Oral Metal-Free Melanin Nanozymes for Natural and Durable Targeted Treatment of Inflammatory Bowel Disease (IBD).

Oral antioxidant nanozymes bring great promise for inflammatory bowel disease (IBD) treatment. To efficiently eliminate reactive oxygen species (ROS), various metal-based nanozymes have been developed for the treatment of IBD but their practical applications are seriously impaired by unstable ROS-eliminating properties and potential metal ion leakage in the digestive tract. Here, the authors for the first time propose metal-free melanin nanozymes (MeNPs) with excellent gastrointestinal stability and biocompatibility as a favorable therapy strategy for IBD. Moreover, MeNPs have extremely excellent natural and long-lasting characteristics of targeting IBD lesions. In view of the dominant role of ROS in IBD, the authors further reveal that oral administration of MeNPs can greatly alleviate the six major pathological features of IBD: oxidative stress, endoplasmic reticulum stress, apoptosis, inflammation, gut barrier disruption, and gut dysbiosis. Overall, this strategy highlights the great clinical application prospects of metal-free MeNPs via harnessing ROS scavenging at IBD lesions, offering a paradigm for antioxidant nanozyme in IBD or other inflammatory diseases.

Revitalizing Ancient Mitochondria with Nano-Strategies: Mitochondria-Remedying Nanodrugs Concentrate on Disease Control.

Mitochondria, widely known as the energy factories of eukaryotic cells, have a myriad of vital functions across diverse cellular processes. Dysfunctions within mitochondria serve as catalysts for various diseases, prompting widespread cellular demise. Mounting research on remedying damaged mitochondria indicates that mitochondria constitute a valuable target for therapeutic intervention against diseases. But the less clinical practice and lower recovery rate imply the limitation of traditional drugs, which need a further breakthrough. Nanotechnology has approached favorable regiospecific biodistribution and high efficacy by capitalizing on excellent nanomaterials and targeting drug delivery. Mitochondria-remedying nanodrugs have achieved ideal therapeutic effects. This review elucidates the significance of mitochondria in various cells and organs, while also compiling mortality data for related diseases. Correspondingly, nanodrug-mediate therapeutic strategies and applicable mitochondria-remedying nanodrugs in disease are detailed, with a full understanding of the roles of mitochondria dysfunction and the advantages of nanodrugs. In addition, the future challenges and directions are widely discussed. In conclusion, this review provides comprehensive insights into the design and development of mitochondria-remedying nanodrugs, aiming to help scientists who desire to extend their research fields and engage in this interdisciplinary subject.

Antioxidative 0-dimensional nanodrugs overcome obstacles in AKI antioxidant therapy.

Acute kidney injury (AKI) is a commonly encountered syndrome associated with various aetiologies and pathophysiological processes leading to enormous health risks and economic losses. In the absence of specific drugs to treat AKI, hemodialysis remains the primary clinical treatment for AKI patients. The revelation of the pathology opens new horizons for antioxidant therapy in the treatment of AKI. However, small molecule antioxidant drugs and common nanozymes have failed to challenge AKI due to their unsatisfactory drug properties and renal physiological barriers. 0-Dimensional (0D) antioxidant nanodrugs stand out at this time thanks to their small size and high performance. Recently, a number of research studies have been carried out around 0D nanodrugs for alleviating AKI, and their multi-antioxidant enzyme mimetic activities, smooth glomerular filtration barrier permeability and excellent biocompatibility have been investigated. Here, we comprehensively summarize recent advances in 0D nanodrugs for AKI antioxidant therapy. We classify these representative studies into three categories according to the characteristics of 0D nanomaterials, namely ultra-small metal nanodots, inorganic non-metallic quantum dots and polymer nanodots. We focus on the antioxidant mechanisms and their distribution in vivo in each inspiring work, and the purpose and ingenuity of each design are rigorously captured and described. Finally, we provide our reflections and prospects for 0D antioxidant nanodrugs in AKI treatment. This mini review provides unique insights and valuable clues in the design of 0D nanodrugs and other kidney absorbable drugs.

Surface control approach for growth of cerium oxide on flower-like molybdenum disulfide nanosheets enables superior removal of uremic toxins.

