The root strategy of the C4 grasses tends to be 'do-it-yourself'.

Root resource acquisition strategies play a crucial role in understanding plant water uptake and drought adaptation. However, the interrelationships among mycorrhizal associations, root hair development, and fine root strategies, as well as the disparities between C3 and C4 grasses, remain largely unknown. A pot experiment was conducted to determine leaf gas exchange, root morphology, root hair, mycorrhizal fungi, and biomass allocation of three C4 grasses and four C3 grasses, common species of grasslands in Northeast China, under the control and drought conditions. Compared to the C3 grasses, the C4 grasses increased specific surface area by decreasing tissue density, yet exhibited root hair factor at only 21 % of the C3 grasses. Under the drought conditions, the C4 grasses exhibited more intense and extensive adjustments in root traits, characterized by shifts toward a more conservative morphology with increased root diameter and tissue density, as well as reduced mycorrhizal colonization rates. These adaptations led to a decrease in root absorptive function, which was compensated in the C4 grasses by greater root biomass partitioning and root hair factor. Variances in root strategies between plants functional groups were closely related to leaf photosynthetic rate, water and nitrogen use efficiency. We observed that the C4 grasses prefer direct acquisition of soil resources through the fine root pathway over the root hair or mycorrhizal pathway, suggesting a 'do-it-yourself' approach. These findings provide valuable insights into how plant communities of different photosynthetic types might respond to future climate change.

[Preoperative Evaluation of Cervical Lymph Node Metastasis in Patients With Hashimoto's Thyroiditis Combined With Thyroid Papillary Carcinoma Using Machine Learning and Radiomics-Based Features: A Preliminary Study]. / åŸºäºŽå½±åƒç»„å­¦å’Œä¸´åºŠç‰¹å¾çš„æœºå™¨å­¦ä¹ æœ¯å‰è¯„ä¼°æ¡¥æœ¬ç”²çŠ¶è ºç‚Žåˆå¹¶ç”²çŠ¶è ºä¹³å¤´çŠ¶ç™Œé¢ˆéƒ¨æ·‹å·´ç»“è½¬ç§»çš„åˆæ­¥ç ”ç©¶.

Objective: To analyze the radiomic and clinical features extracted from 2D ultrasound images of thyroid tumors in patients with Hashimoto's thyroiditis (HT) combined with papillary thyroid carcinoma (PTC) using machine learning (ML) models, and to explore the diagnostic performance of the method in making preoperative noninvasive identification of cervical lymph node metastasis (LNM). Methods: A total of 528 patients with HT combined with PTC were enrolled and divided into two groups based on their pathological results of the presence or absence of LNM. The groups were subsequently designated the With LNM Group and the Without LNM Group. Three ultrasound doctors independently delineated the regions of interest and extracted radiomic features. Two modes, radiomic features and radiomics-clinical features, were used to construct random forest (RF), support vector machine (SVM), LightGBM, K-nearest neighbor (KNN), and XGBoost models. The performance of these five ML models in the two modes was evaluated by the receiver operating characteristic (ROC) curves on the test dataset, and SHapley Additive exPlanations (SHAP) was used for model visualization. Results: All five ML models showed good performance, with area under the ROC curve (AUC) ranging from 0.798 to 0.921. LightGBM and XGBoost demonstrated the best performance, outperforming the other models (P<0.05). The ML models constructed with radiomics-clinical features performed better than those constructed using only radiomic features (P<0.05). The SHAP visualization of the best-performing models indicated that the anteroposterior diameter, superoinferior diameter, original_shape_VoxelVolume, age, wavelet-LHL_firstorder_10Percentile, and left-to-right diameter had the most significant effect on the LightGBM model. On the other hand, the superoinferior diameter, anteroposterior diameter, left-to-right diameter, original_shape_VoxelVolume, original_firstorder_InterquartileRange, and age had the most significant effect on the XGBoost model. Conclusion: ML models based on radiomics and clinical features can accurately evaluate the cervical lymph node status in patients with HT combined with PTC. Among the 5 ML models, LightGBM and XGBoost demonstrate the best evaluation performance.

Predictors for thoracic aortic growth in patients with type B aortic dissection after thoracic endovascular aortic repair.

