed in cancer immunotherapy, playing a subsidiary role in assisting immunostimulatory drugs by improving their pharmacokinetics and/or creating a favorable microenvironment. Here, the stereotype of the subsidiary role of MnO2 nanoparticles in cancer immunotherapy is challenged. This study unravels an intrinsic immunomodulatory property of MnO2 nanoparticles as a unique nutrient-responsive immunogenic cell death (ICD) inducer, capable of directly modulating immunosurveillance toward tumor cells. MnO2 nanoflowers (MNFs) constructed via a one pot self-assembly approach selectively induce ICD to nutrient-deprived but not nutrient-replete cancer cells, which is confirmed by the upregulated damage associated molecular patterns in vitro and a prophylactic vaccination in vivo. The underlying mechanism of the MNFs-mediated selective ICD induction is likely associated with the concurrently upregulated oxidative stress and autophagy. Built on their unique immunomodulatory properties, an innovative nanomaterials orchestrated cancer starvation-immunotherapy is successfully developed, which is realized by the in situ vaccination with MNFs and vascular disrupting agents that cut off intratumoral nutrient supply, eliciting potent efficacy for suppressing local and distant tumors. These findings open up a new avenue toward biomedical applications of MnO2 materials, enabling an innovative therapeutics paradigm with great clinical significance.

The Role of Dendritic Mesoporous Silica Nanoparticles' Size for Quantum Dots Enrichment and Lateral Flow Immunoassay Performance.

Using dendritic mesoporous silica nanoparticles (DMSNs) for quantum dots (QDs) enrichment and signal amplification is an emerging strategy for improving the detection sensitivity of lateral flow immunoassay (LFIA). In this study, a new and convenient approach is developed to prepare water-dispersible DMSNs-QDs. A series of DMSNs with various diameters (138, 251, 368, and 471 nm) are studied for loading QDs and LFIA applications. The resultant water-dispersible DMSNs-QDs exhibit a high fluorescence retention of 81.8%. The increase in particle size from 138 to 471 nm results in an increase in loading capacity of QDs and a decrease in binding quantity of the DMSNs-QDs in the test line of LFIA. This trade-off leads to an optimal DMSNs-QDs size of 368 nm with a limit of detection reaching 10 pg mL-1 (equivalent to 9.0 × 10-14 m) for the detection of C-reactive protein, which is nearly an order of magnitude more sensitive than the literature. To the best of the authors' knowledge, this study is the first to demonstrate the distinctive role of DMSN's size for QDs enrichment and LFIA. The strategy developed from this work is useful for the rational design of high-quality QDs-based nanoparticles for ultrasensitive detection.