Theranostic Prodrug Vesicles for Reactive Oxygen Species‐Triggered Ultrafast Drug Release and Local‐Regional Therapy of Metastatic Triple‐Negative Breast Cancer

A reactive oxygen species (ROS)‐activatable doxorubicin (Dox) prodrug vesicle (RADV) is presented for image‐guided ultrafast drug release and local‐regional therapy of the metastatic triple‐negative breast cancer (TNBC). RADV is prepared by integrating a ROS‐activatable Dox prodrug, a poly(ethylene glycol) (PEG)‐modified photosensitizer pyropheophorbide‐a, an unsaturated phospholipid 1,2‐dioleoyl‐sn‐glycero‐3‐phosphocholine, and cholesterol into one single nanoplatform. RADV is of extremely high drug loading ratio (27.5 wt%) by self‐assembly of the phospholipid‐mimic Dox prodrug into the liposomal bilayer membrane. RADV displays good colloidal stability to prevent premature drug leakage during the blood circulation and inert photochemotoxicity to avoid nonspecific side effect. RADV passively accumulates at tumor site through the enhanced permeability and retention effect when administrated systemically. Once deposited at the tumor site, RADV generates fluorescent and photoacoustic signals to guide near‐infrared (NIR) laser irradiation, which can induce localized ROS generation, not only to trigger prodrug activation and ultrafast drug release but also conduct photodynamic therapy in a spatiotemporally controlled manner. In combination with NIR laser irradiation, RADV efficiently inhibits the tumor growth and distant metastasis of TNBC. Local‐regional tumor therapy using intelligent theranostic nanomedicine might provide an alternative option for highly efficient treatment of the metastatic TNBC.     

Length-Controlled Construction of Ceria Nanowires with Ultrafine Diameter and Stable Morphology for Targeted Acute Lung Injury Therapy

The overproduction of reactive oxygen species (ROS) is one of the major reasons for the aggravation of acute lung injury (ALI). Smaller-sized ceria nanoparticles featured with higher ROS scavenging capability than their bigger-sized counterparts are potential candidates for ALI therapy. However, smaller-sized ceria nanoparticles are more easily accumulated in spleen and liver rather than lung. Herein, it is reported that this obstacle can be addressed by constructing ceria into ultrafine nanowires, through which the ultrafine diameter ensures the high ROS scavenging activity and the high aspect ratio promotes the lung targeted accumulation. To demonstrate the feasibility of this conception, a platform is developed to realize length-controlled ceria nanowires (diameter of ≈1.5 nm) synthesis. These nanowires are PEGylated using a carefully optimized procedure that can preserve their fragile crystal structures. The PEGylated nanowires exhibit higher ROS scavenging capabilities than the ≈3.9 nm sized nanoparticles. Most importantly, lung targeted accumulation can be realized through modulating the length of the nanowires, where the longer nanowires (>100 nm) show much higher lung accumulation. Due to these properties, the longer ceria nanowires can effectively scavenge the overproduced ROS during the progression of ALI, and thereby inhibit the edema and inflammation in the lung tissue.     

Bioinspired Multiantioxidant-Cooperative Nanotheranostic Platform for Realizing Time-Sensitive Management of Acute Kidney Injury

Targeting the pivotal pathological processes of acute kidney injury (AKI) and parallelly monitoring the treatment process has emerged as an intriguing strategy for the timely tailored treatment of AKI, especially in the acute phase. Unfortunately, current clinical treatment approaches are restricted to supportive care, which shows limited efficiency. Herein, a multiantioxidant-cooperative polydopamine-based nanotheranostic platform (mc-PDATP) is reported to achieve imaging-assisted time-sensitive therapy of AKI. Benefiting from the decoration of atomic Cu, mc-PDATP comprehensively mimics the complicated antioxidant defense system as in natural environment, thus displaying improved catalytic activity to multiple toxic reactive oxygen species (ROS). Consequently, both in vitro and in vivo experiments confirm mc-PDATP can efficiently protect the kidney from ROS attack and rescue the kidney function via targeting the inflammatory network of AKI. In addition, the coordinated atomic Gd contributes to a desired magnetic resonance (MR) T1-weighted contrast effect of mc-PDATP, which can be used to construct the sensitive MR histogram imaging signatures for pinpointing treatment effects in a timely manner. The study represents an innovative strategy for anti-AKI therapy, which will facilitate the development of next-generation theranostic nano-antioxidants.     

A Dual‐Functional Photosensitizer for Ultraefficient Photodynamic Therapy and Synchronous Anticancer Efficacy Monitoring

A dual‐functional photosensitizer that demonstrates exceptional photodynamic therapy (PDT) efficacy while simultaneously self‐monitoring the therapeutic response in real time is reported here. Possessing an ultrahigh ¹O₂ quantum yield of 98.6% in water, the photosensitizer TPCI can efficiently induce cell death in a series of carcinoma cells (IC₅₀ values less than 300 × 10^?9 m ) upon irradiation with an extremely low fluence (460 nm, 4 mW cm^?2 for 10 min). In addition, TPCI can self‐monitor cell death in real time. It is weakly fluorescent in living cells before irradiation and lights up the nuclei concomitantly with cell death during PDT treatment by binding with chromatin to activate its aggregation‐induced emission, attributed to its strong binding affinity with DNA. In vivo studies using mouse models bearing H22 and B16F10 tumor cells validate the ultraefficient PDT efficacy of TPCI as well as the precise real‐time noninvasive readout of the tumor response from the beginning of cancer treatment. The dual‐functional TPCI serves as an excellent candidate for single‐agent photodynamic theranostics, and this work represents a new paradigm for the development of molecules with multiple intrinsic functions for future self‐reporting medical applications.     