OBJECTIVE: To identify independent predictors of thoracic aortic growth in patients with type B aortic dissection (TBAD) undergoing thoracic endovascular aortic repair (TEVAR). METHODS: A retrospective analysis of the patients undergoing TEVAR for TBAD or intramural hematoma (IMH) from April 2014 to April 2023 was performed. The baseline morphological data of TBAD was established through computed tomography angiography (CTA) before discharge. Patients were divided into two groups based on aortic growth: growth and no growth. Aortic growth defined as an increase ≥5 mm in thoracic maximal aortic diameter during any serial follow-up CTA measurement. Logistic regression following propensity score matching (PSM) was used to identify independent predictors for aortic growth. Receiver operating characteristic curve and cutoff value of independent predictors were calculated. Linear regression was used to establish a correlation between anatomical variables and follow-up aortic diameter. RESULTS: A total of 145 patients with TBAD (n = 122) or IMH (n = 23) undergoing TEVAR were included, with a male of 83.4% and a mean age of 56 ± 14.1 years. Patients in growth group and no growth group was 26 (17.9%) and 119 (80.1%), respectively. After using PSM method, matched regression analysis showed residual maximal tear diameter (OR = 0.889, 95% CI 0.830-0.952, p = 0.001) and follow-up aortic diameter (OR = 0.977, 95% CI 0.965-0.989, p < 0.001) were independent predictors for aortic growth. The cutoff value was 8.55 mm for residual tear diameter and 40.65 mm for follow-up maximal aortic diameter. The residual maximal tear diameter showed a linear correlation with follow-up aortic diameter (DW = 1.74, R2 = 6.2%, p = 0.033). CONCLUSIONS: This study suggested that residual maximal tear diameter >8.55 mm and follow-up aortic diameter >40.65 mm could predict aortic growth in patients with TBAD undergoing TEVAR.

A Wearable Fingertip Force Feedback Device System for Object Stiffness Sensing.

Virtual reality technology brings a new experience to human-computer interaction, while wearable force feedback devices can enhance the immersion of users in interaction. This paper proposes a wearable fingertip force feedback device that uses a tendon drive mechanism, with the aim of simulating the stiffness characteristics of objects within virtual scenes. The device adjusts the rotation angle of the torsion spring through a DC motor, and then uses a wire to convert the torque into a feedback force at the user's index fingertips, with an output force of up to 4 N and a force change rate of up to 10 N/s. This paper introduces the mechanical structure and design process of the force feedback device, and conducts a mechanical analysis of the device to select the appropriate components. Physical and psychological experiments are conducted to comprehensively evaluate the device's performance in conveying object stiffness information. The results show that the device can simulate different stiffness characteristics of objects, and users can distinguish objects with different stiffness characteristics well when wearing the force feedback device and interacting with the three-dimensional virtual environments.

LIFU/MMP-2 dual-responsive release of repurposed drug disulfiram from nanodroplets for inhibiting vasculogenic mimicry and lung metastasis in triple-negative breast cancer.

BACKGROUND: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. RESULTS: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. CONCLUSIONS: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings.

Repurposing Disulfiram to Combat Acute Respiratory Distress Syndrome with Targeted Delivery by LET-Functionalized Nanoplatforms.

Acute respiratory distress syndrome (ARDS) is a serious respiratory condition characterized by a damaged pulmonary endothelial barrier that causes protein-rich lung edema, an influx of proinflammatory cells, and treatment-resistant hypoxemia. Damage to pulmonary endothelial cells and inflammation are pivotal in ARDS development with a key role played by endothelial cell pyroptosis. Disulfiram (DSF), a drug that has long been used to treat alcohol addiction, has recently been identified as a potent inhibitor of gasdermin D (GSDMD)-induced pore formation and can thus prevent pyroptosis and inflammatory cytokine release. These findings indicate that DSF is a promising treatment for inflammatory disorders. However, addressing the challenge posed by its intrinsic physicochemical properties, which hinder intravenous administration, and effective delivery to pulmonary vascular endothelial cells are crucial. Herein, we used biocompatible liposomes incorporating a lung endothelial cell-targeted peptide (CGSPGWVRC) to produce DSF-loaded nanoparticles (DTP-LET@DSF NPs) for targeted delivery and reactive oxygen species-responsive release facilitated by the inclusion of thioketal (TK) within the liposomal structure. After intravenous administration, DTP-LET@DSF NPs exhibited excellent cytocompatibility and minor systemic toxicity, effectively inhibited pyroptosis, mitigated lipopolysaccharide (LPS)-induced ARDS, and prevented cytokine storms resulting from excessive immune reactions in ARDS mice. This study presents a straightforward nanoplatform for ARDS treatment that potentially paves the way for the clinical use of this nanomedicine.

