Liquid exfoliation of molybdenum metallenes for non-inflammatory photothermal therapy of tumors.

Tissue damage and cell death occurring during photothermal therapy (PTT) for tumors can induce an inflammatory response that is detrimental to tumor therapy. Herein, ultrathin Mo metallene nanosheets with a thickness of <5 nm prepared by liquid phase exfoliation were explored as functional hyperthermia agents for non-inflammatory ablation of tumors. The obtained Mo metallene nanosheets exhibited good photothermal conversion properties and significant reactive oxygen species (ROS) scavenging ability, thus achieving superior cancer cell ablation and anti-inflammatory effects in vitro. For in vivo experiments, 4T1 tumors were ablated while the inflammation-related cytokine levels did not obviously increase, demonstrating that the inflammatory response induced by PTT was inhibited by the anti-inflammatory properties of Mo metallene nanosheets. Moreover, Mo metallene nanosheets depicted good dispersibility and biocompatibility, beneficial for biomedical applications. This work introduces Mo metallenes as promising hyperthermia agents for non-inflammatory PTT of tumors.

Rhodium-Rhenium Alloy Nanozymes for Non-inflammatory Photothermal Therapy.

Analogous to thermal ablation techniques in clinical settings, cell necrosis induced during tumor photothermal therapy (PTT) can provoke an inflammatory response that is detrimental to the treatment of tumors. In this study, we employed a straightforward one-step liquid-phase reduction process to synthesize uniform RhRe nanozymes with an average hydrodynamic size of 41.7 nm for non-inflammatory photothermal therapy. The obtained RhRe nanozymes showed efficient near-infrared (NIR) light absorption for effective PTT, coupled with a remarkable capability to scavenge reactive oxygen species (ROS) for anti-inflammatory treatment. After laser irradiation, the 4T1 tumors were effectively ablated without obvious tumor recurrence within 14 days, along with no obvious increase in pro-inflammatory cytokine levels. Notably, these RhRe nanozymes demonstrated high biocompatibility with normal cells and tissues, both in vitro and in vivo, as evidenced by the lack of significant toxicity in female BALB/c mice treated with 10 mg/kg of RhRe nanozymes over a 14 day period. This research highlights RhRe alloy nanoparticles as bioactive nanozymes for non-inflammatory PTT in tumor therapy.

Minimally Invasive Delivery of Percutaneous Ablation Agent via Magnetic Colloidal Hydrogel Injection for Treatment of Hepatocellular Carcinoma.

Percutaneous thermotherapy, a minimally invasive operational procedure, is employed in the ablation of deep tumor lesions by means of target-delivering heat. Conventional thermal ablation methods, such as radiofrequency or microwave ablation, to a certain extent, are subjected to extended ablation time as well as biosafety risks of unwanted overheating. Given its effectiveness and safety, percutaneous thermotherapy gains a fresh perspective, thanks to magnetic hyperthermia. In this respect, an injectable- and magnetic-hydrogel-construct-based thermal ablation agent is likely to be a candidate for the aforementioned clinical translation. Adopting a simple and environment-friendly strategy, a magnetic colloidal hydrogel injection is introduced by a binary system comprising super-paramagnetic Fe3O4 nanoparticles and gelatin nanoparticles. The colloidal hydrogel constructs, unlike conventional bulk hydrogel, can be easily extruded through a percutaneous needle and then self-heal in a reversible manner owing to the unique electrostatic cross-linking. The introduction of magnetic building blocks is exhibited with a rapid magnetothermal response to an alternating magnetic field. Such hydrogel injection is capable of generating heat without limitation of deep penetration. The materials achieve outstanding therapeutic results in mouse and rabbit models. These findings constitute a new class of locoregional interventional thermal therapies with minimal collateral damages.

2D Is Better: Engineering Polydopamine into Cationic Nanosheets to Enhance Anti-Inflammatory Capability.

