Explore the vast range of titles available.

Inhibited immune response and low levels of delivery restrict starvation cancer therapy efficacy. Here, we report on the co-delivery of glucose oxidase (GOx) and indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan using a metal-organic framework (MOF)-based nanoreactor, showing an amplified release for tumor starvation/oxidation immunotherapy. The nanosystem significantly overcomes the biobarriers associated with tumor penetration and improves the cargo bioavailability owing to the weakly acidic tumor microenvironment-activated charge reversal and size reduction strategy. The nanosystem rapidly disassembles and releases cargoes in response to the intracellular reactive oxygen species (ROS). GOx competitively consumes glucose and generates ROS, further inducing the self-amplifiable MOF disassembly and drug release. The starvation/oxidation combined IDO-blockade immunotherapy not only strengthens the immune response and stimulates the immune memory through the GOx-activated tumor starvation and recruitment of effector T cells, but also effectively relieves the immune tolerance by IDO blocking, remarkably inhibiting the tumor growth and metastasis in vivo. Inhibited immune response and low levels of delivery inhibit starvation cancer therapies. Here, the authors report on the co-delivery of glucose oxidase and IDO inhibitor 1-methyltryptophan using metal organic frameworks and show amplified release in response to starvation therapy along with immune modulatory effects.

cGAS-STING pathway is a key DNA-sensing machinery and emerges as a promising target to overcome the immunoresistance of solid tumors. Here we describe a bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions and β-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn 2+ -anchored mannose-modified BSAs and β-lapachone-loaded ferritins are crosslinked to afford bioresponsive protein nanoassemblies, which dissociate into monodispersive protein units in acidic perivascular tumor microenvironment (TME), thus enabling enhanced tumor penetration and spatiotemporally controlled Mn 2+ and β-lapachone delivery to DCs and tumor cells, respectively. β-lapachone causes immunogenic tumor cell apoptosis and releases abundant dsDNA into TME, while Mn 2+ enhances the sensitivity of cGAS to dsDNA and augments STING signaling to trigger downstream immunostimulatory signals. The cGAS-STING nanoagonist enhances the tumor-specific T cell-mediated immune response against poorly immunogenic solid tumors in vivo, offering a robust approach for immunotherapy in the clinics. Manganese has a crucial role in cGAS-STING-mediated DNA sensing and has emerged as a STING agonist. Here the authors report the design and characterization of a nanosystem incorporating manganese ions and the chemotherapeutic drug β-lapachone, inducing T-cell mediated anti-tumor immune responses in preclinical cancer models.

Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly β-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics. A tumor cell-intrinsic hyperglycolytic state has been associated with immunosuppression and resistance to immune checkpoint blockade in triple negative breast cancer (TNBC). Here the authors describe an aptamer-based nanoassembly for tumor cell selective inhibition of glycolysis combined with bispecific immune checkpoint blockade, promoting anti-tumor immune responses in preclinical TNBC models.

The elimination of senescent cells can enhance the osteointegration of implants in elderly patients. However, achieving specific clearance of senescent cells without adversely affecting the function of normal cells remains challenging. Here we show an implant surface modification technique to achieve specific clearance of locally senescent cells by modulating their metabolism. Our method involve modifying implants with BPTES, a glutaminase 1 (GLS1) inhibitor, through π-π stacking with dopamine. This modification effectively induces intracellular acidosis in senescent mesenchymal stem cells (MSCs) through suppression of glutaminolysis. Simultaneously, poly(γ-glutamate) (PGA), modified by a layer-by-layer method, serve as a high-density carbon source coating, continuously supporting glutamine metabolism in MSCs without ammonia production. Our results show that modified implants significantly reduce the senescence level around implants and promote osteointegration in aged rats. These findings provide promising insights into the design and application of orthopedic implants for elderly patients. Bone repair and osteointegration of implants is more challenging in aging populations, partially due to increasing cellular senescence. Here, Li et al. report a strategy for implant surface modification which targets senescent cells by modulating their metabolism to promote implant osteointegration.

Remote activation of biomarker sensing holds a great promise of shifting the success of in vitro diagnostics to spatiotemporally controlled in vivo visualization of tumor, and in turn, imaging guided therapy. Herein, a “dual-key-one-lock” nanodevice was designed and built by assembling thermo-activatable probe of trimeric DNA hybrids into a mesoporous polydopamine nanoparticle-based multifunctional nanotransducer (probe host, fluorescence quencher, and photothermal conversion agent), enabling precisely switchable theranostic operations under the co-activation of exo/endogenous stimulations (near-infrared (NIR) light and microRNA (miRNA)). By this design, the NIR irradiation-induced local heat through the porous nanotransducer can be transferred to the DNA nanothermometer for triggering the exposure of the miRNA recognition segment, as well as the subsequent fluorescence activation by strand displacement reactions (SDR). A programmable application of short- (3 min) and long-duration (10 min) NIR irradiation was administered sequentially to induce a milder and a stronger hyperthermia, respectively, to activate the localized miRNA imaging, and in turn, tumor thermoablation under the fluorescence guidance in vivo . By reducing nonspecific activation, dual factor co-activatable nanodevices exhibited a high tumor-to-background ratio (TBR) value of 8.9, as well as a significantly lower (6–9-fold) normal tissue fluorescence as compared with those sensing miRNA solely. The in vivo results show that the tumors were significantly suppressed after the photothermal therapy with the assistance of the accurate miRNA diagnosis. This rationally integrated nanoplatform may pave a new avenue for advanced theranostic systems with high spatiotemporal precision by activatable designs.

