Nanosensitizers for sonodynamic therapy for glioblastoma multiforme: current progress and future perspectives

Glioblastoma multiforme(GBM) is the most common primary malignant brain tumor, and it is associated with poor prognosis. Its characteristics of being highly invasive and undergoing heterogeneous genetic mutation, as well as the presence of the blood–brain barrier(BBB), have reduced the efficacy of GBM treatment. The emergence of a novel therapeutic method, namely, sonodynamic therapy(SDT), provides a promising strategy for eradicating tumors via activated sonosensitizers coupled with low-intensity ultrasound. SDT can provide tumor killing effects for deep-seated tumors, such as brain tumors. However, conventional sonosensitizers cannot effectively reach the tumor region and kill additional tumor cells, especially brain tumor cells. Efforts should be made to develop a method to help therapeutic agents pass through the BBB and accumulate in brain tumors. With the development of novel multifunctional nanosensitizers and newly emerging combination strategies, the killing ability and selectivity of SDT have greatly improved and are accompanied with fewer side effects. In this review, we systematically summarize the findings of previous studies on SDT for GBM, with a focus on recent developments and promising directions for future research.

Nanoscale coordination polymer Fe-DMY downregulating Poldip2-Nox4-H2O2 pathway and alleviating diabetic retinopathy

Diabetic retinopathy(DR)is a prevalent microvascular complication of diabetes and the leading cause of blindness and severe visual impairment in adults.The high levels of glucose trigger multiple intracellular oxidative stress pathways,such as POLDIP2,resulting in excessive reactive oxygen species(ROS)production and increased expression of vascular cell adhesion molecule-1(VCAM-1),hypoxia-inducible factor 1a(HIF-1a),and vascular endothelial growth factor(VEGF),causing microvascular dysfunction.Dihydromyricetin(DMY)is a natural flavonoid small molecule antioxidant.However,it exhibits poor solubility in physiological environments,has a short half-life in vivo,and has low oral bioavailability.In this study,we present,for the first time,the synthesis of ultra-small Fe-DMY nano-coordinated polymer particles(Fe-DMY NCPs),formed by combining DMY with low-toxicity iron ions.In vitro and in vivo experiments confirm that Fe-DMY NCPs alleviate oxidative stress-induced damage to vascular endothelial cells by high glucose,scavenge excess ROS,and improve pathological features of DR,such as retinal vascular leakage and neovascularization.Mechanistic validation indicates that Fe-DMY NCPs can inhibit the activation of the Poldip2-Nox4-H_(2)O_(2) signaling pathway and downregulate vital vascular function indicators such as VCAM-1,HIF-1a,and VEGF.These findings suggest that Fe-DMY NCPs could serve as a safe and effective antioxidant and microangio-protective agent,with the potential as a novel multimeric drug for DR therapy.

Dynamic regulation of the wound repair process:achieving one-stop scar-free repair

At present,the clinical treatment of chronic refractory wounds still faces many challenges:on the one hand,the delivery efficiency of therapeutic drugs is seriously affected by physiological barriers such as bacterial membranes;on the other hand,how to dynamically deliver appropriate drugs at different stages of wound healing is also an important factor affecting wound healing.

Metal natural product complex Ru-procyanidins with quadruple enzymatic activity combat infections from drug-resistant bacteria

Bacterial infection hampers wound repair by impeding the healing process.Concurrently,inflammation at the wound site triggers the production of reactive oxygen species(ROS),causing oxidative stress and damage to proteins and cells.This can lead to chronic wounds,posing severe risks.Therefore,eliminating bacterial infection and reducing ROS levels are crucial for effective wound healing.Nanozymes,possessing enzyme-like catalytic activity,can convert endogenous substances into highly toxic substances,such as ROS,to combat bacteria and biofilms without inducing drug resistance.However,the current nanozyme model with single enzyme activity falls short of meeting the complex requirements of antimicrobial therapy.Thus,developing nanozymes with multiple enzymatic activities is essential.Herein,we engineered a novel metalloenzyme called Ru-procyanidin nanoparticles(Ru-PC NPs)with diverse enzymatic activities to aid wound healing and combat bacterial infections.Under acidic conditions,due to their glutathione(GSH)depletion and peroxidase(POD)-like activity,Ru-PC NPs combined with H2O2 exhibit excellent antibacterial effects.However,in a neutral environment,the Ru-PC NPs,with catalase(CAT)activity,decompose H2O2 to O2,alleviating hypoxia and ensuring a sufficient oxygen supply.Furthermore,Ru-PC NPs possess exceptional antioxidant capacity through their superior superoxide dismutase(SOD)enzyme activity,effectively scavenging excess ROS and reactive nitrogen species(RNS)in a neutral environment.This maintains the balance of the antioxidant system and prevents inflammation.Ru-PC NPs also promote the polarization of macrophages from M1 to M2,facilitating wound healing.More importantly,Ru-PC NPs show good biosafety with negligible toxicity.In vivo wound infection models have confirmed the efficacy of Ru-PC NPs in inhibiting bacterial infection and promoting wound healing.The focus of this work highlights the quadruple enzymatic activity of Ru-PC NPs and its potential to reduce inflammation and promote bacteria-infected wound healing.