Enhanced Antibacterial Activity of Nanocrystalline ZnO Due to Increased ROS‐Mediated Cell Injury

An innovative study aimed at understanding the influence of the particle size of ZnO (from the microscale down to the nanoscale) on its antibacterial effect is reported herein. The antibacterial activity of ZnO has been found to be due to a reaction of the ZnO surface with water. Electron‐spin resonance measurements reveal that aqueous suspensions of small nanoparticles of ZnO produce increased levels of reactive oxygen species, namely hydroxyl radicals. Interestingly, a remarkable enhancement of the oxidative stress, beyond the level yielded by the ZnO itself, is detected following the antibacterial treatment. Likewise, an exposure of bacteria to the small ZnO nanoparticles results in an increased cellular internalization of the nanoparticles and bacterial cell damage. An examination of the antibacterial effect is performed on two bacterial species: Escherichia coli (Gram negative) and Staphylococcus aureus (Gram positive). The nanocrystalline particles of ZnO are synthesized using ultrasonic irradiation, and the particle sizes are controlled using different solvents during the sonication process. Taken as a whole, it is apparent that the unique properties (i.e., small size and corresponding large specific surface area) of small nanometer‐scale ZnO particles impose several effects that govern its antibacterial action. These effects are size dependent and do not exist in the range of microscale particles.     

基于XGBoost和SHAP的急性肾损伤可解释预测模型

重症监护病房(ICU)住院期间发生的急性肾损伤(AKI)与患者发病率和死亡率的增加有关。该研究的目的是提出一个基于机器学习的框架,用于危重病患者的可解释AKI预测,该框架能够同时实现良好的预测和解释能力。该文从重症监护医学信息数据库Ⅲ(MIMIC-III)中提取的数据包括患者的年龄、性别、生命体征和ICU入院第1天及随后的化验值。在该研究中,通过将XGBoost模型与其他4种机器学习模型进行比较,证明了XGBoost模型的预测性能。此外,SHAP(SHapley Additive exPlanation)模型可解释器用于提供个性化评估和解释,以实现个性化的临床决策支持。结果表明,XGBoost能较好地预测AKI,与以往的预测模型相比,此模型更为简单有效,仅用21个特征变量即得到了更稳定的预测结果,预测精度高,模型准确率和受试者工作特征曲线下面积(AUC)分别为0.824和0.840,均高于既往研究结果。此外,该文对两组指标进行了特征依赖分析,发现24h尿量减少和血尿素氮升高可增加AKI风险。综上所述,该可解释预测模型可能有助于临床医生更准确快速地识别重症监护中存在AKI风险的患者,为患者提供更好的治疗。此外,可解释性框架的使用增加了模型透明度,便于临床医生分析预测模型的可靠性。     

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe₂O₃ magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l ‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l ‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l ‐TRAIL@MMBs. Such RGD‐l ‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l ‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l ‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.     

An O2 Self‐Supplementing and Reactive‐Oxygen‐Species‐Circulating Amplified Nanoplatform via H2O/H2O2 Splitting for Tumor Imaging and Photodynamic Therapy

Conventional photodynamic therapy (PDT) has limited applications in clinical cancer therapy due to the insufficient O₂ supply, inefficient reactive oxygen species (ROS) generation, and low penetration depth of light. In this work, a multifunctional nanoplatform, upconversion nanoparticles (UCNPs)@TiO₂@MnO₂ core/shell/sheet nanocomposites (UTMs), is designed and constructed to overcome these drawbacks by generating O₂ in situ, amplifying the content of singlet oxygen (¹O₂) and hydroxyl radical (?OH) via water‐splitting, and utilizing 980 nm near‐infrared (NIR) light to increase penetration depth. Once UTMs are accumulated at tumor site, intracellular H₂O₂ is catalyzed by MnO₂ nanosheets to generate O₂ for improving oxygen‐dependent PDT. Simultaneously, with the decomposition of MnO₂ nanosheets and 980 nm NIR irradiation, UCNPs can efficiently convert NIR to ultraviolet light to activate TiO₂ and generate toxic ROS for deep tumor therapy. In addition, UCNPs and decomposed Mn²⁺ can be used for further upconversion luminescence and magnetic resonance imaging in tumor site. Both in vitro and in vivo experiments demonstrate that this nanoplatform can significantly improve PDT efficiency with tumor imaging capability, which will find great potential in the fight against tumor.     