Midterm Outcomes of Multicenter Castor Single-Branch Stent Graft Use in the Treatment of Thoracic Aortic Diseases.

PURPOSE: The aim of this study was to evaluate the midterm efficacy and safety of a single-branch Castor stent graft in the treatment of thoracic aortic disease. MATERIALS AND METHODS: Clinical data of 106 patients with thoracic aortic disease treated with Castor single-branch stent graft at 3 centers were collected between May 2018 and June 2023. The indicators included technical success, stent-related complication, reintervention, retrograde dissection, endoleak, distal stent graft-induced entry (dSINE), branch patency, and mortality. The outcomes of the Castor stent graft for multibranch reconstruction above the arch was also analyzed. RESULTS: The technical success was 98.1% (104/106), while the surgical success was 93.4% (99/106). The reintervention was 2.8% (3/106), consisting of a case of retrograde type A dissection, an endoleak, and a dSINE. The retrograde dissection was 1.9% (2/106), while type I endoleak was 1.9% (2/106). The new dSINE was 2.8% (3/106), and the branch patency rate was 100%. The mortality was 1.9% (2/106). The mean follow-up time was 29.1±17.7 months. The 2-year post-surgery cumulative survival rate was 91.0%±3.1%, while the cumulative branch patency rate was 96.2%±2.2%. In addition, the cumulative freedom from stent-related reintervention rate was 93.2%±2.8%. A comparison showed no significant difference in the stent-related complication, branch patency, endoleak, reintervention, and mortality when the proximal end of the Castor stent graft was anchored to zones 1 or 2 of the aorta. CONCLUSION: Castor single-branch stent graft showed favorable early and midterm outcomes in the treatment of thoracic aortic disease. In addition, it was feasible to combine Castor stent graft with other advanced techniques for multibranch aortic arch reconstruction. CLINICAL IMPACT: The Castor single-branch stent graft was approval by the Chinese Food and Drug Administration in 2017. However, there were few studies on the mid-term outcomes for thoracic aortic disease after launching, which mainly focused on small single-center retrospective study. In the study, we assessed the mid-term outcomes of Castor stent graft through multi-center cases, Castor stent graft combined with other advanced techniques (such as fenestration and hybrid) for multi-branch reconstruction of aortic arch were also conducted. We found Castor single-branch stent graft showed favorable early and mid-term outcomes in the treatment of thoracic aortic disease. Additionally, it was feasible to combine Castor stent graft with other advanced technique for multi-branch aortic arch reconstruction. As an off-the-shelf branched stent graft with a wide range of models, it could be also used in most emergent situation. The Castor stent graft was expected to become more widely used in the future.

Self-Reinforced Bimetallic Mito-Jammer for Ca2+ Overload-Mediated Cascade Mitochondrial Damage for Cancer Cuproptosis Sensitization.

Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria-mediated cell death. However, the highly adaptive nature and damage-repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self-reinforced bimetallic Mito-Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) -modified metal-organic frameworks (MOF). After cellular, Mito-Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+-based Fenton-like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu-ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Decomposable Nanoagonists Enable NIR-Elicited cGAS-STING Activation for Tandem-Amplified Photodynamic-Metalloimmunotherapy.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has emerged as an efficient strategy to improve the therapeutic outcomes of immunotherapy. However, the "constantly active" mode of current STING agonist delivery strategies typically leads to off-target toxicity and hyperimmunity. To address this critical issue, herein a metal-organic frameworks-based nanoagonist (DZ@A7) featuring tumor-specific and near-infrared (NIR) light-enhanced decomposition is constructed for precisely localized STING activation and photodynamic-metalloimmunotherapy. The engineered nanoagonist enabled the generation of mitochondria-targeted reactive oxygen species under NIR irradiation to specifically release mitochondrial DNA (mtDNA) and inhibit the repair of nuclear DNA via hypoxia-responsive drugs. Oxidized tumor mtDNA serves as an endogenous danger-associated molecular pattern that activates the cGAS-STING pathway. Concurrently, NIR-accelerated zinc ions overloading in cancer cells further enhance the cGAS enzymatic activity through metalloimmune effects. By combining the synergistically enhanced activation of the cGAS-STING pathway triggered by NIR irradiation, the engineered nanoagonist facilitated the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes for primary tumor eradication, which also established a long-term anti-tumor immunity to suppress tumor metastasis. Therefore, the developed nanoagonist enabled NIR-triggered, agonist-free, and tandem-amplified activation of the cGAS-STING pathway, thereby offering a distinct paradigm for photodynamic-metalloimmunotherapy.