Antibacterial mechanism and transcriptomic analysis of a nearinfrared triggered upconversion nanoparticles@AgBiS2 for synergetic bacteria-infected therapy

Methicillin-resistant Staphylococcus aureus(MRSA)has become a rising clinical problem as its occurrence has increased due to the overuse and misuse of antibiotics.In this work,upconversion nanoparticles@AgBiS2 core–shell were produced with enhanced photothermal transformation efficiency and ability to produce reactive oxygen species for synergistic photodynamic photothermal and photodynamic antibacterial performance.The nanoparticles exhibit good antibacterial effects in vitro and satisfactory therapeutic performance on healing MRSA-infected wounds in vivo experiments.RNA-sequencing technique has been used to investigate and reveal that photothermal–photodynamic therapy using the nanoparticles can interfere with metabolic processes such as galactose metabolism in MRSA bacteria,destroy the transport system on the surface of MRSA,and affect quorum sensing to hinder the formation of biofilms to achieve effective antibacterial efficacy.It was demonstrated that this work presents an alternative near-infrared photoactive multimodal nanostructure for antibacterial applications.

Anti-inflammatory catecholic chitosan hydrogel for rapid surgical trauma healing and subsequent prevention of tumor recurrence

Although occupying pillar position in clinical cancer treatments,surgery itself and surgical trauma would elicit series of local/systemic inflammation-related responses that resulted in high rate of tumor recurrence.Herein,chitosan with conjugated gallic acid(CSG)molecules were coordinated with Fe3+to form CSG/Fe3+hydrogel for filling the tumo r-resected cavity with considerable wet-adhesion ability and anti-inflammatory performance.With the assistance of doxorubicin hydrochloride(DOX·HCl),CSG/Fe3+/DOX hydrogel exhibited syne rgistic photothermal-chemo tumo r-inhibited performance under near-infrared(NIR)light irradiation for eradicating residual and/or surgical trauma-recruited cancer cells.Thus,our study attempts to show a paradigm that realizes quick surgical trauma healing,inflammation inhibition and prevention of postsurgical tumor recurrence.

Platelet membrane-coated C-TiO_(2) hollow nanospheres for combined sonodynamic and alkyl-radical cancer therapy

The therapeutic efficiency of sonodynamic therapy(SDT)mainly depends on the presence of oxygen(O_(2))to generate harmful reactive oxygen species(ROS);thus,the hypoxic tumor microenvironment significantly limits the efficacy of SDT.Therefore,the development of oxygen-independent free radical generators and associated combination therapy tactics can be a promising field to facilitate the anticancer capability of SDT.In this study,a biomimetic drug delivery system(C-TiO_(2)/AIPH@PM)composed of an alkyl-radical generator(2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride,AIPH)-loaded C-TiO_(2) hollow nanoshells(HNSs)as the inner cores,and a platelet membrane(PM)as the outer shells is successfully prepared for synergistic SDT and oxygen-independent alkyl-radical therapy.The PM encapsulation can significantly prolong the blood circulation time of CTiO_(2)/AIPH@PM compared with C-TiO_(2)/AIPH while enabling C-TiO_(2)/AIPH@PM to achieve tumor targeting.C-TiO_(2)/AIPH@PM can efficiently produce ROS and alkyl radicals,which can achieve a more thorough tumor eradication regardless of the normoxic or hypoxic conditions.Furthermore,the generation of these radicals improves the efficiency of SDT.In addition,nitrogen(N_(2))produced due to the decomposition of AIPH enhances the acoustic cavitation effect and lowers the cavitation threshold,thereby enhancing the penetration of CTiO_(2)/AIPH@PM at the tumor sites.Both in vitro and in vivo experiments demonstrate that CTiO_(2)/AIPH@PM possesses good biosafety,ultrasound imaging performance,and excellent anticancer efficacy.This study provides a new strategy to achieve oxygen-independent free radical production and enhance therapeutic efficacy by combining SDT and free radical therapy.

CA242围手术期变化模式及纵向轨迹与结直肠癌预后的关联:一项回顾性纵向队列研究

以往关于CA242的研究大多局限于术前水平,忽略了其围手术期变化模式和纵向轨迹.基于一项结直肠癌(CRC)患者的回顾性队列,本研究根据术前和术后CA242水平确定了围手术期CA242变化模式,利用随访期间CA242的重复测量识别了CA242纵向轨迹,并评估了其与CRC预后的关系.结果显示,围手术期CA242变化模式是CRC的独立预后因素.术后CA242持续升高患者的无复发生存率(RFS)低于术后CA242恢复正常的患者,且术后/术前CA242比值可进一步对这两组患者进行复发风险分层.轨迹分析发现,术后3年内CA242存在低稳定、早期上升和晚期上升三种纵向变化模式.纵向轨迹与RFS显著相关,且独立于术前和术后CA242.在CEA正常的患者中,CA242的围手术期变化模式和纵向轨迹与RFS之间仍然存在显著关联,表明在CEA基础上测量CA242有助于识别预后较差的高危CRC患者.基于本研究结果,建议对CRC患者进行CA242的常规术后随访.

