Developing Hypoxia-Sensitive System via Designing Tumor-Targeted Fullerene-Based Photosensitizer for Multimodal Therapy of Deep Tumor.

Photodynamic therapy (PDT) has been approved for clinic. However, powerless efficiency for deep hypoxic tumor therapy remains an enormous challenge for PDT. Herein, a hypoxia-sensitive nanotherapeutic system (FTCD-SRGD) based on fullerene (C70 ) and anoxic activating chemical prodrug tirapazamine (TPZ) is rationally designed for multimodal therapy of deep hypoxic tumors. To enhance the accumulation and achieve specific drug release in tumor, the FTCD-SRGD is modified with cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGDfK) peptide and disulfide bonds. With the exacerbated hypoxic microenvironment created by C70 consuming O2 for generating reactive oxygen species (ROS), TPZ is activated to produce toxic radical species to ablate deep tumors, which achieves a synergistic treatment of C70 -mediated PDT and hypoxia-enhanced chemotherapy. Additionally, given this hypoxia-sensitive system-induced immunogenic cell death (ICD) activating anticancer cytotoxic T lymphocyte to result in more susceptible tumor to immunotherapy, FTCD-SRGD plus immune checkpoint inhibitor (anti-PD-L1) fully inhibit deep hypoxic tumors by promoting infiltration of effector T cells in tumors. Collectively, it is the first time to develop a multimodal therapy system with fullerene-based hypoxia-sensitive PS for deep tumors. The powerful multimodal nanotherapeutic system for combining hypoxia-enhanced PDT and immunotherapy to massacre deep hypoxic tumors can provide a paradigm to combat the present bottleneck of tumor therapy.

The electrochemistry of stable sulfur isotopes versus lithium.

Sulfur in nature consists of two abundant stable isotopes, with two more neutrons in the heavy one (34S) than in the light one (32S). The two isotopes show similar physicochemical properties and are usually considered an integral system for chemical research in various fields. In this work, a model study based on a Li-S battery was performed to reveal the variation between the electrochemical properties of the two S isotopes. Provided with the same octatomic ring structure, the cyclo-34S8 molecules form stronger S-S bonds than cyclo-32S8 and are more prone to react with Li. The soluble Li polysulfides generated by the Li-34S conversion reaction show a stronger cation-solvent interaction yet a weaker cation-anion interaction than the 32S-based counterparts, which facilitates quick solvation of polysulfides yet hinders their migration from the cathode to the anode. Consequently, the Li-34S cell shows improved cathode reaction kinetics at the solid-liquid interface and inhibited shuttle of polysulfides through the electrolyte so that it demonstrates better cycling performance than the Li-32S cell. Based on the varied shuttle kinetics of the isotopic-S-based polysulfides, an electrochemical separation method for 34S/32S isotope is proposed, which enables a notably higher separation factor than the conventional separation methods via chemical exchange or distillation and brings opportunities to low-cost manufacture, utilization, and research of heavy chalcogen isotopes.

An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re-Epithelization and Skin Constriction for Enhancing Wound Closure.

Delayed re-epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large-scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active-shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re-epithelization and skin constriction to accelerate large-scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7-fold and ≈1.7-fold better re-epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.

Self-Cascade Redox Modulator Trilogically Renovates Intestinal Microenvironment for Mitigating Endotoxemia.

Endotoxemia is a life-threatening multiple organ failure disease caused by bacterial endotoxin infection. Unfortunately, current single-target therapy strategies have failed to prevent the progression of endotoxemia. Here, we reported that alanine fullerene redox modulator (AFRM) remodeled the intestinal microenvironment for multiple targets endotoxemia mitigation by suppressing inflammatory macrophages, inhibiting macrophage pyroptosis, and repairing epithelial cell barrier integrity. Specifically, AFRM exhibited broad-spectrum and self-cascade redox regulation properties with superoxide dismutase (SOD)-like enzyme, peroxidase (POD)-like enzyme activity, and hydroxyl radical (•OH) scavenging ability. Guided by proteomics, we demonstrated that AFRM regulated macrophage redox homeostasis and down-regulated LPS/TLR4/NF-κB and MAPK/ERK signaling pathways to suppress inflammatory hyperactivation. Of note, AFRM could attenuate inflammation-induced macrophage pyroptosis via inhibiting the activation of gasdermin D (GSDMD). In addition, our results revealed that AFRM could restore extracellular matrix and cell-tight junction proteins and protect the epithelial cell barrier integrity by regulating extracellular redox homeostasis. Consequently, AFRM inhibited systemic inflammation and potentiated intestinal epithelial barrier damage repair during endotoxemia in mice. Together, our work suggested that fullerene based self-cascade redox modulator has the potential in the management of endotoxemia through synergistically remodeling the inflammation and epithelial barriers in the intestinal microenvironment.