Two-dimensional speckle tracking imaging analyses of the correlations between left atrial appendage function and stroke risk in nonvalvular atrial fibrillation patients.

Stroke incidence is the most severe complication associated with atrial fibrillation (AF), and the most common site of thrombus formation in AF patients is the left atrial appendage (LAA). This study was developed to use two-dimensional speckle tracking imaging (2D-STI) to explore associations between LAA strain/strain rate and stroke incidence and to evaluate the value of utilizing LAA strain and strain rate values to support the stratification of nonvalvular AF (NVAF) patients based on stroke risk. A total of 486 AF patients who had undergone transesophageal echocardiography to exclude potential intracardiac thrombosis between March 2021 and November 2022 were consecutively enrolled. Patients meeting the inclusion criteria were separated into two groups according to their history of stroke/transient ischemic attack (TIA). LAA strain and strain rate values in these patients were measured via 2D-STI. Multivariable logistic regression analysis was employed to determine independent risk factors for the construction of a combined predictive model. Of the 333 analyzed patients (134 females, aged 65 (56,72) years), 39 (11.71%, 39/333) had a history of stroke at the time of evaluation. Multivariate logistic regression analysis demonstrated that nonparoxysmal AF, CHA2DS2VASc score, LAA thrombus/spontaneous echo contrast (SEC), LAA strain, and strain rate were all predictors of stroke incidence among NVAF patients. The combined predictive model demonstrated excellent discriminative ability, with an AUC of 0.91 (95%CI 0.87-0.95, P < 0.001), and a sensitivity and specificity of 79.49% and 89.46%, respectively. The Hosmer-Lemeshow test confirmed good calibration, yielding a value of 0.98. Comparative decision curve analysis showed that the model provided superior net benefits compared to the CHA2DS2VASc score. Furthermore, the model exhibited improved predictive performance and reclassification for stroke when compared to the CHA2DS2VASc score (AUC 0.91 vs. 0.88, Z = 2.32, P = 0.02), accompanied by a significant increase in the net reclassification index (+ 5.44%, P < 0.001) and integrated discrimination improvement (8.21%, P < 0.001). These data demonstrate that LAA strain and strain rate, as measured via 2D-STI, can offer value when assessing LAA function in AF patients, potentially providing further predictive value to extant clinical risk scoring strategies.

The role of left ventricular hypertrophy measured by echocardiography in screening patients with ischaemia with non-obstructive coronary arteries: a cross-sectional study.

Many patients with ischaemia with non-obstructive coronary arteries (INOCA) have a poor prognosis. This study aims to explore the diagnostic value of left ventricular hypertrophy (LVH)-related ultrasound parameters in INOCA patients. The study group consisted of 258 patients with INOCA in this retrospective cross-sectional study, and these patients were free of obstructive coronary artery disease, previous revascularization, atrial fibrillation, ejection fraction < 50%, major distortions of left ventricular geometry, suspected non-ischaemic causes. Control individuals were matched 1:1 with study group according to age, sex, cardiovascular risk factors, and time of hospital stay. According to left ventricular mass index (LVMI) and relative wall thickness, left ventricular geometry was composed of concentric hypertrophy, eccentric hypertrophy, concentric remodeling and normal geometry. LVH-related parameters, left ventricular geometry, demographic characteristics, laboratory parameters and other echocardiographic indicators were compared between the two groups. Subgroup analysis was performed based on sex. LVMI in the study group was higher than that in the control group (86.86 ± 18.83 g/m2 vs 82.25 ± 14.29 g/m2, P = 0.008). The ratio of LVH was higher in the study group (20.16% vs 10.85%, P = 0.006). After subgroup analysis based on sex, LVMI differences (85.77 ± 18.30 g/m2 vs 81.59 ± 14.64 g/m2, P = 0.014) and the ratio of LVH differences (25.00% vs 14.77%, P = 0.027) still existed in females between the two groups. There was no difference in the constituent ratio of left ventricular geometry between the two groups (P = 0.157). Sex-based subgroup analysis showed no difference in the constituent ratio of left ventricular geometry between the two groups in females (P = 0.242). The degree of LVH in the study group was higher than that in the control group, suggesting that LVH may play an important role in the occurrence and development of INOCA. Moreover, LVH-related ultrasound parameters may be of higher diagnostic value for female INOCA patients than for male INOCA patients.