Polydopamine nanomaterials have emerged as one of the most popular organic materials for the management of oxidative stress-mediated inflammatory diseases. However, their current anti-inflammatory ability is still unsatisfactory because of limited phenolic hydroxyl groups, and oxidation reaction-medicated reactive oxygen and nitrogen species (RONS) scavenging. Herein, via fusing dimension engineering and surface charge engineering, 2D cationic polydopamine nanosheets (PDA NSs) capable of scavenging multiple danger signals to enhance anti-inflammatory capability are reported. Compared with conventional spherical polydopamine nanoparticles, 2D PDA NSs exhibit three- to fourfold enhancement in RONS scavenging capability, which should be attributed to high specific surface area and abundant phenol groups of 2D ultrathin structure. To further enhance the anti-inflammatory ability, polylysine molecules are absorbed on the surface of PDA NSs to endow the scavenging capability of cell-free DNA (cfDNA), another typical inflammatory factor to exacerbate the pathogenesis of inflammation. Molecular mechanisms reveal that cationic PDA NSs can concurrently activate Keap1-Nrf2 and block TLR9 signaling pathway, achieving synergistical inflammation inhibition. As a proof of concept, cationic PDA NSs with RONS and cfDNA dual-scavenging capability effectively alleviate the inflammatory bowel disease in both delayed and prophylactic models, much better than the clinical drug 5-aminosalicylic acid.

Silver Nanowire Reinforced Conductive and Injectable Colloidal Gel for Effective Wound Healing via Electrical Stimulation.

The remarkable biocapacity, injectability, and adaptability of colloidal gels have led to their widespread usage in tissue engineering as irregular defect implants. However, multifunctionalities including electroconductivity and antibacterial property are highly required for colloidal gels. In addition, the inherently weak mechanical property of physically crosslinked colloidal gels limits their application. Herein, we present Ag nanowires (Ag NWs)-reinforced colloidal gels composed of biocompatible gelatin nanoparticles and polydopamine-modified Ag NWs through the controlled electrostatic assembly, which are injectable and conductive. One-dimensional Ag NWs can significantly improve the mechanical and electrical properties of the colloidal gel while maintaining its inherent excellent injectability. Owing to the network of Ag NWs, the storage modulus and conductivity of the optimized Ag NW colloidal gel are 7.5 and 13 times higher, respectively, than those of the colloidal gel made up of polydopamine-modified Ag nanoparticles with equivalent Ag concentration. Furthermore, this Ag NW colloidal gel can adapt to sharp wounds on skin, which accelerates the healing of a MRSA-infected wound via electrical stimulation. This article is protected by copyright. All rights reserved.

Activatable probes with potential for intraoperative tumor-specific fluorescence-imaging guided surgery.

Owing to societal development and aging population, the impact of cancer on human health and quality of life has increased. Early detection and surgical treatment are the most effective approaches for most cancer patients. As the scope of conventional tumor resection is determined by auxiliary examination and surgeon experience, there is often insufficient recognition of tiny tumors. The ability to detect such tumors can be improved by using fluorescent tumor-specific probes for surgical navigation. This review mainly describes the design principles and mechanisms of activatable probes for the fluorescence imaging of tumors. This type of probe is nonfluorescent in normal tissue but exhibits obvious fluorescence emission upon encountering tumor-specific substrates, such as enzymes or bioactive molecules, or changes in the microenvironment, such as a low pH. In some cases, a single-factor response does not guarantee the effective fluorescence labeling of tumors. Therefore, two-factor-activatable fluorescence imaging probes that react with two specific factors in tumor cells have also been developed. Compared with single biomarker testing, the simultaneous monitoring of multiple biomarkers may provide additional insight into the role of these substances in cancer development and aid in improving the accuracy of early cancer diagnosis. Research and progress in this field can provide new methods for precision medicine and targeted therapy. The development of new approaches for early diagnosis and treatment can effectively improve the prognosis of cancer patients and help enhance their quality of life.

Chiral Sulfur Nanosheets for Dual-Selective Inhibition of Gram-Positive Bacteria.

