Ultrasound-Triggered Azo Free Radicals for Cervical Cancer Immunotherapy.

PD-1 blockade is a first-line treatment for recurrent/metastatic cervical cancer but benefits only a small number of patients due to low preexisting tumor immunogenicity. Using immunogenic cell death (ICD) inducers is a promising strategy for improving immunotherapy, but these compounds are limited by the hypoxic environment of solid tumors. To overcome this issue, the nanosensitizer AIBA@MSNs were designed based on sonodynamic therapy (SDT), which induces tumor cell death under hypoxic conditions through azo free radicals in a method of nonoxygen radicals. Mechanistically, the azo free radicals disrupt both the structure and function of tumor mitochondria by reversing the mitochondrial membrane potential and facilitating the collapse of electron transport chain complexes. More importantly, the AIBA@MSN-based SDT serves as an effective ICD inducer and improves the antitumor immune capacity. The combination of an AIBA@MSN-based SDT with a PD-1 blockade has the potential to improve response rates and provide protection against relapse. This study provides insights into the use of azo free radicals as a promising SDT strategy for cancer treatment and establishes a basic foundation for nonoxygen-dependent SDT-triggered immunotherapy in cervical cancer treatment.

Anti-inflammatory and anti-oxidative electrospun nanofiber membrane promotes diabetic wound healing via macrophage modulation.

BACKGROUND: In the inflammatory milieu of diabetic chronic wounds, macrophages undergo substantial metabolic reprogramming and play a pivotal role in orchestrating immune responses. Itaconic acid, primarily synthesized by inflammatory macrophages as a byproduct in the tricarboxylic acid cycle, has recently gained increasing attention as an immunomodulator. This study aims to assess the immunomodulatory capacity of an itaconic acid derivative, 4-Octyl itaconate (OI), which was covalently conjugated to electrospun nanofibers and investigated through in vitro studies and a full-thickness wound model of diabetic mice. RESULTS: OI was feasibly conjugated onto chitosan (CS), which was then grafted to electrospun polycaprolactone/gelatin (PG) nanofibers to obtain P/G-CS-OI membranes. The P/G-CS-OI membrane exhibited good mechanical strength, compliance, and biocompatibility. In addition, the sustained OI release endowed the nanofiber membrane with great antioxidative and anti-inflammatory activities as revealed in in vitro and in vivo studies. Specifically, the P/G-CS-OI membrane activated nuclear factor-erythroid-2-related factor 2 (NRF2) by alkylating Kelch-like ECH-associated protein 1 (KEAP1). This antioxidative response modulates macrophage polarization, leading to mitigated inflammatory responses, enhanced angiogenesis, and recovered re-epithelization, finally contributing to improved healing of mouse diabetic wounds. CONCLUSIONS: The P/G-CS-OI nanofiber membrane shows good capacity in macrophage modulation and might be promising for diabetic chronic wound treatment.

Nanoscale Metal-Organic Frameworks-Mediated Degradation of Mutant p53 Proteins and Activation of cGAS-STING Pathway for Enhanced Cancer Immunotherapy.

Activating cGAS-STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance of the cGAS-STING pathway. Herein, multifunctional ZIF-8@MnO2 nanoparticles are constructed to degrade mutp53 and facilitate the cGAS-STING pathway. The synthesized ZIF-8@MnO2 can release Zn2+ and Mn2+ in cancer cells to induce oxidative stress and cytoplasmic leakage of fragmented mitochondrial double-stranded DNAs (dsDNAs). Importantly, the released Zn2+ induces variable degradation of multifarious p53 mutants through proteasome ubiquitination, which can alleviate the inhibitory effects of mutp53 on the cGAS-STING pathway. In addition, the released Mn2+ further increases the sensitivity of cGAS to dsDNAs as immunostimulatory signals. Both in vitro and in vivo results demonstrate that ZIF-8@MnO2 effectively promotes the cGAS-STING pathway and synergizes with PD-L1 checkpoint blockades, leading to remarkable regression of local tumors as well as distant metastases of breast cancer. This study proposes an inorganic metal ion-based nanoplatform to enhance the cGAS-STING-mediated antitumor immunotherapy, especially to those tumors with mutp53 expression.