Ultrasound-responsive nanomaterials represent a promising approach for achieving non-invasive and localized drug delivery within tumor microenvironments. In this study, we developed a piezocatalysis-assisted hydrogel system that integrates reactive oxygen species (ROS) generation with stimulus-responsive drug release. The platform combines piezoelectric barium titanate (BTO) nanoparticles with a ROS-sensitive hydrogel matrix, forming an ultrasound-activated dual-function therapeutic system. Upon ultrasound irradiation, the BTO nanoparticles generate ROS—predominantly hydroxyl radicals (•OH) and singlet oxygen (1O2)—through the piezoelectric effect, which triggers hydrogel degradation and facilitates the controlled release of encapsulated therapeutic agents. The composition and kinetics of ROS generation were evaluated using radical scavenging assays and fluorescence probe techniques, while the drug release behavior was validated under simulated oxidative environments and acoustic fields. Structural and compositional characterizations (TEM, XRD, and XPS) confirmed the quality and stability of the nanoparticles, and cytocompatibility was assessed using 3T3 fibroblasts. This synergistic strategy, combining piezocatalytic ROS generation with hydrogel disintegration, demonstrates a feasible approach for designing responsive nanoplatforms in ultrasound-mediated drug delivery systems.

Macrophages play a central role in immunological responses to metallic species associated with the localized corrosion of metallic implants, and mediating in peri-implant inflammations. Herein, the pathways of localized corrosion-macrophage interactions were systematically investigated on 316L stainless steel (SS) implant metals. Electrochemical monitoring under macrophage-mediated inflammatory conditions showed a decreased pitting corrosion resistance of 316L SSs in the presence of RAW264.7 cells as the cells would disrupt biomolecule adsorbed layer on the metal surface. The pitting potentials were furtherly decreased when the RAW264.7 cells were induced to the M1 pro-inflammatory phenotype by the addition of lipopolysaccharide (LPS), and pitting corrosion preferentially initiated at the peripheries of macrophages. The overproduction of aggressive ROS under inflammatory conditions would accelerate the localized corrosion of 316L SS around macrophages. Under pitting corrosion condition, the viability and pro-inflammatory polarization of RAW264.7 cells were region-dependent, lower viability and more remarkable morphology transformation of macrophages in the pitting corrosion region than the pitting-free region. The pitting corrosion of 316L SS induced high expression of CD86, TNF-α, IL-6 and high level of intracellular ROS in macrophages. Uneven release of metallic species (Fe2+, Cr3+, Ni2+, etc) and uneven distribution of surface overpotential stimulated macrophage inflammatory responses near the corrosion pits. A synergetic effect of localized corrosion and macrophages was revealed, which could furtherly promote localized corrosion of 316L SS and macrophage inflammatory reactions. Our results provided direct evidence of corrosion-macrophage interaction in metallic implants and disclosed the pathways of this mutual stimulation effect. [Display omitted] •Macrophages decreased pitting corrosion resistance of 316 L stainless steel.•Pitting corrosion mediated region-dependent macrophage behavior.•Corrosion-inflammation interaction pathways were revealed.