Recovering intestinal redox homeostasis to resolve systemic inflammation for preventing remote myocardial injury by oral fullerenes.

The unbalanced immune state is the dominant feature of myocardial injury. However, the complicated pathology of cardiovascular diseases and the unique structure of cardiac tissue lead to challenges for effective immunoregulation therapy. Here, we exploited oral fullerene nanoscavenger (OFNS) to maintain intestinal redox homeostasis to resolve systemic inflammation for effectively preventing distal myocardial injury through bidirectional communication along the heart-gut immune axis. Observably, OFNS regulated redox microenvironment to repair cellular injury and reduce inflammation in vitro. Subsequently, OFNS prevented myocardial injury by regulating intestinal redox homeostasis and recovering epithelium barrier integrity in vivo. Based on the profiles of transcriptomics and proteomics, we demonstrated that OFNS balanced intestinal and systemic immune homeostasis for remote cardioprotection. Of note, we applied this principle to intervene myocardial infarction in mice and mini-pigs. These findings highlight that locally addressing intestinal redox to inhibit systemic inflammation could be a potent strategy for resolving remote tissue injury.

A smart risk-responding polymer membrane for safer batteries.

Safety concerns related to the abuse operation and thermal runaway are impeding the large-scale employment of high-energy-density rechargeable lithium batteries. Here, we report that by incorporating phosphorus-contained functional groups into a hydrocarbon-based polymer, a smart risk-responding polymer is prepared for effective mitigation of battery thermal runaway. At room temperature, the polymer is (electro)chemically compatible with electrodes, ensuring the stable battery operation. Upon thermal accumulation, the phosphorus-containing radicals spontaneously dissociate from the polymer skeleton and scavenge hydrogen and hydroxyl radicals to terminate the exothermic chain reaction, suppressing thermal generation at an early stage. With the smart risk-responding strategy, we demonstrate extending the time before thermal runaway for a 1.8-Ah Li-ion pouch cell by 100% (~9 hours) compared with common cells, creating a critical time window for safety management. The temperature-triggered automatic safety-responding strategy will improve high-energy-density battery tolerance against thermal abuse risk and pave the way to safer rechargeable batteries.

Liposomes embedded with PEGylated iron oxide nanoparticles enable ferroptosis and combination therapy in cancer.

Ferroptosis, an iron-dependent regulated cell death process driven by excessive lipid peroxides, can enhance cancer vulnerability to chemotherapy, targeted therapy and immunotherapy. As an essential upstream process for ferroptosis activation, lipid peroxidation of biological membranes is expected to be primarily induced by intrabilayer reactive oxygen species (ROS), indicating a promising strategy to initiate peroxidation by improving the local content of diffusion-limited ROS in the lipid bilayer. Herein, liposomes embedded with PEG-coated 3 nm γ-Fe2O3 nanoparticles in the bilayer (abbreviated as Lp-IO) were constructed to promote the intrabilayer generation of hydroxyl radicals (•OH) from hydrogen peroxide (H2O2), and the integration of amphiphilic PEG moieties with liposomal bilayer improved lipid membrane permeability to H2O2 and •OH, resulting in efficient initiation of lipid peroxidation and thus ferroptosis in cancer cells. Additionally, Lp-IO enabled traceable magnetic resonance imaging and pH/ROS dual-responsive drug delivery. Synergistic antineoplastic effects of chemotherapy and ferroptosis, and alleviated chemotherapeutic toxicity, were achieved by delivering doxorubicin (capable of xCT and glutathione peroxidase inhibition) with Lp-IO. This work provides an efficient alternative for triggering therapeutic lipid peroxidation and a ferroptosis-activating drug delivery vehicle for combination cancer therapies.

Oral nano-antioxidants improve sleep by restoring intestinal barrier integrity and preventing systemic inflammation.