Due to the high incidence of kidney disease, there is an urgent need to develop wearable artificial kidneys. This need is further exacerbated by the coronavirus disease 2019 pandemic. However, the dialysate regeneration system of the wearable artificial kidney has a low adsorption capacity for urea, which severely limits its application. Therefore, nanomaterials that can effectively remove uremic toxins, especially urea, to regenerate dialysate are required and should be further investigated and developed. Herein, flower-like molybdenum disulphide (MoS2) nanosheets decorated with highly dispersed cerium oxide (CeO2) were prepared (MoS2/CeO2), and their adsorption performances for urea, creatinine, and uric acid were studied in detail. Due to the open interlayer structures and the combination of MoS2 and CeO2, which can provide abundant adsorption active sites, the MoS2/CeO2 nanomaterials present excellent uremic toxin adsorption activities. Further, uremic toxin adsorption capacities were also assessed using a self-made fixed bed device under dynamic conditions, with the aim of developing MoS2/CeO2 for the practical adsorption of uremic toxins. In addition, the biocompatibility of MoS2/CeO2 was systematically analyzed using hemocompatibility and cytotoxicity assays. Our data suggest that MoS2/CeO2 can be safely used for applications requiring close contact with blood. Our findings confirm that novel 2-dimensional nanomaterial adsorbents have significant potential for dialysis fluid regeneration.

Emerging Sonodynamic Therapy-Based Nanomedicines for Cancer Immunotherapy.

Cancer immunotherapy effect can be greatly enhanced by other methods to induce immunogenic cell death (ICD), which has profoundly affected immunotherapy as a highly efficient paradigm. However, these treatments have significant limitations, either by causing damage of the immune system or limited to superficial tumors. Sonodynamic therapy (SDT) can induce ICD to promote immunotherapy without affecting the immune system because of its excellent spatiotemporal selectivity and low side effects. Nevertheless, SDT is still limited by low reactive oxygen species yield and the complex tumor microenvironment. Recently, some emerging SDT-based nanomedicines have made numerous attractive and encouraging achievements in the field of cancer immunotherapy due to high immunotherapeutic efficiency. However, this cross-cutting field of research is still far from being widely explored due to huge professional barriers. Herein, the characteristics of the tumor immune microenvironment and the mechanisms of ICD are firstly systematically summarized. Subsequently, the therapeutic mechanism of SDT is fully summarized, and the advantages and limitations of SDT are discussed. The representative advances of SDT-based nanomedicines for cancer immunotherapy are further highlighted. Finally, the application prospects and challenges of SDT-based immunotherapy in future clinical translation are discussed.

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney.

Currently, there are no clinical drugs available to treat acute kidney injury (AKI). Given the high prevalence and high mortality rate of AKI, the development of drugs to effectively treat AKI is a huge unmet medical need and a research hotspot. Although existing evidence fully demonstrates that reactive oxygen and nitrogen species (RONS) burst at the AKI site is a major contributor to AKI progression, the heterogeneity, complexity, and unique physiological structure of the kidney make most antioxidant and anti-inflammatory small molecule drugs ineffective because of the lack of kidney targeting and side effects. Recently, nanodrugs with intrinsic kidney targeting through the control of size, shape, and surface properties have opened exciting prospects for the treatment of AKI. Many antioxidant nanodrugs have emerged to address the limitations of current AKI treatments. In this review, we systematically summarized for the first time about the emerging nanodrugs that exploit the pathological and physiological features of the kidney to overcome the limitations of traditional small-molecule drugs to achieve high AKI efficacy. First, we analyzed the pathological structural characteristics of AKI and the main pathological mechanism of AKI: hypoxia, harmful substance accumulation-induced RONS burst at the renal site despite the multifactorial initiation and heterogeneity of AKI. Subsequently, we introduced the strategies used to improve renal targeting and reviewed advances of nanodrugs for AKI: nano-RONS-sacrificial agents, antioxidant nanozymes, and nanocarriers for antioxidants and anti-inflammatory drugs. These nanodrugs have demonstrated excellent therapeutic effects, such as greatly reducing oxidative stress damage, restoring renal function, and low side effects. Finally, we discussed the challenges and future directions for translating nanodrugs into clinical AKI treatment.

Efficient Therapy of Inflammatory Bowel Disease (IBD) with Highly Specific and Durable Targeted Ta2 C Modified with Chondroitin Sulfate (TACS).