Near‐Infrared Chemiluminescent Reporters for In Vivo Imaging of Reactive Oxygen and Nitrogen Species in Kidneys

Despite the superior sensitivity of chemiluminescence over fluorescence, most chemiluminescence reporters only emit visible light, and have low water solubility, making them poorly equipped for in vivo imaging applications. Herein two near‐infrared (NIR) chemiluminescent reporters (NCRs) with high renal clearance for real‐time imaging of reactive oxygen and nitrogen species in the kidneys are synthesized. NCRs comprise a β‐cyclodextrin unit and a modified dicyanomethylene‐4H‐pyran containing Schaap's dioxetane as the renal‐clearance enabler and the chemiluminescent moiety, respectively. NCR1 and NCR2 specifically activate their NIR chemiluminescence towards superoxide anion (O₂^??) and peroxynitrite (ONOO^?), respectively. By virtue of their nanomolar sensitivity and high renal clearance, NCRs not only detect subtle upregulation of endogenous RONS in cells but also enable noninvasive monitoring of RONS in the kidneys under nephrotoxic exposure. The earlier activation of NCR1 relative to NCR2 implies the sequential upregulation of O₂^?? and ONOO^? during drug‐induced acute kidney injury (AKI). Moreover, detection of the fluorescence of excreted NCRs permits urinalysis of AKI, detecting the upregulation of RONS at least 24 h earlier than histological analysis. Thus, this study not only introduces ultrasensitive NIR chemiluminescent probes but also provides guidelines to transform them into legitimate imaging agents for organ‐specific in vivo detection.     

A Phosphorescent Nanoparticle‐Based Probe for Sensing and Imaging of (Intra)Cellular Oxygen in Multiple Detection Modalities

Monitoring cell and tissue oxygenation is important for the analysis of cell development and differentiation, mitochondrial function, and common (patho)physiological conditions such as ischemia, cancer, neurodegenerative disorders. A number of materials for sensing cellular oxygen (O₂) by optical means have been described in recent years, but the diverse range of biological models and measurement tasks demands more versatile, flexible, and simple O₂ sensors. A new cell‐penetrating phosphorescent nanosensor material called MM2 probe is presented. In it, the highly photostable phosphorescent reporter dye Pt(II)‐5,10,15,20‐tetrakis‐(2,3,4,5,6‐pentafluorophenyl)‐porphyrin (PtTFPP; emission at 650 nm) and poly(9,9‐dioctylfluorene) (PFO) fluorophore act as Förster resonance energy transfer (FRET) donor and two‐photon antennae are embedded in cationic hydrogel nanoparticles. Such probe formulation provides efficient delivery into the cell and subsequent sensing and high‐resolution imaging of cellular O₂ in different detection modalities, including ratiometric intensity and phosphorescence lifetime‐based sensing under one‐photon and two photon excitation. MM2 probe combines high brightness, photo‐ and chemical stability, low toxicity, and ease of fabrication and use. Its versatility and analytical performance are demonstrated in physiological experiments with adherent cells and neurospheres representing 2D and 3D respiring objects and detection on time‐resolved fluorescent readers, confocal and multiphoton microscopes, and customized microsecond fluorescence/phosphorescence lifetime imaging microscopy (FLIM) systems.     

A Hydrogen‐Bonded‐Supramolecular‐Polymer‐Based Nanoprobe for Ratiometric Oxygen Sensing in Living Cells

The first example of a ratiometric optical oxygen nanoprobe based on a hydrogen‐bonded supramolecular polymer has been reported. The supramolecular polymer based nanoprobe (SPNP) is prepared from the co‐assembly of a bis‐ureidopyrimidinone (bis‐UPy)‐containing phosphorescent indicator (Por(Pd)‐bisUPy), fluorescent reference dye (BF₂‐bisUPy), and skeleton unit (DPA‐bisUPy) through quadruple hydrogen bonds by a mini‐emulsion method. The water‐dispersible SPNP is highly sensitive to oxygen (Q = 95%), with full reversibility, excellent storage stability and photostability, and good cell‐penetrating ability, and exhibits low cytotoxicity toward living cells. The preparation of the SPNP is straightforward and its function is easily tuned by changing the monomeric structure. This work is expected to lead to the design of other SPNPs for other important analytes in biological systems.     

A Synergistic System for Lithium–Oxygen Batteries in Humid Atmosphere Integrating a Composite Cathode and a Hydrophobic Ionic Liquid‐Based Electrolyte

Moisture in air is a major obstacle for realizing practical lithium‐air batteries. Here, we integrate a hydrophobic ionic liquid (IL)‐based electrolyte and a cathode composed of electrolytic manganese dioxide and ruthenium oxide supported on Super P (carbon black) to construct a promising system for Li‐O₂ battery that can be sustained in humid atmosphere (RH: 51%). A high discharge potential of 2.94 V and low charge potential of 3.34 V for 218 cycles are achieved. The outstanding performance is attributed to the synergistic effect of the unique hydrophobic IL‐based electrolyte and the composite cathode. This is the first time that such excellent performance is achieved in humid O₂ atmosphere and these results are believed to facilitate the realization of practical lithium‐air batteries.