Elemental sulfur is the oldest known antimicrobial agent. However, conventional sulfur in the clinic suffers from poor aqueous solubility and limited antibacterial activity, greatly hindering its practical use. Herein, we report a reform strategy coupling dimension engineering with chirality transfer to convert conventional 3D sulfur particles into chiral 2D sulfur nanosheets (S-NSs), which exhibit 50-fold improvement of antibacterial capability and dual-selective inhibition against Gram-positive bacteria. Benefiting from the inherent selectivity of S-NSs and chirality selectivity from decorated d-histidine, the obtained chiral S-NSs are proven to precisely kill Gram-positive drug-resistant bacteria, while no obvious bacterial inhibition is observed for Gram-negative bacteria. Mechanism studies reveal that S-NSs produce numerous reactive oxygen specipoes and hydrogen sulfide after incubation with bacteria, thus causing bacterial membrane destruction, respiratory chain damage, and ATP production inhibition. Upon spraying chiral S-NSs dispersions onto MRSA-infected wounds, the skin healing process was greatly accelerated in 8 days due to metabolism inhibition and oxidative damage of bacteria, indicating the excellent treatment efficiency of MRSA-infected wounds. This work converts the traditional well-known sulfur into modern antibacterial agents with a superior Gram-selectivity bactericidal capability.

Anti-Her2 affibody-decorated arsenene nanosheets induce ferroptosis through depleting intracellular GSH to overcome cisplatin resistance.

Ferroptosis, a form of regulated cell death induced by excessive accumulation of reactive oxygen species and lipid peroxidation, has recently attracted extensive attention due to its ability to effectively suppress tumors and overcome drug resistance. Unlike previously reported metal nanomaterials that induce ferroptosis via the Fenton reaction, arsenene nanosheets can effectively deplete intracellular glutathione and then induce ferroptosis by inhibiting glutathione peroxidase 4. In this study, we designed target-modified arsenene nanosheets loaded with cisplatin (Her2-ANs@CDDP), which are capable of selective uptake by tumor cells. Her2-ANs@CDDP promotes both apoptosis and ferroptosis through a reciprocal cascade reaction between cisplatin and the carrier, respectively, and we demonstrate that it can significantly inhibit the activity of drug-resistant cells. Arsenene nanosheets kill drug-resistant tumor cells by inducing ferroptosis and restoring the sensitivity of drug-resistant cells to cisplatin. Cisplatin-loaded arsenene nanosheets can be prepared simply, and exert synergistic effects that overcome drug resistance. They show great potential for applications in the clinical treatment of chemotherapy-insensitive osteosarcoma, expanding the uses of arsenic in the treatment of solid tumors.

Synthetic nanoparticles for the delivery of CRISPR/Cas9 gene editing system: classification and biomedical applications.

Gene editing has great potential in biomedical research including disease diagnosis and treatment. Clustered regularly interspaced short palindromic repeats (CRISPR) is the most straightforward and cost-effective method. The efficient and precise delivery of CRISPR can impact the specificity and efficacy of gene editing. In recent years, synthetic nanoparticles have been discovered as effective CRISPR/Cas9 delivery vehicles. We categorized synthetic nanoparticles for CRISPR/Cas9 delivery and discribed their advantages and disadvantages. Further, the building blocks of different kinds of nanoparticles and their applications in cells/tissues, cancer and other diseases were described in detail. Finally, the challenges encountered in the clinical application of CRISPR/Cas9 delivery materials were discussed, and potential solutions were provided regarding efficiency and biosafety issues.

Emerging metallenes: synthesis strategies, biological effects and biomedical applications.

Metallenes, atomically thin-layered materials composed of coordination-deficient metal atoms, have emerged as a new category of two-dimensional materials. Metallenes exhibit exciting properties with a fusion of atom economy, ultrathin structure, photonic properties, and catalytic activity, which make them intriguing for a wide range of applications in biomedicine. The development of biomedical applications of metallenes is in its infancy yet fast-growing. In this review, after a brief introduction of the definition, structures, properties, and classification of metallenes, we outline two common synthesis strategies and identify their shortcomings. Then, we comprehensively discuss the biological effects of metallenes, such as nano-biointeractions and signaling pathway regulation. We also highlight their recent advances in biomedical applications, including antitumor, biosensing, bioimaging, antibacterial, and anti-inflammation. Finally, we provide personal perspectives on remaining challenges and future opportunities for the biomedical applications of metallenes.

Manganese Prussian blue nanozymes with antioxidant capacity prevent acetaminophen-induced acute liver injury.

