Ascidian-Inspired Temperature-Switchable Hydrogels with Antioxidant Fullerenols for Protecting Radiation-Induced Oral Mucositis and Maintaining the Homeostasis of Oral Microbiota.

A key characteristic of radiation-induced oral mucositis (RIOM) is oxidative stress mediated by the "reactive oxygen species (ROS) storm" generated from water radiolysis, resulting in severe pathological lesions, accompanied by a disturbance of oral microbiota. Therefore, a sprayable in situ hydrogel loaded with "free radical sponge" fullerenols (FOH) is developed as antioxidant agent for RIOM radioprotection. Inspired by marine organisms, 3,4,5-trihydroxyphenylalanine (TOPA) which is enriched in ascidians is grafted to clinically approved temperature-switchable Pluronic F127 to produce gallic acid (containing the TOPA fragment)-modified Pluronic F127 (MGA) hydrogels to resist the fast loss of FOH via biomimetic adhesion during oral movement and saliva erosion. Based on this, progressive RIOM found in mice is alleviated by treatment of FOH-loaded MGA hydrogels whether pre-irradiation prophylactic administration or post-irradiation therapeutic administration, which contributes to maintaining the homeostasis of oral microbiota. Mechanistically, FOH inhibits cell apoptosis by scavenging radiation-induced excess ROS and up-regulates the inherent enzymatic antioxidants, thereby protecting the proliferation and migration of mucosal epithelial cells. In conclusion, this work not only provides proof-of-principle evidence for the oral radioprotection of FOH by blocking the "ROS storm", but also provides an effective and easy-to-use hydrogel system for mucosal in situ administration.

Alleviation of Photoreceptor Degeneration Based on Fullerenols in rd1 Mice by Reversing Mitochondrial Dysfunction via Modulation of Mitochondrial DNA Transcription and Leakage.

Poor therapeutic outcomes of antioxidants in ophthalmologic clinical applications, including glutathione during photoreceptor degeneration in retinitis pigmentosa (RP), are caused by limited anti-oxidative capacity. In this study, fullerenols are synthesized and proven to be highly efficient in vitro radical scavengers. Fullerenol-based intravitreal injections significantly improve the flash electroretinogram and light/dark transition tests performed for 28 days on rd1 mice, reduce the thinning of retinal outer nuclear layers, and preserve the Rhodopsin, Gnat-1, and Arrestin expressions of photoreceptors. RNA-sequencing, RT-qPCR, and Western blotting validate that mitochondrial DNA (mt-DNA)-encoded genes of the electron transport chain (ETC), such as mt-Nd4l, mt-Co1, mt-Cytb, and mt-Atp6, are drastically downregulated in the retinas of rd1 mice, whereas nuclear DNA (n-DNA)-encoded genes, such as Ndufa1 and Atp5g3, are abnormally upregulated. Fullerenols thoroughly reverse the abnormal mt-DNA and n-DNA expression patterns of the ETC and restore mitochondrial function in degenerating photoreceptors. Additionally, fullerenols simultaneously repress Flap endonuclease 1 (FEN1)-mediated mt-DNA cleavage and mt-DNA leakage via voltage-dependent anion channel (VDAC) pores by downregulating the transcription of Fen1 and Vdac1, thereby inactivating the downstream pro-inflammatory cGAS-STING pathway. These findings demonstrate that fullerenols can effectively alleviate photoreceptor degeneration in rd1 mice and serve as a viable treatment for RP.

Eco-Friendly and Scalable Synthesis of Fullerenols with High Free Radical Scavenging Ability for Skin Radioprotection.