Magnetic resonance imaging with upconversion nanoprobes capable of crossing the blood-cerebrospinal fluid barrier.

The central nervous system (CNS) maintains homeostasis with its surrounding environment by restricting the ingress of large hydrophilic molecules, immune cells, pathogens, and other external harmful substances to the brain. This function relies heavily on the blood-cerebrospinal fluid (B-CSF) and blood-brain barrier (BBB). Although considerable research has examined the structure and function of the BBB, the B-CSF barrier has received little attention. Therapies for disorders associated with the central nervous system have the potential to benefit from targeting the B-CSF barrier to enhance medication penetration into the brain. In this study, we synthesized a nanoprobe ANG-PEG-UCNP capable of crossing the B-CSF barrier with high targeting specificity using a hydrocephalus model for noninvasive magnetic resonance ventriculography to understand the mechanism by which the CSF barrier may be crossed and identify therapeutic targets of CNS diseases. This magnetic resonance nanoprobe ANG-PEG-UCNP holds promising potential as a safe and effective means for accurately defining the ventricular anatomy and correctly locating sites of CSF obstruction.

Molybdenum Nanodots for Acute Lung Injury Therapy.

Acute respiratory disease syndrome (ARDS) is a common critical disease with high morbidity and mortality rates, yet specific and effective treatments for it are currently lacking. ARDS was especially apparent and rampant during the COVID-19 pandemic. Excess reactive oxygen species (ROS) production and an uncontrolled inflammatory response play a critical role in the disease progression of ARDS. Herein, we developed molybdenum nanodots (MNDs) as a functional nanomaterial with ultrasmall size, good biocompatibility, and excellent ROS scavenging ability for the treatment of acute lung injury (ALI). MNDs, which were administered intratracheally, significantly ameliorated lung oxidative stress, inflammatory response, protein permeability, and histological severity in ALI mice without inducing any safety issues. Importantly, transcriptomics analysis indicated that MNDs protected lung tissues by inhibiting the activation of the Nod-like receptor protein 3 (NLRP3)-dependent pyroptotic pathway. This work presents a promising therapeutic agent for patients suffering from ARDS.

Tungsten-based nanoparticles as contrast agents for liver tumor detection using dual-energy computed tomography.

Dual-energy computed tomography (DECT) is a commonly used imaging technique for detecting and diagnosing liver cancer. Currently, it is performed using clinically approved iodinated small molecule contrast agents (CAs). However, these iodinated CAs have several drawbacks, including sub-optimal contrast generation and contra-indication in patients with renal insufficiency. Herein, we synthesized tungsten-based CAs (i.e., WO3-x NPs) with excellent biocompatibility and investigated their effectiveness in DECT imaging. WO3-x NPs significantly enhanced the contrast between liver tumors and normal liver tissues as indicated by in vivo DECT imaging. Furthermore, WO3-x NPs exhibited excellent biocompatibility and minimal systemic toxicity. This study introduces a novel class of CAs for DECT and presents a promising method for accurate early diagnosis of liver tumors.

Flexible multilevel nonvolatile biocompatible memristor with high durability.

Current protein or glucose based biomemristors have low resistance-switching performance and require complex structural designs, significantly hindering the development of implantable memristor devices. It is imperative to discover novel candidate materials for biomemristor with high durability and excellent biosafety for implantable health monitoring. Herein, we initially demonstrate the resistance switching characteristics of a nonvolatile memristor in a configuration of Pt/AlOOH/ITO consisting of biocompatible AlOOH nanosheets sandwiched between a Indium Tin Oxides (ITO) electrode and a platinum (Pt) counter-electrode. The hydrothermally synthesized AlOOH nanosheets have excellent biocompatibility as confirmed through the Cell Counting Kit-8 (CCK-8) tests. Four discrete resistance levels are achieved in this assembled device in responsible to different compliance currents (ICC) for the set process, where the emerging multilevel states show high durability over 103 cycles, outperforming the protein-based biomemristors under similar conditions. The excellent performance of the Pt/AlOOH/ITO memristor is attributed to the significant role of hydrogen proton with pipe effect, as confirmed by both experimental results and density functional theory (DFT) analyses. The present results indicate the nonvolatile memristors with great potential as the next generation implantable multilevel resistive memories for long-term human health monitoring.