PTC-MAS: A Deep Learning-Based Preoperative Automatic Assessment of Lymph Node Metastasis in Primary Thyroid Cancer.

BACKGROUND: Identifying cervical lymph node metastasis (LNM) in primary thyroid cancer preoperatively using ultrasound is challenging. Therefore, a non-invasive method is needed to assess LNM accurately. PURPOSE: To address this need, we developed the Primary Thyroid Cancer Lymph Node Metastasis Assessment System (PTC-MAS), a transfer learning-based and B-mode ultrasound images-based automatic assessment system for assessing LNM in primary thyroid cancer. METHODS: The system has two parts: YOLO Thyroid Nodule Recognition System (YOLOS) for obtaining regions of interest (ROIs) of nodules, and LMM assessment system for building the LNM assessment system using transfer learning and majority voting with extracted ROIs as input. We retained the relative size features of nodules to improve the system's performance. RESULTS: We evaluated three transfer learning-based neural networks (DenseNet, ResNet, and GoogLeNet) and majority voting, which had the area under the curves (AUCs) of 0.802, 0.837, 0.823, and 0.858, respectively. Method III preserved relative size features and achieved higher AUCs than Method II, which fixed nodule size. YOLOS achieved high precision and sensitivity on a test set, indicating its potential for ROIs extraction. CONCLUSIONS: Our proposed PTC-MAS system effectively assesses primary thyroid cancer LNM based on preserving nodule relative size features. It has potential for guiding treatment modalities and avoiding inaccurate ultrasound results due to tracheal interference.

Imageological/Structural Study regarding the Improved Pharmacokinetics by 68Ga-Labeled PEGylated PSMA Multimer in Prostate Cancer.

PMSA (prostate-specific membrane antigen) is currently the most significant target for diagnosing and treating PCa (prostate cancer). Herein, we reported a series 68Ga/177Lu-labeled multimer PSMA tracer conjugating with PEG chain, including [68Ga]Ga-DOTA-(1P-PEG4), [68Ga]Ga-DOTA-(2P-PEG0), [68Ga]Ga-DOTA-(2P-PEG4), and [68Ga]Ga/[177Lu]Lu-DOTA-(2P-PEG4)2, which showed an advantage of a multivalent effect and PEGylation to achieve higher tumor accumulation and faster kidney clearance. To figure out how structural optimizations based on a PSMA multimer and PEGylation influence the probe's tumor-targeting ability, biodistribution, and metabolism, we examined PSMA molecular probes' affinities to PC-3 PIP (PSMA-highly-expressed PC-3 cell line), and conducted pharmacokinetics analysis, biodistribution detection, small animal PET/CT, and SPECT/CT imaging. The results showed that PEG4 and PSMA dimer optimizations enhanced the probes' tumor-targeting ability in PC-3 PIP tumor-bearing mice models. Compared with the PSMA monomer, the PEGylated PSMA dimer reduced the elimination half-life in the blood and increased uptake in the tumor, and the biodistribution results were consistent with PET/CT imaging results. [68Ga]Ga-DOTA-(2P-PEG4)2 exhibited higher tumor-to-organ ratios. When labeled by lutetium-177, relatively high accumulation of DOTA-(2P-PEG4)2 was still detected in PC-3 PIP tumor-bearing mice models after 48 h, indicating its prolonged tumor retention time. Given the superiority in imaging, simple synthetic processes, and structural stability, DOTA-(2P-PEG4)2 is expected to be a promising tumor-targeting diagnostic molecular probe in future clinical practice.

Usefulness of Therapeutic Drug Monitoring and Pharmacogenetics for a Patient Treated with Olanzapine, Buspirone, and Fluvoxamine: A Case Study.

BACKGROUND: A patient, with a mental disorder caused by an intracranial infection, treated with olanzapine, fluvoxamine, and buspirone. The plasma exposure of olanzapine was too high at standard doses, with evidence indicating that it was caused by drug-drug interactions. METHODS: Using pharmacogenomics and therapeutic drug monitoring to guide drug dose adjustment for a patient in clinical practice. RESULTS: The patient underwent pharmacogenetic testing in addition to therapeutic drug monitoring as part of a pharmacist-led comprehensive evaluation of medication therapy management in a clinical setting, resulting in improved clinical efficacy that allowed discharge from a psychiatric hospital. CONCLUSIONS: This case study demonstrates that therapeutic drug monitoring combined with pharmacogenetic-guided dose adjustment can aid in the management of patients receiving complex pharmacological treatments.