Radiation dermatitis is a common but torturous side effect during radiotherapy, which greatly decreases the life quality of patients and potentially results in detrimental cessation of tumor treatment. Fullerenol, known as "free radical sponge," is a great choice for skin radioprotection because of its broad-spectrum free radical scavenging performance, good chemical stability, and biosafety. In this work, a facile scalable and eco-friendly synthetic method of fullerenols by catalyst assistant mechanical chemistry strategy is provided. As no organic solvent or high concentration of acid and alkali is introduced to this synthetic system, large-scale (>20 g) production of fullerenols with high yield (>95%) is obtained and no complicated purification is required. Then, the skin radioprotective performance of fullerenols is systematically explored for the first time. In vitro results indicate that fullerenols significantly block the reactive oxygen species-induced damage and enhance the viability of irradiated human keratinocyte cells. In vivo experiments suggest that medical sodium hyaluronate hydrogels loaded with fullerenols are suitable for skin administration and powerfully mitigate radiodermatitis via effectively protecting epidermal stem cells. The work not only provides an efficient gram-scale and eco-friendly synthetic method of fullerenols, but also promotes the development of fullerenols as potential skin radioprotectors.

Clinically Approved Carbon Nanoparticles with Oral Administration for Intestinal Radioprotection via Protecting the Small Intestinal Crypt Stem Cells and Maintaining the Balance of Intestinal Flora.

The exploration of an old drug for new biomedical applications has an absolute predominance in shortening the clinical conversion time of drugs for clinical application. In this work, carbon nanoparticles suspension injection (CNSI), the first clinically approved carbon nanoparticles in China, is explored as a new nano-radioprotective agent for potent intestinal radioprotection. CNSI shows powerful radioprotective performance in the intestine under oral administration, including efficient free radical scavenging ability, good biosafety, high chemical stability, and relatively long retention time. For example, CNSI shows high reactive oxygen species (ROS) scavenging activities, which effectively alleviates the mitochondrial dysfunction and DNA double-strand breaks to protect the cells against radiation-induced damage. Most importantly, this efficient ROS scavenging ability greatly helps restrain the apoptosis of the small intestinal epithelial and crypt stem cells, which decreases the damage of the mechanical barrier and thus relieves radiation enteritis. Moreover, CNSI helps remove the free radicals in the intestinal microenvironment and thus maintain the balance of intestinal flora so as to mitigate the radiation enteritis. The finding suggests a new application of clinically approved carbon nanoparticles, which not only promotes the development of new intestinal radioprotector, but also has a great potential for clinical transformation.

Ergothioneine-Sodium Hyaluronate Dressing: A Promising Approach for Protecting against Radiation-Induced Skin Injury.

Radiotherapy commonly causes damage to healthy tissues, particularly radiation-induced skin injury (RISI) that affects a significant majority of patients undergoing radiotherapy. Effective treatments for RISI are lacking. This study focuses on the pathogenesis of RISI, which primarily involves oxidative stress. Excessive reactive oxygen species (ROS) generation during radiation induces damage to biological macromolecules, triggering oxidative stress and inflammation. To address this, ergothioneine (EGT), a natural and biocompatibile thiol compound with excellent antioxidant activity, is explored as a potential radiation-protective agent. By utilizing its specific transport and absorption in the skin tissue, as well as its efficient and stable clearance of radiation-induced "ROS storm", EGT is combined with sodium hyaluronate (NaHA) to develop a novel radiation protective dressing suitable for the skin. This EGT-NaHA dressing demonstrates an effective ability to scavenge free radicals and reduce oxidative stress in vitro and in vivo, reducing cellular apoptosis and inflammation. These results demonstrate the protective properties of EGT against RISI, with far-reaching implications for research and development in the field of radioprotection.

Fullerenols Ameliorate Social Deficiency and Rescue Cognitive Dysfunction of BTBR T+Itpr3tf/J Autistic-Like Mice.