A general method for endowing hydrophobic nanoparticles with water dispersion abilities.

Inorganic nanoparticles with long-chain ligands are usually hydrophobic. However, simple and practical methods for converting hydrophobic nanoparticles to hydrophilic nanoparticles are still lacking. Herein, we developed a general method involving using dimercaptosuccinic acid (DMSA) for endowing hydrophobic nanoparticles with water dispersion abilities. By mixing a tetrahydrofuran solution of DMSA with a cyclohexane solution of hydrophobic nanoparticles, the long-chain ligands were replaced with DMSA, with the replacement due to the strong and broad-spectrum coordination abilities of sulphydryls and carboxyls. Four representative kinds of hydrophobic nanoparticles, namely Ag, NaGdF4, TiO2, and ZnS nanoparticles, were selected for verifying the performance of this DMSA-based modification method. Meanwhile, this method can also widen the applications of hydrophobic nanoparticles and facilitate their being subjected to further graft modifications. We hope that our research will increase the chances for applications of nanomaterials to be made.

Regulating electron transportation by tungsten oxide nanocapacitors for enhanced radiation therapy.

In the process of radiation therapy (RT), the cytotoxic effects of excited electrons generated from water radiolysis tend to be underestimated due to multiple biochemical factors, particularly the recombination between electrons and hydroxyl radicals (·OH). To take better advantage of radiolytic electrons, we constructed WO3 nanocapacitors that reversibly charge and discharge electrons to regulate electron transportation and utilization. During radiolysis, WO3 nanocapacitors could contain the generated electrons that block electron-·OH recombination and contribute to the yield of ·OH at a high level. These contained electrons could be discharged from WO3 nanocapacitors after radiolysis, resulting in the consumption of cytosolic NAD+ and impairment of NAD+-dependent DNA repair. Overall, this strategy of nanocapacitor-based radiosensitization improves the radiotherapeutic effects by increasing the utilization of radiolytic electrons and ·OH, warranting further validation in multiple tumour models and preclinical experiments.

Urchin-like ceria nanoparticles for enhanced gene therapy of osteoarthritis.

Osteoarthritis (OA) is the most common degenerative joint disease in the world. Gene therapy based on delivering microRNAs (miRNAs) into cells has potential for the treatment of OA. However, the effects of miRNAs are limited by the poor cellular uptake and stability. Here, we first identify a type of microRNA-224-5p (miR-224-5p) from clinical samples of patients with OA that can protect articular cartilage from degeneration and further synthesize urchin-like ceria nanoparticles (NPs) that can load miR-224-5p for enhanced gene therapy of OA. Compared with traditional sphere ceria NPs, the thorns of urchin-like ceria NPs can efficiently promote the transfection of miR-224-5p. In addition, urchin-like ceria NPs have excellent performance of scavenging reactive oxygen species (ROS), which can regulate the microenvironment of OA to further improve the gene treatment of OA. The combination of urchin-like ceria NPs and miR-224-5p not only exhibits favorable curative effect for OA but also provides a promising paradigm for translational medicine.

Spectral computed tomography-guided radiotherapy of osteosarcoma utilizing BiOI nanosheets.