Non-invasive localization of lesions and specific targeted therapy are still the main challenges for inflammatory bowel disease (IBD). Ta, as a medical metal element, has been widely used in the treatment of different diseases because of its excellent physicochemical properties but is still far from being explored in IBD. Here, Ta2 C modified with chondroitin sulfate (CS) (TACS) is evaluated as a highly targeted therapy nanomedicine for IBD. Specifically, TACS is modified with dual targeting CS functions due to IBD lesion-specific positive charges and high expression of CD44 receptors. Thanks to the acid stability, sensitive CT imaging function, and strong reactive oxygen species (ROS) elimination ability, oral TACS can accurately locate and delineate IBD lesions through non-invasive CT imaging, and specifically targeted treat IBD effectively because high levels of ROS are a central factor in the progression of IBD. As expected, TACS has much better imaging and therapeutic effects than clinical CT contrast agent and first-line drug 5-aminosalicylic acid, respectively. The mechanism of TACS treatment mainly involves protection of mitochondria, elimination of oxidative stress, inhibiting macrophage M1 polarization, protection of intestinal barrier, and restoration of intestinal flora balance. Collectively, this work provides unprecedented opportunities for oral nanomedicines to targeted therapy of IBD.

Selenium Nanodots (SENDs) as Antioxidants and Antioxidant-Prodrugs to Rescue Islet ß Cells in Type 2 Diabetes Mellitus by Restoring Mitophagy and Alleviating Endoplasmic Reticulum Stress.

Preventing islet ß-cells death is crucial for treating type 2 diabetes mellitus (T2DM). Currently, clinical drugs are being developed to improve the quality of T2DM care and self-care, but drugs focused on reducing islets ß-cell death are lacking. Given that ß-cell death in T2DM is dominated ultimately by excessive reactive oxygen species (ROS), eliminating excessive ROS in ß-cells is a highly promising therapeutic strategy. Nevertheless, no antioxidants have been approved for T2DM therapy because most of them cannot meet the long-term and stable elimination of ROS in ß-cells without eliciting toxic side-effects. Here, it is proposed to restore the endogenous antioxidant capacity of ß-cells to efficiently prevent ß-cell death using selenium nanodots (SENDs), a prodrug of the antioxidant enzyme glutathione peroxidase 1 (GPX1). SENDs not only scavenge ROS effectively, but also "send" selenium precisely to ß-cells with ROS response to greatly enhance the antioxidant capacity of ß-cells by increasing GPX1 expression. Therefore, SENDs greatly rescue ß-cells by restoring mitophagy and alleviating endoplasmic reticulum stress (ERS), and demonstrate much stronger efficacy than the first-line drug metformin for T2DM treatment. Overall, this strategy highlights the great clinical application prospects of SENDs, offering a paradigm for an antioxidant enzyme prodrug for T2DM treatment.

Nanomaterial-based biosensor developing as a route toward in vitro diagnosis of early ovarian cancer.

The grand challenges of ovarian cancer early diagnosis have led to an alarmingly high mortality rate from ovarian cancer (OC) in the past half century. In vitro diagnosis (IVD) has great potential in the early diagnosis of OC through non-invasive and dynamic analysis of biomarkers. However, common IVDs often fail to provide reliable test results due to lack of sensitivity, specificity, and convenience. In recent years, the discovery of new biomarkers and the progress of nanomaterials can solve the shortcomings of traditional IVD for early OC. These emerging biosensors based on nanomaterials offer great improvements in convenience, speed, selectivity, and sensitivity of IVD. In this review, we firstly systematically summarized the limits of commercial IVD biosensors of OC and the latest discovery of new biomarkers for OC. The representative optimization strategies for six potential ovarian cancer biomarkers are systematically discussed with emphasis on nanomaterial selection and the design of detection principles. Then, various strategies adopted by emerging biosensors based on nanomaterials are also introduced in detail, including optical, electrochemical, microfluidic, and surface plasmon sensors. Finally, current challenges of early OC IVD are proposed, and future research directions on this promising field are also discussed.

State-of-the-art advancements in Liver-on-a-chip (LOC): Integrated biosensors for LOC.