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition that affects social interaction and communication and can cause stereotypic behavior. Fullerenols, a type of carbon nanomaterial known for its neuroprotective properties, have not yet been studied for their potential in treating ASD. We aimed to investigate its role in improving autistic behaviors in BTBR T+Itpr3tf/J (BTBR) mice and its underlying mechanism, which could provide reliable clues for future ASD treatments. Methods: Our research involved treating C57BL/6J (C57) and BTBR mice with either 0.9% NaCl or fullerenols (10 mg/kg) daily for one week at seven weeks of age. We then conducted ASD-related behavioral tests in the eighth week and used RNA-seq to screen for vital pathways in the mouse hippocampus. Additionally, we used real-time quantitative PCR (RT-qPCR) to verify related pathway genes and evaluated the number of stem cells in the hippocampal dentate gyrus (DG) by Immunofluorescence staining. Results: Our findings revealed that fullerenols treatment significantly improved the related ASD-like behaviors of BTBR mice, manifested by enhanced social ability and improved cognitive deficits. Immunofluorescence results showed that fullerenols treatment increased the number of DCX+ and SOX2+/GFAP+ cells in the DG region of BTBR mice, indicating an expanded neural progenitor cell (NPC) pool of BTBR mice. RNA-seq analysis of the mouse hippocampus showed that VEGFA was involved in the rescued hippocampal neurogenesis by fullerenols treatment. Conclusion: In conclusion, our findings suggest that fullerenols treatment improves ASD-like behavior in BTBR mice by upregulating VEGFA, making nanoparticle- fullerenols a promising drug for ASD treatment.

Colon-Targeted Release of Gel Microspheres Loaded with Antioxidative Fullerenol for Relieving Radiation-Induced Colon Injury and Regulating Intestinal Flora.

Radiation-induced colitis is a serious clinical problem worldwide. However, the current treatment options for this condition have limited efficacy and can cause side effects. To address this issue, colon-targeted fullerenol@pectin@chitosan gel microspheres (FPCGMs) are developed, which can aggregate on colon tissue for a long time, scavenge free radicals generated in the process of radiation, and regulate intestinal flora to mitigate damage to colonic tissue. First, FPCGMs exhibit acid resistance and colon-targeted release properties, which reduce gastrointestinal exposure and extend the local colonic drug residence time. Second, fullerenol, which has a superior scavenging ability and chemical stability, reduces oxidative stress in colonic epithelial cells. Based on this, it is found that FPCGMs significantly reduce inflammation in colonic tissue, mitigated damage to tight junctions of colonic epithelial cells, and significantly relieved radiation-induced colitis in mice. Moreover, 16S ribosomal DNA (16S rDNA) sequencing results show that the composition of the intestinal flora is optimized after FPCGMs are utilized, indicating that the relative abundance of probiotics increases while harmful bacteria are inhibited. These findings suggest that it is a promising candidate for treating radiation-induced colitis.

Mussel-Inspired Tantalum Nanocomposite Hydrogels for In Situ Oral Cancer Treatment.

Oral squamous cell carcinoma (OSCC) is one of the most common oral malignancies. Radiotherapy is the primary noninvasive treatment of OSCC for avoiding surgery-induced facial deformities and impaired oral function. However, the specificity of in situ OSCC limits radiotherapeutic effects because of the hypoxia-induced low radiosensitivity of tumors and the low radiation tolerance of surrounding normal tissues. Here, we design a highly efficient and low-toxic radiosensitization strategy. On the one hand, biocompatible poly(vinyl pyrrolidone)-modified tantalum nanoparticles (Ta@PVP NPs) not only have strong X-ray deposition capability to upregulate oxidative stress but also have photothermal conversion efficiency to improve hypoxia for tumor radiosensitivity. On the other hand, to optimize the spatial distribution of Ta@PVP NPs within tumors, mussel-inspired catechol with bioadhesive properties is grafted on tumor microenvironment-responsive sodium alginate (DAA) to form in situ hydrogels for precision radiotherapy. On this basis, we find that Ta@PVP-DAA hydrogels effectively inhibit OSCC development in mice under photothermal-assisted radiotherapy without facial deformities and damage to surrounding normal tissues. Overall, our work not only promotes the exploration of Ta@PVP NPs as new radiosensitizers for OSCC but also develops a nanocomposite hydrogel system strategy as a promising paradigm for the precision treatment of orthotopic tumors.