As an aggressive malignant bone tumor, osteosarcoma (OS) is usually found in children and adolescents. Computed tomography (CT) is an important tool for the clinical evaluation of osteosarcoma, but limits to low diagnostic specificity due to single parameters of traditional CT and modest signal-to-noise ratio of clinical iodinated contrast agents. As one kind of spectral CT, dual-energy CT (DECT), with the advantage of a provision of multi-parameter information, makes it possible to acquire the best signal-to-noise ratio image, accurate detection, as well as imaging-guided therapy of bone tumors. Hereby, we synthesized BiOI nanosheets (BiOI NSs) as a DECT contrast agent with superior imaging capability compared to iodine agents for clinical detection of OS. Meanwhile, the synthesized BiOI NSs with great biocompatibility is able to achieve effective radiotherapy (RT) by enhancing X-ray dose deposition at the tumor site, leading to DNA damage, which in turn inhibits tumor growth. This study offers a promising new avenue for DECT imaging-guided treatment of OS. STATEMENT OF SIGNIFICANCE: Osteosarcoma (OS) is a common primary malignant bone tumor. Traditional surgical procedures and conventional CT scans are often used for the treatment and monitoring of OS, but the effects are generally unsatisfactory. In this work, BiOI nanosheets (NSs) was reported for dual-energy CT (DECT) imaging-guided OS radiotherapy. The powerful and constant X-ray absorption of BiOI NSs at any energy guarantees excellent enhanced DECT imaging performance, allowing detailed visualization of OS through images with a better signal-to-noise ratio and guiding radiotherapy process. The deposition of X-rays could be greatly enhanced by Bi atoms to induce serious DNA damage in radiotherapy. Taken together, the BiOI NSs for DECT-guided radiotherapy will greatly improve the current treatment status of OS.

Interfering biosynthesis by nanoscale metal-organic frameworks for enhanced radiation therapy.

Radiation therapy (RT) is one of the most widely used cancer treatments. However, the vigorous biosynthesis of cancer cells plays an important role for RT resistance. Herein, we develop a hafnium-based nanoscale metal-organic frameworks (Hf-nMOFs) loaded with 3-bromopyruvate (3-BrPA) to overcome RT resistance and achieve favorable RT efficacy. The deposition of X-rays is greatly enhanced by Hf-nMOFs to induce stronger damage to DNA in RT. Simultaneously, as an inhibitor of glycolysis, the loaded 3-BrPA can reduce the supply of energy and interfere with the biosynthesis of proteins to decrease the DNA damage repair. As a result, the 3-BrPA@Hf-nMOFs (BHT) will overcome the RT resistance and enhance the curative effect of RT. Up and down-regulated genes as well as the related pathways in cellular metabolism and biosynthesis are well investigated to reveal the radiosensitization mechanism of BHT. In addition, the Hf element endows BHT with CT imaging capability to real-timely monitor the therapeutic process. Hence, the designed strategy of biosynthesis-targeted radiosensitization could decrease the doses of ionizing radiations and provide fresh perspectives on cancer treatment.

Nanostructured polyvinylpyrrolidone-curcumin conjugates allowed for kidney-targeted treatment of cisplatin induced acute kidney injury.

Acute kidney injury (AKI) leads to unacceptably high mortality due to difficulties in timely intervention and less efficient renal delivery of therapeutic drugs. Here, a series of polyvinylpyrrolidone (PVP)-curcumin nanoparticles (PCurNP) are designed to meet the renal excretion threshold (∼45 kDa), presenting a controllable delivery nanosystem for kidney targeting. Renal accumulation of the relatively small nanoparticles, 89Zr-PCurNP M10 with the diameter between 5 and 8 nm, is found to be 1.7 times and 1.8 times higher than the accumulation of 89Zr-PCurNP M29 (20-50 nm) and M40 (20-50 nm) as revealed by PET imaging. Furthermore, serum creatinine analysis, kidney tissues histology, and tubular injury scores revealed that PCurNP M10 efficiently treated cisplatin-induced AKI. Herein, PCurNP offers a novel and simple strategy for precise PET image-guided drug delivery of renal protective materials.

Engineered nanodrug targeting oxidative stress for treatment of acute kidney injury.

Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid decline in renal function, and is associated with a high risk of death. Many pathological changes happen in the process of AKI, including crucial alterations to oxidative stress levels. Numerous efforts have thus been made to develop effective medicines to scavenge excess reactive oxygen species (ROS). However, researchers have encountered several significant challenges, including unspecific biodistribution, high biotoxicity, and in vivo instability. To address these problems, engineered nanoparticles have been developed to target oxidative stress and treat AKI. This review thoroughly discusses the methods that empower nanodrugs to specifically target the glomerular filtration barrier and presents the latest achievements in engineering novel ROS-scavenging nanodrugs in clustered sections. The analysis of each study's breakthroughs and imperfections visualizes the progress made in developing effective nanodrugs with specific biodistribution and oxidative stress-targeting capabilities. This review fills the blank of a comprehensive outline over current progress in applying nanotechnology to treat AKI, providing potential insights for further research.

Lactic acid modified rare earth-based nanomaterials for enhanced radiation therapy by disturbing the glycolysis.

Deficient deposition of X-rays and strong capacity of repairing damage DNA of cancer cells limit the effect of radiation therapy (RT). Herein, we synthesize CsLu2F7 nanoparticles with lactic acid (LA) ligands (CsLu2F7-LA) to overcome these limitations. The high-Z atoms of Lu and Cs can deposit more X-rays for generating enhanced hydroxyl radicals (·OH). Meanwhile, the LA ligand will guide CsLu2F7-LA to target monocarboxylic acid transporter (MCT) and impede the transportation of free LA, leading to decreased glycolysis and DNA damage repair. Consequently, the curative effect of RT will be enhanced and the strategy of LA accumulation induced radiosensitization is proved by in vivo and in vitro experiments, which will bring prospects for enhanced RT with nanomedicine.

Oral zero-valent-molybdenum nanodots for inflammatory bowel disease therapy.

Inflammatory bowel disease (IBD) affects millions of people each year. The overproduction of reactive oxygen species (ROS) plays a critical role in the progress of IBD and will be a potential therapeutic target. Here, we synthesize a kind of oral zero-valent-molybdenum nanodots (ZVMNs) for the treatment of IBD by scavenging ROS. These ultrasmall ZVMNs can successfully pass through the gastric acid and then be absorbed by the intestine. It has been verified that ZVMNs can down-regulate the quantity of ROS and reduce colitis in a mouse IBD model without distinct side effects. In addition, RNA sequencing reveals a further mechanism that the ZVMNs can protect colon tissues from oxidative stress by inhibiting the nuclear factor κB signaling pathway and reducing the production of excessive pro-inflammatory factors. Together, the ZVMNs will offer a promising alternative treatment option for patients suffering from IBD.

Spectral computed tomography with inorganic nanomaterials: State-of-the-art.

Recently, spectral computed tomography (CT) technology has received great interest in the field of radiology. Spectral CT imaging utilizes the distinct, energy-dependent X-ray absorption properties of substances in order to provide additional imaging information. Dual-energy CT and multi-energy CT (Spectral CT) are capable of constructing monochromatic energy images, material separation images, energy spectrum curves, constructing effective atomic number maps, and more. However, poor contrast, due to neighboring X-ray attenuation of organs and tissues, is still a challenge to spectral CT. Hence, contrast agents (CAs) are applied for better differentiation of a given region of interest (ROI). Currently, many different kinds of inorganic nanoparticulate CAs for spectral CT have been developed due to the limitations of clinical iodine (I)-based contrast media, leading to the conclusion that inorganic nanomedicine applied to spectral CT will be a powerful collaboration both in basic research and in clinics. In this review, the underlying principles and types of spectral CT techniques are discussed, and some evolving clinical diagnosis applications of spectral CT techniques are introduced. In particular, recent developments in inorganic CAs used for spectral CT are summarized. Finally, the challenges and future developments of inorganic nanomedicine in spectral CT are briefly discussed.