Liver models are vital for the liver diseases and drug research as many novel drugs. However, traditional liver models cannot meet this need, mainly because they cannot replicate the complex physiological structure and microenvironment of the liver, especially the O2 and nutrient gradients. Liver-on-a-chip (LOC), based on microfluidic technology, can not only closely simulate the physiological structure and microenvironment of the liver through the design of suitable microchannels, but can also incorporate advanced biosensors with high sensitivity and potential for rapid responses to microenvironmental signals and liver function indicators. Nevertheless, LOCs have not been widely exploited for liver disease research or the screening of drugs for hepatotoxicity because of considerable professional barriers. In this review, we comprehensively summarize recent progress in LOC development and the embedding of biosensors into LOCs. We first introduce the physiological characteristics and microenvironment of the liver and then summarize the fabrication process and advantages of LOCs. We subsequently focus on recent advances relating to three-dimensional (3D) hepatocyte organization and the simulation of hepatic sinusoids and lobules in LOCs and further systematically summarize the research progress in biosensor-integrated LOCs. Finally, we discuss the potential value of LOCs and the challenges facing their exploitation. In conclusion, this review provides insights into the design and development of biosensor-integrated LOCs aiming to promote further research into this promising platform.

Nucleus-Targeting Phototherapy Nanodrugs for High-Effective Anti-Cancer Treatment.

DNA is always one of the most important targets for cancer therapy due to its leading role in the proliferation of cancer cells. Phototherapy kills cancer cells by generating reactive oxygen species (ROS) and local hyperthermia under light. It has attracted extensive interest in the clinical treatment of tumors because of many advantages such as non-invasiveness, high patient compliance, and low toxicity and side effects. However, the short ROS diffusion distance and limited thermal diffusion rate make it difficult for phototherapy to damage DNA deep in the nucleus. Therefore, nucleus-targeting phototherapy that can destroy DNAs via in-situ generation of ROS and high temperature can be a very effective strategy to address this bottleneck. Recently, some emerging nucleus-targeting phototherapy nanodrugs have demonstrated extremely effective anticancer effects. However, reviews in the field are still rarely reported. Here, we comprehensively summarized recent advances in nucleus-targeting phototherapy in recent years. We classified nucleus-targeting phototherapy into three categories based on the characteristics of these nucleus-targeting strategies. The first category is the passive targeting strategy, which mainly targets the nucleus by adjusting the physicochemical characteristics of phototherapy nanomedicines. The second category is to mediate the phototherapy nanodrugs into the nucleus by modifying functional groups that actively target the nucleus. The third category is to assist nanodrugs enter into the nucleus in a light-controlled way. Finally, we provided our insights and prospects for nucleus-targeting phototherapy nanodrugs. This minireview provides unique insights and valuable clues in the design of phototherapy nanodrugs and other nucleus-targeting drugs.

Nanodrugs Detonate Lysosome Bombs.

Cancer cell lysosomes contain various hydrolases and non-degraded substrates that are corrosive enough to destroy cancer cells. However, many traditional small molecule drugs targeting lysosomes have strong side effects because they cannot effectively differentiate between normal and cancer cells. Most lysosome-based research has focused on inducing mild lysosomal membrane permeabilization (LMP) to release anticancer drugs from lysosomal traps into the cancer cell cytoplasm. In fact, lysosomes are particularly powerful "bombs". Achieving cancer cell-selective LMP induction may yield high-efficiency anticancer effects and extremely low side effects. Nanodrugs have diverse and combinable properties and can be specifically designed to selectively induce LMP in cancer cells by taking advantage of the differences between cancer cells and normal cells. Although nanodrugs-induced LMP has made great progress recently, related reviews remain rare. Herein, we first comprehensively summarize the advances in nanodrugs-induced LMP. Next, we describe the different nanodrugs-induced LMP strategies, namely nanoparticles aggregation-induced LMP, chemodynamic therapy (CDT)-induced LMP, and magnetic field-induced LMP. Finally, we analyze the prospect of nanodrugs-induced LMP and the challenges to overcome. We believe this review provides a unique perspective and inspiration for designing lysosome-targeting drugs.

Nanomedicine Strategies for Heating "Cold" Ovarian Cancer (OC): Next Evolution in Immunotherapy of OC.

Immunotherapy has revolutionized cancer treatment, dramatically improving survival rates of melanoma and lung cancer patients. Nevertheless, immunotherapy is almost ineffective against ovarian cancer (OC) due to its cold tumor immune microenvironment (TIM). Many traditional medications aimed at remodeling TIM are often associated with severe systemic toxicity, require frequent dosing, and show only modest clinical efficacy. In recent years, emerging nanomedicines have demonstrated extraordinary immunotherapeutic effects for OC by reversing the TIM because the physical and biochemical features of nanomedicines can all be harnessed to obtain optimal and expected tissue distribution and cellular uptake. However, nanomedicines are far from being widely explored in the field of OC immunotherapy due to the lack of appreciation for the professional barriers of nanomedicine and pathology, limiting the horizons of biomedical researchers and materials scientists. Herein, a typical cold tumor-OC is adopted as a paradigm to introduce the classification of TIM, the TIM characteristics of OC, and the advantages of nanomedicines for immunotherapy. Subsequently, current nanomedicines are comprehensively summarized through five general strategies to substantially enhance the efficacy of immunotherapy by heating the cold OC. Finally, the challenges and perspectives of this expanding field for improved development of clinical applications are also discussed.