Corrigendum: Effect of 131 I with and without artificial liver support system in patients with Graves' disease and severe liver dysfunction: A retrospective study.

[This corrects the article DOI: 10.3389/fendo.2022.1034374.].

Tumor-penetrating nanoplatform with ultrasound "unlocking" for cascade synergistic therapy and visual feedback under hypoxia.

BACKGROUND: Combined therapy based on the effects of cascade reactions of nanoplatforms to combat specific solid tumor microenvironments is considered a cancer treatment strategy with transformative clinical value. Unfortunately, an insufficient O2 supply and the lack of a visual indication hinder further applications of most nanoplatforms for solid tumor therapy. RESULTS: A visualizable nanoplatform of liposome nanoparticles loaded with GOD, H(Gd), and PFP and grafted with the peptide tLyP-1, named tLyP-1H(Gd)-GOD@PFP, was constructed. The double-domain peptide tLyP-1 was used to specifically target and penetrate the tumor cells; then, US imaging, starvation therapy and sonodynamic therapy (SDT) were then achieved by the ultrasound (US)-activated cavitation effect under the guidance of MR/PA imaging. GOD not only deprived the glucose for starvation therapy but also produced H2O2, which in coordination with 1O2 produced by H(Gd), enable the effects of SDT to achieve a synergistic therapeutic effect. Moreover, the synergistic therapy was enhanced by O2 from PFP and low-intensity focused ultrasound (LIFU)-accelerated redox effects of the GOD. The present study demonstrated that the nanoplatform could generate a 3.3-fold increase in ROS, produce a 1.5-fold increase in the maximum rate of redox reactions and a 2.3-fold increase in the O2 supply in vitro, and achieve significant tumor inhibition in vivo. CONCLUSION: We present a visualizable nanoplatform with tumor-penetrating ability that can be unlocked by US to overcome the current treatment problems by improving the controllability of the O2 supply, which ultimately synergistically enhanced cascade therapy.

NIR Activated Multimodal Therapeutics Based on Metal-Phenolic Networks-Functionalized Nanoplatform for Combating against Multidrug Resistance and Metastasis.

Multidrug resistance (MDR) and metastasis in cancer have become increasingly serious problems since antitumor efficiency is greatly restricted by a single therapeutic modality and the insensitive tumor microenvironment (TME). Herein, metal-phenolic network-functionalized nanoparticles (t-P@TFP NPs) are designed to realize multiple therapeutic modalities and reshape the TME from insensitive to sensitive under multimodal imaging monitoring. After a single irradiation, a near-infrared laser-activated multistage reaction occurs. t-P@TFP NPs trigger the phase transition of perfluoropentane (PFP) to release tannic acid (TA)/ferric ion (Fe3+ )-coated paclitaxel (PTX) and cause hyperthermia in the tumor region to efficiently kill cancer cells. Additionally, PTX is released after the disassembly of the TA-Fe3+ film by the abundant adenosine triphosphate (ATP) in the malignant tumor, which concurrently inhibits ATP-dependent drug efflux to improve sensitivity to chemotherapeutic agents. Furthermore, hyperthermia-induced immunogenic cell death (ICD) transforms "cold" tumors into "hot" tumors with the assistance of PD-1/PD-L1 blockade to evoke antitumor immunogenicity. This work carefully reveals the mechanisms underlying the abilities of these multifunctional NPs, providing new insights into combating the proliferation and metastasis of multidrug-resistant tumors.

Peptide Supramolecular Assembly-Instructed In Situ Self-Aggregation for Stratified Targeting Sonodynamic Therapy Enhancement of AIE Luminogens.