Sleep deprivation (SD) is a severe public health threat that can cause systemic inflammation and nerve damage. Few effective and side-effect-free drugs are available to address SD. However, the bidirectional communications between the brain and gut provide new strategies for anti-SD therapeutics. Here we explored oral delivery of fullerene nano-antioxidants (FNAO) in the SD model to improve sleep by regulating abnormal intestinal barrier and systemic inflammation via the brain-gut axis. SD caused excessive reactive oxygen species (ROS) production and hyperactive inflammatory responses in the intestines of zebrafish and mouse models, leading to disturbed sleep patterns and reduced brain nerve activity. Of note, based on the property of the conjugated π bond of the C60 structure to absorb unpaired electrons, oral FNAO efficiently reduced the excessive ROS in the intestines, maintained redox homeostasis and intestinal barrier integrity, and ameliorated intestinal and systemic inflammation, resulting in superior sleep improvement. Our findings suggest that maintaining intestinal homeostasis may be a promising avenue for SD-related nerve injury therapy.

Achieving the dual goals of biomass production and soil rehabilitation with sown pasture on marginal cropland: Evidence from a multi-year field experiment in Northeast Inner Mongolia.

Grassland is the primary land use in China but has experienced severe degradation in recent decades due to overgrazing and conversion to agricultural production. Here, we conducted a field experiment in northeastern Inner Mongolia to test the effectiveness of sown pastures in lowering the grazing pressure on grasslands and raising the quality of marginal soils. Alfalfa and smooth bromegrass monocultures and mixture were sown in a marginal cropland field in Hulunber in June 2016. Biomass productivity, soil physicochemical, and biological properties were monitored annually from 2016 to 2020. The results showed that the marginal cropland soil responded consistently positively to sown pastures for major soil properties. Soil organic carbon (SOC) and total nitrogen (TN) increased by 48 and 21%, respectively, from 2016 to 2020 over the 0-60 cm soil depth range. Soil microbes responded proactively too. The soil microbial biomass C (SMBC) and N (SMBN) increased by 117 and 39%, respectively, during the period of 2016-2020. However, by the end of the experiment, the soil of a natural grassland field, which was included in the experiment as a control, led the sown pasture soil by 28% for SOC, 35% for TN, 66% for SMBC, and 96% for SMBN. Nevertheless, the natural grassland soil's productive capacity was inferior to that of the sown pasture soil. The average aboveground biomass productivity of sown pastures was measured at 8.4 Mg ha-1 in 2020, compared to 5.0 Mg ha-1 for natural grassland, while the root biomass of sown pastures was averaged at 7.5 Mg ha-1, leading the natural grassland by 15%. Our analyses also showed that the sown pastures' biomass productivity advantage had a much-neglected potential in natural grassland protection. If 50% of the available marginal cropland resources in Hulunber under the current environmental protection law were used for sown pastures, the livestock grazing pressure on the natural grasslands would decrease by a big margin of 38%. Overall, these results represent systematic empirical and analytical evidence of marginal cropland soil's positive responses to sown pastures, which shows clearly that sown pasture is a valid measure both for soil rehabilitation and biomass production.

Amphiphilic Aminated Derivatives of [60]Fullerene as Potent Inhibitors of Tumor Growth and Metastasis.

Malignant proliferation and metastasis are the hallmarks of cancer cells. Aminated [70]fullerene exhibits notable antineoplastic effects, promoting it a candidate for multi-targeted cancer drugs. It is an urgent need to reveal the structure-activity relationship for antineoplastic aminated fullerenes. Herein, three amphiphilic derivatives of [60]fullerene with clarified molecular structures are synthesized: TAPC-4, TAPC-3, and TCPC-4. TAPC-4 inhibits the proliferation of diverse tumor cells via G0/G1 cell cycle arrest, reverses the epithelial-mesenchymal transition, and abrogates the high mobility of tumor cells. TAPC-4 can be excreted from the organism and achieves an in vivo inhibition index of 75.5% in tumor proliferation and 87.5% in metastatic melanoma with a wide safety margin. Molecular dynamics simulations reveal that the amphiphilic molecular structure and the ending amino groups promote the targeting of TAPC-4 to heat shock protein Hsp90-beta, vimentin, and myosin heavy chain 9 (MYH9), probably resulting in the alteration of cyclin D1 translation, vimentin expression, and MYH9 location, respectively. This work initially emphasizes the dominant role of the amphiphilic structure and the terminal amino moieties in the antineoplastic effects of aminated fullerenes, providing fundamental support for their anti-tumor drug development.

Evidence for the association of triatomic molecules in ultracold 23Na40K + 40K mixtures.