Adhesive Ergothioneine Hyaluronate Gel Protects against Radiation Gastroenteritis by Alleviating Apoptosis, Inflammation, and Gut Microbiota Dysbiosis.

Radiation gastroenteritis represents one of the most prevalent and hazardous complications of abdominopelvic radiotherapy, which not only severely reduces patients' life quality but also restricts radiotherapy efficacy. However, there is currently no clinically available oral radioprotector for this threatening disease due to its complex pathogenesis and the harsh gastrointestinal environment. To this end, this study developed a facile but effective oral radioprotector, ergothioneine hyaluronate (EGT@HA) gel, protecting against radiation gastroenteritis by synergistically regulating oxidative stress, inflammation, and gut microbiota. In vitro and cellular experiments verified the chemical stability and free radical scavenging ability of EGT and its favorable cellular radioprotective efficacy by inhibiting intracellular reactive oxidative species (ROS) generation, DNA damage, mitochondrial damage, and apoptosis. At the in vivo level, EGT@HA with prolonged gastrointestinal residence mitigated radiation-induced gastrointestinal tissue injury, apoptosis, neutrophil infiltration, and gut flora dysbiosis. For the first time, this work investigated the protective effects of EGT@HA gel on radiation gastroenteritis, which not only hastens the advancement of the novel gastrointestinal radioprotector but also provides a valuable gastrointestinal radioprotection paradigm by synergistically modulating oxidative stress, inflammation, and gut microbiota disturbance.

Fullerenols Mitigate Radiation-Induced Myocardial Injury.

Radiation-induced heart disease is a serious side effect of radiation therapy that can lead to severe consequences. However, effective and safe methods for their prevention and treatment are presently lacking. This study reports the crucial function of fullerenols in protecting cardiomyocytes from radiation injury. First, fullerenols are synthesized using a simple base-catalyzed method. Next, the as-prepared fullerenols are applied as an effective free radical scavenger and broad-spectrum antioxidant to protect against X-ray-induced cardiomyocyte injury. Their ability to reduce apoptosis via the mitochondrial signaling pathway at the cellular level is then verified. Finally, it is observed in animal models that fullerenols accumulate in the heart and alleviate myocardial damage induced by X-rays. This study represents a timely and essential analysis of the prevention and treatment of radiological myocardial injury, providing new insights into the applications of fullerenols for therapeutic strategies.

Fullerol rescues the light-induced retinal damage by modulating Müller glia cell fate.

Excessive light exposure can damage photoreceptors and lead to blindness. Oxidative stress serves a key role in photo-induced retinal damage. Free radical scavengers have been proven to protect against photo-damaged retinal degeneration. Fullerol, a potent antioxidant, has the potential to protect against ultraviolet-B (UVB)-induced cornea injury by activating the endogenous stem cells. However, its effects on cell fate determination of Müller glia (MG) between gliosis and de-differentiation remain unclear. Therefore, we established a MG lineage-tracing mouse model of light-induced retinal damage to examine the therapeutic effects of fullerol. Fullerol exhibited superior protection against light-induced retinal injury compared to glutathione (GSH) and reduced oxidative stress levels, inhibited gliosis by suppressing the TGF-ß pathway, and enhanced the de-differentiation of MG cells. RNA sequencing revealed that transcription candidate pathways, including Nrf2 and Wnt10a pathways, were involved in fullerol-induced neuroprotection. Fullerol-mediated transcriptional changes were validated by qPCR, Western blotting, and immunostaining using mouse retinas and human-derived Müller cell lines MIO-M1 cells, confirming that fullerol possibly modulated the Nrf2, Wnt10a, and TGF-ß pathways in MG, which suppressed gliosis and promoted the de-differentiation of MG in light-induced retinal degeneration, indicating its potential in treating retinal diseases.

Biocompatible Tantalum Nanoparticles as Radiosensitizers for Enhancing Therapy Efficacy in Primary Tumor and Metastatic Sentinel Lymph Nodes.