As one of the leading cases of acute liver failure triggered by excessive Acetaminophen (APAP), breakdown of the antioxidant system, inflammatory response, and inescapable apoptosis following overaccumulation of reactive oxygen species (ROS) play crucial roles in the mechanisms of APAP-induced liver injury (AILI). Therefore, cutting off ROS overproduction at the source is considered promising. Here, manganese Prussian blue nanozymes (MPBZs) with superior antioxidant enzyme-like activity are prepared as an effective strategy for hepatocyte protection, in which MPBZs accumulated in the liver show anti-oxidation properties by scavenging superfluous ROS. Importantly, in addition to alleviating oxidative stress, bioactive MPBZs with abundant variable valence states as a natural antioxidant enzymes mediated the responses of multi-biological signaling pathways in vitro and in vivo, including Nrf2-Keap1, NF-κB, and mitochondrial-induced apoptosis signaling pathways, enhancing tolerance for imminent AILI. Taking nanomedicine, hepatology, and catalytic chemistry into consideration, the revealed superior performance of AILI prevention suggests that MPBZ-based nano-detoxification therapy may offer an effective alternative against AILI.

AIPH-Encapsulated Thermo-Sensitive Liposomes for Synergistic Microwave Ablation and Oxygen-Independent Dynamic Therapy.

Microwave ablation (MWA) is a novel treatment modality that can lead to the death of tumor cells by heating the ions and polar molecules in the tissue through high-speed vibration and friction. However, the single hyperthermia is not sufficient to completely inhibit tumor growth. Herein, a thermodynamic cancer-therapeutic modality has been fabricated which could be able to overcome hypoxia's limitations in the tumor microenvironment. Using thermo-sensitive liposomes (TSLs) and oxygen-independent radical generators (2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride [AIPH]), a nano-drug delivery system denoted as ATSL is developed for efficient sequential cancer treatment. Under the microwave field, the temperature rise of local tissue could not only lead to the damage of tumor cells but also induce the release of AIPH encapsulated in ATSL to produce free radicals, eliciting tumor cell death. In addition, the ATSL developed here would avoid the side effects caused by the uncontrolled diffusion of AIPH to normal tissues. The ATSLs have shown excellent therapeutic effects both in vitro and in vivo, suggesting its highly promising potential for clinic.

Renal Clearable Mo-Based Polyoxometalate Nanoclusters: A Promising Radioprotectant against Ionizing Irradiation.

In response to diffused ionizing radiation damage throughout the body caused by nuclear leaks and inaccurate radiotherapy, radioprotectants with considerable free radical scavenging capacities, along with negligible adverse effects, are highly regarded. Herein, unlike being performed as toxic chemotherapeutic drug candidates, molybdenum-based polyoxometalate nanoclusters (Mo-POM NCs) were developed as a non-toxic potent radioprotectant with impressive free radical scavenging capacities for ionizing radiation protection. In comparison to the clinically used radioprotectant drug amifostine (AM), the as-prepared Mo-POM NCs exhibited effective shielding capacity by virtue of their antioxidant properties resulting from a valence shift of molybdenum ions, alleviating not only ionizing radiation-induced DNA damage but also disruption of the radiation-sensitive hematopoietic system. More encouragingly, without trouble with long-term retention in the body, ultra-small sized Mo-POM NCs prepared by the mimetic Folin-Ciocalteu assay can be removed from the body through the renal-urinary pathway and the hepato-enteral excretory system after completing the mission of radiation protection. This work broadened the biological applications of metal-based POM chemotherapeutic drugs to act as a neozoic radioprotectant.

Liquid exfoliation of ultrasmall zirconium carbide nanodots as a noninflammatory photothermal agent in the treatment of glioma.

Photothermal therapy (PTT), like other clinical translational tumor ablation techniques, requires a temperature increase above 50 °C to cause necrosis and death of tumor cells. Although the tumor can be eliminated rapidly by PTT, the inflammatory response is triggered by the large amounts of released reactive oxygen species (ROS). Therefore, liquid exfoliation was used to create ultrasmall zirconium carbide nanodots (NDs) with an average diameter of approximately 4.5 nm as noninflammatory/anti-inflammatory photosensitizers for PTT of glioma. Ultrasmall ZrC NDs showed excellent photothermal stability and biocompatibility but no obvious toxicity. Moreover, the ultrasmall ZrC NDs effectively ablated glioma at relatively low concentrations and inhibited tumor migration and proliferation in vitro and in vivo. Furthermore, the excellent ROS-scavenging ability of ultrasmall ZrC NDs suppressed the inflammatory response to PTT. Intriguingly, we found that ZrC had the capability of performing CT imaging. We demonstrated that the ultrasmall ZrC NDs created in this study could effectively and safely treat glioma without inflammation.