Postmenopausal osteoporosis (PMOP) is a prevalent condition among elderly women. After menopause, women exhibit decreased iron excretion, which is prone to osteoporosis. To design a specific titanium implant for PMOP, we first analyze miRNAs and DNA characteristics of postmenopausal patients with and without osteoporosis. The results indicate that iron overload disrupts iron homeostasis in the pathogenesis of PMOP. Further experiments confirm that iron overload can cause lipid peroxidation and ferroptosis of MSCs, thus breaking bone homeostasis. Based on the findings above, we have designed a novel Ti implant coated with nanospheres of caffeic acid (CA) and deferoxamine (DFO). CA can bind on the Ti surface through the two adjacent phenolic hydroxyls and polymerize into polycaffeic acid (PCA) dimer, as well as the PCA nanospheres with the repetitive 1,4-benzodioxan units. DFO was grafted with PCA through borate ester bonds. The experimental results showed that modified Ti can inhibit the ferroptosis of MSCs in the pathological environment of PMOP and promote osseointegration in two main ways. Firstly, DFO was released under high oxidative stress, chelating with excess iron and decreasing the labile iron pool in MSCs. Meanwhile, CA and DFO activated the KEAP1/NRF2/HMOX1 pathway in MSCs and reduced the level of intracellular lipid peroxidation. So, the ferroptosis of MSCs is inhibited by promoting the SLC7A11/GSH/GPX4 pathway. Furthermore, the remained CA coating on the Ti surface could reduce the extracellular oxidative stress and glutathione level. This study offers a novel inspiration for the specific design of Ti implants in the treatment of PMOP. In this work, we first analyzed the miRNAs based on the plasma samples of postmenopausal patients with and without osteoporosis. A novel CA nanospheres and DFO film on the Ti implant surface for the regulation of ferroptosis was designed, which can alleviate iron overload and oxidative stress of PMOP and improve the integration ability of bone and implant. This offers a framework for future smart biomaterial design, leveraging disease databases to develop optimal biomaterials for specific pathologies. [Display omitted] •Iron overload disrupts iron homeostasis in the pathogenesis of PMOP.•A novel Ti implant coated with nanospheres of caffeic acid (CA) and deferoxamine (DFO) is designed.•Ti-CA-DFO can inhibit the ferroptosis of MSCs by promoting SLC7A11/GSH/GPX4 pathway in the pathological environment of PMOP.•Ti-CA-DFO can reduce the extracellular oxidative stress and glutathione level.

The high glutathione (GSH) environment poses a significant challenge for inducing ferroptosis in tumor cells, necessitating the development of nanoplatforms that can deplete intracellular GSH. In this study, we developed an engineered nanoplatform (MIL-100@Era/L-Arg-HA) that enhances ferroptosis through gas therapy. First, we confirmed that the Fe element in the nanoplatform undergoes valence changes under the influence of high GSH and H2O2 in tumor cells. Meanwhile, L-Arg generates NO gas in the presence of intracellular H2O2, which reacts with GSH. Additionally, Erastin depletes GSH by inhibiting the cystine/glutamate antiporter system, reducing cystine uptake and impairing GPX4, while also increasing intracellular H2O2 levels by activating NOX4 protein expression. Through these combined GSH-depletion mechanisms, we demonstrated that MIL-100@Era/L-Arg-HA effectively depletes GSH levels, disrupts GPX4 function, and increases intracellular lipid ROS levels in vitro. Furthermore, this nanoplatform significantly inhibited tumor cell growth and extended the survival time of tumor-bearing mice in vivo. This engineered nanoplatform, which enhances ferroptosis through gas therapy, shows significant promise for ferroptosis-based cancer therapy and offers potential strategies for clinical tumor treatment. [Display omitted] •The nanoplatform uses Fe to deplete GSH for activating ferroptosis, and produces NO to enhance GSH depletion and ferroptosis.•Erastin increases H2O2 levels and reduces cysteine uptake, accelerating GSH depletion and ferroptosis.•The nanoplatform depletes intracellular GSH through multiple pathways to activate ferroptosis.

The rheumatoid arthritis (RA) microenvironment is often followed by a vicious circle of high inflammation, endogenous gas levels imbalance, and poor treatment. To break the circle, we develop a dual-gas-mediated injectable hydrogel for modulating the immune microenvironment of RA and simultaneously releasing therapeutic drugs. The hydrogel (DNRS gel) could be broken down on-demand by consuming excessive nitric oxide (NO) and releasing therapeutic hydrogen sulfide (H2S), resulting in endogenous gas restoration, inflammation alleviation, and macrophage polarization to M2 type. Additionally, the hydrogel could suppress osteoclastogenesis and enhance osteogenesis. Furthermore, the intra-articularly injected hydrogel with methotrexate (MTX/DNRS gel) significantly alleviated inflammation and clinical symptoms and promoted the repair of bone erosion in the collagen-induced arthritis rat model. As a result, in vivo results demonstrated that MTX/DNRS gel restored the microenvironment and improved the therapeutic effect of MTX. This study provides a novel understanding of developing versatile smart delivery platforms for RA treatment. A self-healing injectable DNRS gel was fabricated with metal-free click reaction for remodeling the inflammatory microenvironment of rheumatoid arthritis, which could deplete excessive NO and release anti-inflammatory H2S while releasing MTX. Finally, the MTX/DNRS gel could efficiently break the vicious circle of the RA microenvironment, relieving the inflammation, and paving the way for the healing of bone erosion. [Display omitted] •Injectable hydrogel depleted overproduced NO and released anti-inflammatory H2S.•The endogenous gas-inflammation-bone metabolic homeostasis relationship was revealed.•Hydrogel alleviated the symptoms on the CIA model and reduced the total number of injections.