Emerging early diagnostic methods for acute kidney injury.

Many factors such as trauma and COVID-19 cause acute kidney injury (AKI). Late AKI have a very high incidence and mortality rate. Early diagnosis of AKI provides a critical therapeutic time window for AKI treatment to prevent progression to chronic renal failure. However, the current clinical detection based on creatinine and urine output isn't effective in diagnosing early AKI. In recent years, the early diagnosis of AKI has made great progress with the advancement of information technology, nanotechnology, and biomedicine. These emerging methods are mainly divided into two aspects: First, predicting AKI through models construct by machine learning; Second, early diagnosis of AKI through detection of newly-discovered early biomarkers. Currently, these methods have shown great potential and become an attractive tool for the early diagnosis of AKI. Therefore, it is very important to discuss and summarize these methods for the early diagnosis of AKI. In this review, we first systematically summarize the application of machine learning in AKI prediction algorithms and specific scenarios. In addition, we introduce the key role of early biomarkers in the progress of AKI, and then comprehensively summarize the application of emerging detection technologies for early AKI. Finally, we discuss current challenges and prospects of machine learning and biomarker detection. The review is expected to provide new insights for early diagnosis of AKI, and provided important inspiration for the design of early diagnosis of other major diseases.

Nanotherapies for sepsis by regulating inflammatory signals and reactive oxygen and nitrogen species: New insight for treating COVID-19.

SARS-CoV-2 has caused up to 127 million cases of COVID-19. Approximately 5% of COVID-19 patients develop severe illness, and approximately 40% of those with severe illness eventually die, corresponding to more than 2.78 million people. The pathological characteristics of COVID-19 resemble typical sepsis, and severe COVID-19 has been identified as viral sepsis. Progress in sepsis research is important for improving the clinical care of these patients. Recent advances in understanding the pathogenesis of sepsis have led to the view that an uncontrolled inflammatory response and oxidative stress are core factors. However, in the traditional treatment of sepsis, it is difficult to achieve a balance between the inflammation, pathogens (viruses, bacteria, and fungi), and patient tolerance, resulting in high mortality of patients with sepsis. In recent years, nanomaterials mediating reactive oxygen and nitrogen species (RONS) and the inflammatory response have shown previously unattainable therapeutic effects on sepsis. Despite these advantages, RONS and inflammatory response-based nanomaterials have yet to be extensively adopted as sepsis therapy. To the best of our knowledge, no review has yet discussed the pathogenesis of sepsis and the application of nanomaterials. To help bridge this gap, we discuss the pathogenesis of sepsis related to inflammation and the overproduction RONS, which activate pathogen-associated molecular pattern (PAMP)-pattern recognition receptor (PRR) and damage-associated molecular pattern (DAMP)-PRR signaling pathways. We also summarize the application of nanomaterials in the treatment of sepsis. As highlighted here, this strategy could synergistically improve the therapeutic efficacy against both RONS and inflammation in sepsis and may prolong survival. Current challenges and future developments for sepsis treatment are also summarized.

ROS-Scavenging Nanomaterials to Treat Periodontitis.

The incidence of periodontitis is very high, and up to 45-50% of people are suffering from periodontitis. Periodontitis is caused by pathogens that invade teeth-supporting tissues such as gingiva, periodontal ligament, and alveolar bone. Pathogens trigger host immune responses characterized by the overproduction of reactive oxygen species (ROS). The development of effective ROS scavengers through nanotechnology has been emerging as a promising strategy for the treatment of periodontitis. Nanomaterial-based antioxidants can effectively scavenge ROS, prevent ROS-mediated tissue damage, and relieve inflammation in periodontitis. This mini-review focuses on the generation of ROS in periodontitis and its molecular mechanism of destroying periodontal tissue. Meanwhile, we summarize the research progress of ROS-scavenging nanomaterials in the treatment of periodontitis and discuss the challenges and prospects of its application.