Ultrasmall zirconium carbide nanodots for synergistic photothermal-radiotherapy of glioma.

Glioma is characterized by highly invasive, progressive, and lethal features. In addition, conventional treatments have been poorly effective in treating glioma. To overcome this challenge, synergistic therapies combining radiotherapy (RT) with photothermal therapy (PTT) have been proposed and extensively explored as a highly feasible cancer treatment strategy. Herein, ultrasmall zirconium carbide (ZrC) nanodots were successfully synthesized with high near-infrared absorption and strong photon attenuation for synergistic PTT-RT of glioma. ZrC-PVP nanodots with an average size of approximately 4.36 nm were prepared by the liquid exfoliation method and modified with the surfactant polyvinylpyrrolidone (PVP), with a satisfactory absorption and photothermal conversion efficiency (53.4%) in the near-infrared region. Furthermore, ZrC-PVP nanodots can also act as radiosensitizers to kill residual tumor cells after mild PTT due to their excellent photon attenuating ability, thus achieving a significant synergistic therapeutic effect by combining RT and PTT. Most importantly, both in vitro and in vivo experimental results further validate the high biosafety of ZrC-PVP NDs at the injected dose. This work systematically evaluates the feasibility of ZrC-PVP NDs for glioma treatment and provides evidence of the application of zirconium-based nanomaterials in photothermal radiotherapy.

Ultrathin Hafnium Disulfide Atomic Crystals with ROS-Scavenging and Colon-Targeting Capabilities for Inflammatory Bowel Disease Treatment.

The exciting success of NBTXR3 in the clinic has triggered a tumult of activities in the design and development of hafnium-based nanoparticles. However, due to the concerns of nondegradation and limited functions, the biomedical applications of Hf-based nanoparticles mainly focus on tumors. Herein, tannic acid capped hafnium disulfide (HfS2@TA) nanosheets, a 2D atomic crystal of hafnium-based materials prepared by liquid-phase exfoliation, were explored as high-performance anti-inflammatory nanoagents for the targeted therapy of inflammatory bowel disease (IBD). Benefiting from the transformation of the S2-/S6+ valence state and huge specific surface area, the obtained HfS2@TA nanosheets were not only capable of effectively eliminating reactive oxygen species/reactive nitrogen species and downregulating pro-inflammatory factors but also could be excreted via kidney and hepatointestinal systems. Unexpectedly, HfS2@TA maintained excellent targeting capability to an inflamed colon even in the harsh digestive tract environment, mainly attributed to the electrostatic interactions between negatively charged tannic acid and positively charged inflamed epithelium. Encouragingly, upon oral or intravenous administration, HfS2@TA quickly inhibited inflammation and repaired the intestinal mucosa barrier in both dextran sodium sulfate and 2,4,6-trinitrobenzenesulfonic acid induced IBD models. This work demonstrated that ultrathin HfS2@TA atomic crystals with enhanced colon accumulation were promising for the targeted therapy of IBD.

Injectable magnetic montmorillonite colloidal gel for the postoperative treatment of hepatocellular carcinoma.

Bioactive materials have been extensively developed for the adjuvant therapy of cancer. However, few materials can meet the requirements for the postoperative resection of hepatocellular carcinoma (HCC) due to massive bleeding and high recurrence. In particular, combination therapy for HCC has been highly recommended in clinical practice, including surgical resection, interventional therapy, ablation therapy and chemotherapy. Herein, an injectable magnetic colloidal gel (MCG) was developed by controllable electrostatic attraction between clinically available magnetic montmorillonites and amphoteric gelatin nanoparticles. The optimized MCG exhibited an effective magnetic heating effect, remarkable rheological properties, and high gel network stability, realizing the synergistic treatment of postoperative HCC by stimuli-responsive drug delivery, hemostasis and magnetic hyperthermia. Furthermore, a minimal invasive MCG-induced interventional magnetic hyperthermia therapy (MHT) under ultrasound guidance was realized on hepatic tumor rabbits, providing an alternative therapeutics to treat the postoperative recurrence. Overall, MCG is a clinically available injectable formulation for adjuvant therapy after HCC surgical resection.