The emergence of aggregation-induced emission luminogens (AIEgens) has attracted substantial scientific attention. However, their antitumor efficacy in photodynamic therapy (PDT) is significantly restricted by the poor water solubility and limited treatment depth. Therefore, a novel AIEgens-involved therapeutic platform with good permeability and bioavailability is urgently required. Herein, supramolecular chemistry is combined with the AIEgen bis-pyrene (BP) to construct a peptide-AIEgen hybrid nanosystem (PAHN). After intravenous injection, the versatile nanoplatform not only improved the hydrophilicity of BP but also achieved stratified targeting from tumor to mitochondrial and induced mitochondrial dysfunction, thus activating caspase-3 upregulation. Then, sonodynamic therapy (SDT), an alternative modality with high tissue penetrability, is performed to evoke reactive oxygen species (ROS) generation for BP. More importantly, since the hydrophilic shell is separated from the nanosystem by the specific cleavage of caspase-3, the resulting decrease in hydrophilicity induced tight self-aggregation of PAHN residues in situ, further allowing more absorbed energy to be used for ROS generation under ultrasound irradiation and enhancing SDT efficacy. Moreover, severe oxidative stress resulting from ROS imbalance in the mitochondria initiates the immunogenic cell death process, thus evoking antitumor immunogenicity. This PAHN provides prospective ideas into AIE-involved antitumor therapy and design of peptide-AIEgens hybrids.

Biomimetic, pH-Responsive Nanoplatforms for Cancer Multimodal Imaging and Photothermal Immunotherapy.

Photothermal therapy (PTT), by converting light to thermal energy, has become a novel and noninvasive technique for tumor thermal ablation in clinical practice. However, as a result of phagocytosis of reticuloendothelial cells, current photothermal agents (PTAs) derived from exogenous materials suffer from incompetent tumor targeting and brief internal circulation time. The resulting poor accumulation of PTAs in the target area severely reduces the efficacy of PTT. In addition, the potential toxicity of PTAs, excessive laser exposure, and possibilities of tumor recurrence and metastasis following PTT are still intractable problems that severely influence patients' quality of life. Herein, a biomimetic pH-responsive nanoprobe was prepared via cancer cell membrane coating polydopamine (PDA)-CaCO3 nanoparticles (CPCaNPs) for photoacoustic (PA)/ultrasonic (US)/thermal imaging-guided PTT. When CPCaNPs targeted and infiltrated into the tumor's acidic microenvironment, the decomposed CO2 bubbles from homologous targeting CPCaNPs enhanced ultrasonic (US) signals obviously. At the same time, the PDA of CPCaNPs not only performed efficient PTT of primary tumors but also generated photoacoustic (PA) signals. In addition, an immune checkpoint pathway blockade was combined, which inhibited tumor recurrence and metastasis significantly and improved the immunosuppressive microenvironment after PTT to a large extent. Thus, these proposed biomimetic pH-responsive CPCaNPs provide a promising strategy for precise PTT immunotherapy under the intelligent guidance of PA/US/thermal imaging and show great potential for clinical translation.

Nanoenabled Tumor Energy Metabolism Disorder via Sonodynamic Therapy for Multidrug Resistance Reversal and Metastasis Inhibition.

Cancer multidrug resistance (MDR) is an important reason that results in chemotherapy failure. As a main mechanism of MDR, overexpressed P-glycoprotein (P-gp) utilizes adenosine triphosphate (ATP) to actively pump chemotherapy drugs out of cells. In addition, metabolic reprogramming of drug-resistant tumor cells (DRTCs) exacerbates the specific hypoxic microenvironment and promotes tumor metastasis and recurrence. Therefore, we propose a novel sonodynamic therapy (SDT) paradigm to induce energy metabolism disorder and drug resistance change of DRTCs. A US-controlled "Nanoenabled Energy Metabolism Jammer" (TL@HPN) is designed using perfluoropentane (PFP) adsorbing oxygen in the core, and a targeting peptide (CGNKRTR) is attached to the liposome as the delivery carrier shell to incorporate hematoporphyrin monomethyl ether (HMME) and paclitaxel (PTX). The TL@HPN with ultrasonic/photoacoustic imaging (PAI/USI) precisely controlled the release of drugs and oxygen after being triggered by ultrasound (US), which attenuated the hypoxic microenvironment. SDT boosted the reactive oxygen species (ROS) content in tumor tissues, preferentially inducing mitochondrial apoptosis and maximizing immunogenic cell death (ICD). Persistently elevated oxidative stress levels inhibited ATP production and downregulated P-gp expression by disrupting the redox balance and electron transfer of the respiratory chain. We varied the effect of TL@HPN combined with PD-1/PD-L1 to activate autoimmunity and inhibit tumor metastasis, providing a practical strategy for expanding the use of SDT-mediated tumor energy metabolism.