Chemical Factory-Guaranteed Enhanced Chemodynamic Therapy for Orthotopic Liver Cancer.

In the field of nanomedicine, there is a tendency of matching designed nanomaterials with a suitable type of orthotopic cancer model, not just a casual subcutaneous one. Under this condition, knowing the specific features of the chosen cancer model is the priority, then introducing a proper therapy strategy using designed nanomaterials. Here, the Fenton chemistry is combined with zinc peroxide nanoparticles in the treatment of orthotopic liver cancer which has a "chemical factory" including that liver is the main place for iron storage, metabolism, and also the main metabolic sites for the majority of ingested substances, guaranteeing customized and enhanced chemodynamic therapy and normal liver cells protection as well. The good results in vitro and in vivo can set an inspiring example for exploring and utilizing suitable nanomaterials in corresponding cancer models, ensuring well-fitness of nanomaterials for disease and satisfactory therapeutic effect.

Acid Neutralization and Immune Regulation by Calcium-Aluminum-Layered Double Hydroxide for Osteoporosis Reversion.

Osteoporosis is a kind of global chronic bone disease characterized by progressive loss of bone mass and bone quality reduction, leading to a largely increased risk of bone fragility. In clinics, the current treatment of osteoporosis relies on the inhibition of bone damage by osteoclasts but ignores the function of immune cells in the progress of osteoporosis, leading to much compromised therapeutic efficacy. In this work, a highly effective osteoporosis-immunotherapeutic modality is established for the treatment of osteoporosis based on acid neutralization in synergy with immune microenvironment regulation by a specially designed nanocatalytic medicine, calcein functionalized calcium-aluminum-layered double hydroxide (CALC) nanosheets. Briefly, the mildly alkaline CALC nanosheets could neutralize the acidic microenvironment of osteoporosis accompanying the acidity-responsive LDH degradation. Subsequently, calcium phosphate nanoparticles (CAPs) are generated by the reaction between the released Ca2+ from LDH degradation and endogenous phosphates, resulting in M2 phenotype anti-inflammatory differentiation of bone macrophages through a c-Maf transcriptional factor pathway and the following activity enhancements of regulatory T cells (Treg) and the deactivation of T helper 17 cells (TH17). Both in vitro and in vivo results show an excellent therapeutic efficacy on osteoporosis featuring a significant BV/TV (%) enhancement of femurs from 6.2 to 10.7, demonstrating high feasibility of this therapeutic concept through the combined acid neutralization and immune regulation. Such an inorganic nanomaterial-based strategy provides a novel, efficient, and biosafe therapeutic modality for intractable osteoporosis treatment, which will benefit patients suffering from osteoporosis.

High relaxivity Gd3+-based organic nanoparticles for efficient magnetic resonance angiography.

Contrast-enhanced MR angiography (MRA) is a critical technique for vascular imaging. Nevertheless, the efficacy of MRA is often limited by the low rate of relaxation, short blood-circulation time, and metal ion-released potential long-term toxicity of clinical available Gd-based contrast agents. In this work, we report a facile and efficient strategy to achieve Gd-chelated organic nanoparticles with high relaxivity for T1-weighted MRA imaging. The Gd-chelated PEG-TCPP nanoparticles (GPT NPs) have been engineered composite structured consisting of Gd-chelated TCPP and PEG. The spherical structure of TCPP offers more chemical sites for Gd3+ coordination to improve the relaxivity and avoid leakage of the Gd3+ ions. The synthesized GPT NPs exhibit a high relaxation rate of 35.76 mM- 1 s- 1 at 3.0 T, which is higher than the rates for most reported MR contrast agents. Therefore, GPT NPs can be used for MRA with much stronger vascular signals, longer circulation time, and high-resolution arterial vascular visualization than those using clinical MR contrast agents at the same dose. This work may make the T1 MRI contrast agents for high-resolution angiography possible and offer a new candidate for preclinical and clinical applications of MR vascular imaging and vascular disease diagnosis.