Evoking robust immunogenic cell death by synergistic sonodynamic therapy and glucose depletion using Au clusters/single atoms modified TiO_(2)nanosheets

Facilitated by reactive oxygen species(ROS)-involved therapies,tumor cells undergo immunogenic cell death(ICD)to stimulate long-term immunity response.However,it is hard to trigger abundant and large-scale ICD for satisfactory cancer immunotherapy.Herein,a multifunctional sonosensitizer that consists of Au single atoms and clusters anchored on TiO_(2)nanosheets(named Au_(S/C)-TiO_(2))is reported for augmented sonodynamic therapy(SDT)and glucose depletion,which ultimately induce robust ICD due to the improved ROS generation and strong endoplasmic reticulum(ER)stress.The synergy effect between Au cluster/single atom with TiO_(2)nanosheets intensifies apoptosis and ICD pathways to inhibit 80%of tumor cells through in vivo analyses.Furthermore,immune cells in vivo analyses verify the effectiveness of Au_(S/C)-TiO_(2)sonosensitizer towards the induction of antitumor immunity.This study thus reveals that simultaneous presence of ROS generation and strong ER stress can efficiently evoke a strong ICD-mediated immune response.

Biomimetic copper single-atom nanozyme system for self-enhanced nanocatalytic tumor therapy

Single-atom nanozymes(SAZs)with peroxidase(POD)-like activity have good nanocatalytic tumor therapy(NCT)capabilities.However,insufficient hydrogen peroxide(H2O2)and hydrogen ions in the cells limit their therapeutic effects.Herein,to overcome these limitations,a biomimetic single-atom nanozyme system was developed for self-enhanced NCT.We used a previously described approach to produce platelet membrane vesicles.Using a high-temperature carbonization approach,copper SAZs with excellent POD-like activity were successfully synthesized.Finally,through physical extrusion,a proton pump inhibitor(PPI;pantoprazole sodium)and the SAZs were combined with platelet membrane vesicles to create PPS.Both in vivo and in vitro,PPS displayed good tumor-targeting and accumulation abilities.PPIs were able to simultaneously regulate the hydrogen ion,glutathione(GSH),and H2O2 content in tumor cells,significantly improve the catalytic ability of SAZs,and achieve self-enhanced NCT.Our in vivo studies showed that PPS had a tumor suppression rate of>90%.PPS also limited the synthesis of GSH in cells at the source;thus,glutamine metabolism therapy and NCT were integrated into an innovative method,which provides a novel strategy for multimodal tumor therapy.

Micro/nanodevices for assessment and treatment in stomatology and ophthalmology

Micro/nanodevices have been widely applied for the real-time monitoring of intracellular activities and the delivery of exogenous substances in the past few years.This review focuses on miniaturized micro/nanodevices for assessment and treatment in stomatology and ophthalmology.We first summarize the recent progress in this field by examining the available materials and fabrication techniques,device design principles,mechanisms,and biosafety aspects of micro/nanodevices.Following a discussion of biochemical sensing technology from the cellular level to the tissue level for disease assessment,we then summarize the use of microneedles and other micro/nanodevices in the treatment of oral and ocular diseases and conditions,including oral cancer,eye wrinkles,keratitis,and infections.Along with the identified key challenges,this review concludes with future directions as a small fraction of vast opportunities,calling for joint efforts between clinicians and engineers with diverse backgrounds to help facilitate the rapid development of this burgeoning field in stomatology and ophthalmology.

NiCo-LDH nanosheets strongly coupled with GO-CNTs as a hybrid electrocatalyst for oxygen evolution reaction

The rational fabrication of highly efficient electrocatalysts with low cost toward oxygen evolution reaction(OER)is greatly desired but remains a formidable challenge.In this work,we present a facile and straightforward method of incorporating NiCo-layered double hydroxide(NiCo-LDH)into GO-dispersed CNTs(GO-CNTs)with interconnected configuration.X-ray absorption spectroscopy(XAS)reveals the strong electron interaction between NiCo-LDH and the underlying GO-CNTs substrate,which is supposed to facilitate charge transfer and accelerate the kinetics for OER.By tuning the amount of CNTs,the optimized NiCo-LDH/GO-CNTs composite can achieve a low overpotential of 290 mV at 10 mA·cm^(−2) current density,a small Tafel slope of 66.8 mV·dec^(−1) and robust stability,superior to the pure NiCo-LDH and commercial RuO_(2) in alkaline media.The preeminent oxygen evolution performance is attributed to the synergistic effect stemming from the merits and the intimate electron interaction between LDH and GO-CNTs.This allows NiCo-LDH/GO-CNTs to be potentially applied in an industrial non-noble metal-based water electrolyzer as the anodic catalysts.