Ultracold assembly of diatomic molecules has enabled great advances in controlled chemistry, ultracold chemical physics and quantum simulation with molecules1-3. Extending the ultracold association to triatomic molecules will offer many new research opportunities and challenges in these fields. A possible approach is to form triatomic molecules in a mixture of ultracold atoms and diatomic molecules by using a Feshbach resonance between them4,5. Although ultracold atom-diatomic-molecule Feshbach resonances have been observed recently6,7, using these resonances to form triatomic molecules remains challenging. Here we report on evidence of the association of triatomic molecules near the Feshbach resonance between 23Na40K molecules in the rovibrational ground state and 40K atoms. We apply a radio-frequency pulse to drive the free-bound transition in ultracold mixtures of 23Na40K and 40K and monitor the loss of 23Na40K molecules. The association of triatomic molecules manifests itself as an additional loss feature in the radio-frequency spectra, which can be distinguished from the atomic loss feature. The observation that the distance between the association feature and the atomic transition changes with the magnetic field provides strong evidence for the formation of triatomic molecules. The binding energy of the triatomic molecules is estimated from the measurements. Our work contributes to the understanding of the complex ultracold atom-molecule Feshbach resonances and may open up an avenue towards the preparation and control of ultracold triatomic molecules.

Fullerene nanoparticles for the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a long-term, recurrent inflammatory bowel disease for which no effective cure is yet available in the clinical setting. Repairing the barrier dysfunction of the colon and reducing intestinal inflammation are considered key objectives to cure UC. Here we demonstrate a novel therapeutic strategy based on a C60 fullerene suspension (C60FS) to treat dinitrobenzene sulfonic acid-induced UC in an animal model. C60FS can repair the barrier dysfunction of UC and effectively promote the healing of ulcers; it also manifests better treatment effects compared with mesalazine enema. C60FS can reduce the numbers of basophils in the blood of UC rats and mast cells in the colorectal tissue, thereby effectively alleviating inflammation. The expression of H1R, H4R, and VEGFR2 receptors in colorectal tissues is inhibited by C60FS, and the levels of histamine and prostaglandin in the rat blood are reduced. This work presents a reliable strategy based on fullerene to cure UC and provides a novel guide for UC treatment.

Gadofullerene inhibits the degradation of apolipoprotein B100 and boosts triglyceride transport for reversing hepatic steatosis.

Hepatic steatosis is a widespread metabolic disease characterized by excessive accumulation of triglyceride (TG) in liver. So far, effective approved drugs for hepatic steatosis are still in development, and removing the unnecessary TG from the hepatocytes is an enormous challenge. Here, we explore a promising anti-hepatic steatosis strategy by boosting hepatocellular TG transport using ß-alanine-modified gadofullerene (GF-Ala) nanoparticles. We confirm that GF-Ala could reverse hepatic steatosis in oleic acid-induced hepatocytes, fructose-induced mice, and obesity-associated transgenic ob/ob mice. Observably, GF-Ala improves hepatomegaly and hepatic lipid accumulation, reduces lipid peroxidation, and repairs abnormal mitochondria. Of note, we demonstrate that GF-Ala markedly inhibits the posttranslational degradation of apolipoprotein B100 (ApoB100) and boosts hepatocellular TG transport based on their superior antioxidant property. Together, we conclude that GF-Ala could potently ameliorate hepatic TG transport and maintain hepatic metabolic homeostasis without apparent toxicity, being beneficial for treatments of hepatic steatosis and other fatty liver diseases.

Fullerene nanoparticles: a promising candidate for the alleviation of silicosis-associated pulmonary inflammation.

Chronic exposure to crystalline silica causes the development of silicosis, which is one of the most important occupational diseases worldwide. In the early stage of silicosis, inhaled silica crystals initiate oxidative stress, a cycle of persistent inflammation and lung injury. And it is crucial to prevent the deteriorative progression in the onset of the disease. Herein, we present a promising candidate for the treatment of crystalline silica-induced pulmonary inflammation, using a silicosis mouse model caused by intratracheal instillation based on local administration of ß-alanine and hydroxyl functionalized C70 fullerene nanoparticles (FNs). The results demonstrate that FNs could significantly alleviate inflammatory cells infiltration, lower the secretion of pro-inflammatory cytokines, and reduce the destruction of lung architecture stimulated by crystalline silica. Further investigations reveal that FNs could effectively inhibit the activation of NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome, and thus prevent the secretion of mature IL-1ß and neutrophil influx, deriving from the superior ROS scavenging capability. Importantly, FNs could not cause any obvious toxicity after pulmonary administration.

Gadofullerene nanoparticles for robust treatment of aplastic anemia induced by chemotherapy drugs.