Three birds with one stone: co-encapsulation of diclofenac and DL-menthol for realizing enhanced energy deposition, glycolysis inhibition and anti-inflammation in HIFU surgery.

Despite attracting increasing attention in clinic, non-invasive high-intensity focused ultrasound (HIFU) surgery still commonly suffers from tumor recurrence and even matastasis due to the generation of thermo-resistance in non-apoptotic tumor cells and adverse therapy-induced inflammation with enhanced secretion of growth factors in irradiated region. In this work, inspired by the intrinsic property that the expression of thermo-resistant heat shock proteins (HSPs) is highly dependent with adenosine triphosphate (ATP), dual-functionalized diclofenac (DC) with anti-inflammation and glycolysis-inhibition abilities was successfully co-encapsulated with phase-change dl-menthol (DLM) in poly(lactic-co-glycolic acid) nanoparticles (DC/DLM@PLGA NPs) to realize improved HIFU surgery without causing adverse inflammation. Both in vitro and in vivo studies demonstrated the great potential of DC/DLM@PLGA NPs for serving as an efficient synergistic agent for HIFU surgery, which can not only amplify HIFU ablation efficacy through DLM vaporization-induced energy deposition but also simultaneously sensitize tumor cells to hyperthermia by glycolysis inhibition as well as diminished inflammation. Thus, our study provides an efficient strategy for simultaneously improving the curative efficiency and diminishing the harmful inflammatory responses of clinical HIFU surgery.

A tumour microenvironment-mediated Bi2-xMnxO3 hollow nanospheres via glutathione depletion for photothermal enhanced chemodynamic collaborative therapy.

Photothermal-enhanced chemodynamic therapy (CDT) has been attracting increasing attention for effective tumour treatment. Nevertheless, even though Mn-based nanostructures are promising CDT agents, their photothermal conversion capacities are not good enough for an ideal combination therapy. In this work, a bifunctional Bi2-xMnxO3 nanoplatform was developed, with tumour microenvironment (TME)-triggered photothermal therapy (PTT)-enhanced CDT, for a collaborative therapy for tumours. The doping of a small amount of Bi tuned the photothermal and CDT performance of Bi2-xMnxO3, thus promoting the photothermal conversion ability as well as accelerating the ˙OH generation. The existence of reductive Mn4+ could disrupt the internal tumour redox balance by enhancing glutathione (GSH) consumption to improve the CDT effect. Meanwhile, the mild photothermal effect could accelerate the depletion of GSH and the generation of ˙OH in the tumour region after laser irradiation, thus promoting the CDT effect. This manganese-based nanoplatform provides a good strategy for tumour therapy via TME-mediated PTT-enhanced CDT.

Phototherapy Using a Fluoroquinolone Antibiotic Drug to Suppress Tumor Migration and Proliferation and to Enhance Apoptosis.

In this work, a fluoroquinolone antibiotic drug (sparfloxacin (SP)) was selected as a chemotherapy drug and photosensitizer for combined therapy. A facile chemical process was developed to incorporate SP and upconversion nanoparticles (UCNPs) into the thermally sensitive amphiphilic polymer polyethylene glycol-poly(2-hexoxy-2-oxo-1,3,2-dioxaphospholane). In vitro and in vivo experiments showed that 60% of the SP molecules can be released from the micelles of thermal-sensitive polymers using a 1 W cm-2 980 nm laser, and this successfully inhibits cell migration and metastasis by inhibiting type II topoisomerases in nuclei. Additionally, intracellular metal ions were chelated by SP to induce cancer cell apoptosis by decreasing the activity of superoxide dismutase and catalase. In particular, the fluoroquinolone molecules produced singlet oxygen (1O2) to kill cancer cells, and this was triggered by UCNPs when irradiation was performed with a 980 nm laser. Overall, SP retained a weak chemotherapeutic effect, achieved enhanced photosensitizer-like effects, and was able to repurpose old drugs to elevate the therapeutic efficacy against cancer, increase the specificity for suppressing tumor migration and proliferation, and enhance apoptosis.