Metastasis of breast carcinoma is commonly realized through lymphatic circulation, which seriously threatens the lives of breast cancer patients. Therefore, efficient therapy for both primary tumor and metastatic sentinel lymph nodes (SLNs) is highly desired to inhibit cancer growth and metastasis. During breast cancer treatment, radiotherapy (RT) is a common clinical method. However, the efficacy of RT is decreased by the radioresistance to a hypoxic microenvironment and inevitable side effects for healthy issues at high radiation doses. Considering the above-mentioned, we provide high biocompatible poly(vinylpyrrolidone) coated Ta nanoparticles (Ta@PVP NPs) for photothermal therapy (PTT) assisted RT for primary tumor and metastatic SLNs. On the one hand, for primary tumor treatment, Ta@PVP NPs with a high X-ray mass attenuation coefficient (4.30 cm2/kg at 100 keV) can deposit high radiation doses within tumors. On the other hand, for metastatic SLNs treatment, the effective delivery of Ta@PVP NPs from the primary tumor into SLNs is monitored by computed tomography and photoacoustic imaging, which greatly benefit the prognosis and treatment for metastatic SLNs. Moreover, Ta@PVP NPs-mediated PTT could enhance the RT effect, and immunogenic cell death caused by RT/PTT could induce an immune response to improve the therapeutic effect of metastatic SLNs. This study not only explores the potential of Ta@PVP NPs as effective radiosensitizers and photothermal agents for combined RT and PTT but also offers an efficient strategy to cure both primary tumor and metastatic SLNs in breast carcinoma.

Fullerenol protects cornea from ultraviolet B exposure.

The eyes are highly susceptible to the oxidative stress induced by ultraviolet B (UVB, wavelength between 280 ∼ 320 nm), which could cause severe damage to the cornea. Fullerenols are effective antioxidants to alleviate UVB-induced injury, while their application for the eyes is still rare. In present study, we investigated the protective performance and mechanism of fullerenols on cornea under UVB radiation in vivo and in vitro. The synthesized fullerenols exhibited broad-spectrum free radical scavenging properties (applicable to both reactive oxygen species (ROS) and reactive nitrogen species (RNS)) and photo-stability. When compared with another widely used antioxidant glutathione (GSH), the administration of fullerenols markedly decreased the injured area, corneal edema, cell death, and increased the cell proliferation in UVB-induced rat cornea. The effects of fullerenols were confirmed in UVB-exposed human corneal epithelial cells (hCECs), where elevated cell viability and proliferation, decreased oxidative free radical production, repaired mitochondrial dysfunction and DNA lesions were observed. RNA sequencing (RNA-Seq) analysis demonstrated that fullerenol alleviated UVB-induced corneal injury through down-regulation of oxidative stress-related genes and up-regulation of proliferation-associated genes. Our results demonstrate the suitability of fullerenols as a potential exogenous treatment in ameliorating UVB-induced cornea damage.

Rational Design of Nanomaterials for Various Radiation-Induced Diseases Prevention and Treatment.

Radiation treatments often unfavorably damage neighboring healthy organs and cause a series of radiation sequelae, such as radiation-induced hematopoietic system diseases, radiation-induced gastrointestinal diseases, radiation-induced lung diseases, and radiation-induced skin diseases. Recently, emerging nanomaterials have exhibited good superiority for these radiation-induced disease treatments. Given this background, the rational design principle of nanomaterials, which helps to optimize the therapeutic efficiency, has been an increasing need. Consequently, it is of great significance to perform a systematic summarization of the advances in this field, which can trigger the development of new high-performance nanoradioprotectors with drug efficiency maximization. Herein, this review highlights the advances and perspectives in the rational design of nanomaterials for preventing and treating various common radiation-induced diseases. Furthermore, the sources, clinical symptoms, and pathogenesis/injury mechanisms of these radiation-induced diseases will also be introduced. Furthermore, current challenges and directions for future efforts in this field are also discussed.