Aplastic anemia (AA) is characterized as hypoplasia of bone marrow hematopoietic cells and hematopenia of peripheral blood cells. Though the supplement of exogenous erythropoietin (EPO) has been clinically approved for AA treatment, the side-effects hinder its further application. Here a robust treatment for AA induced by chemotherapy drugs is explored using gadofullerene nanoparticles (GFNPs). Methods: The gadofullerene were modified with hydrogen peroxide under alkaline conditions to become the water-soluble nanoparticles (GFNPs). The physicochemical properties, in vitro chemical construction, stability, hydroxyl radical scavenging ability, in vitro cytotoxicity, antioxidant activity, in vivo treatment efficacy, therapeutic mechanism and biological distribution, metabolism, toxicity of GFNPs were examined. Results: GFNPs with great stability and high-efficiency antioxidant activity could observably increase the number of red blood cells (RBC) in the peripheral blood of AA mice and relieve the abnormal pathological state of bone marrow. The erythropoiesis mainly includes hemopoietic stem cells (HSCs) differentiation, erythrocyte development in bone marrow and erythrocyte maturation in peripheral blood. The positive control-EPO promotes erythropoiesis by regulating HSCs differentiation and erythrocyte development in bone marrow. Different from the anti-AA mechanism of EPO, GFNPs have little impact on both the differentiation of HSCs and the myeloid erythrocyte development, but notably improve the erythrocyte maturation. Besides, GFNPs can notably decrease the excessive reactive oxygen species (ROS) and inhibit apoptosis of hemocytes in blood. In addition, GFNPs are mostly excreted from the living body and cause no serious toxicity. Conclusion: Our work provides an insight into the advanced nanoparticles to powerfully treat AA through ameliorating the erythrocyte maturation during erythropoiesis.

Functional Gadofullerene Nanoparticles Trigger Robust Cancer Immunotherapy Based on Rebuilding an Immunosuppressive Tumor Microenvironment.

Cancer immunotherapy as a novel cancer therapeutic strategy has shown enormous promise. However, the immunosuppressive tumor microenvironment (ITM) is a primary obstacle. Tumor-associated macrophages (TAMs) as a major component of immune cells in a tumor microenvironment are generally polarized to the M2 phenotype that not only accelerates tumor growth but also influences the infiltration of lymphocytes and leads to immunosuppression. Thus, rebuilding ITM by re-educating TAMs and increasing infiltration of lymphocytes is a promising strategy. Herein, gadofullerene (GF-Ala) nanoparticles are demonstrated to reprogram TAMs to M1-like and increase the infiltration of cytotoxic T lymphocytes (CTLs), achieving effective inhibition of tumor growth. Notably, the modulation of ITM by GF-Ala promotes the anticancer efficacy of anti-PD-L1 immune checkpoint inhibitor, achieving superior synergistic treatment. Additionally, GF-Ala nanoparticles can be mostly excreted from the body and cause no obvious toxicity. Together, this study provides an effective immunomodulation strategy using gadofullerene nanoparticles by rebuilding ITM and synergizing immune checkpoint blockade therapy.

Gadofullerene Nanoparticles Reverse Dysfunctions of Pancreas and Improve Hepatic Insulin Resistance for Type 2 Diabetes Mellitus Treatment.

Type 2 diabetes mellitus (T2DM) has been one of the most prevalent metabolic disorders. Nonetheless, the commonly used anti-T2DM drugs failed to substant to treat T2DM when anti-T2DM was withdrawn. Here we put forward a superior and sustainable anti-diabetic strategy using intraperitoneal administration of amino-acid-functionalized gadofullerene nanoparticles (GFNPs) in db/db diabetic mice. Highly accumulated in the pancreas and liver, GFNPs could prominently decrease hyperglycemia, along with permanently maintaining normal blood sugar levels in T2DM mice and even stopping administration. Importantly, GFNPs reversed the pancreas islets dysfunctions by reducing oxidative stress and inflammation responses and fundamentally normalized the insulin secretory function of the pancreas islets. Mechanistically, GFNPs improved hepatic insulin resistance by regulating glucose and lipid metabolism through the activation of IRS2/PI3K/AKT signal pathways, resulting in inhibiting gluconeogenesis and increasing glycogenesis in the liver. Additionally, GFNPs relieved hepatic steatosis in the liver, ultimately maintaining systemic glucose and lipid metabolic homeostasis without obvious toxicity. Together, GFNPs reverse the dysfunctions of the pancreas and improve hepatic insulin resistance, providing a promising approach for T2DM treatment.