Copper homeostasis and cuproptosis in cardiovascular disease therapeutics.

Copper (Cu) homeostasis is gaining increasing attention in human health as both Cu overload and deficiency evokes pathological changes including cardiovascular diseases (CVDs). Cu supplementation, nanocarriers, and chelators have all exhibited therapeutic promise in some human diseases, although how Cu dyshomeostasis and cuproptosis, a novel form of regulated cell death, contribute to CVD pathology remains elusive. Here, we discuss Cu dyshomeostasis and the potential role of cuproptosis in various CVDs. We evaluate underlying cellular mechanisms, aiming to provide some insights regarding the utility of targeting Cu dyshomeostasis and cuproptosis as a novel strategy in the management of CVDs.

Clinical application of electroacupuncture in enhanced recovery after surgery.

Enhanced recovery after surgery (ERAS) is currently the recommended surgical strategy, the main content of which is to reduce perioperative stress response and postoperative complications through perioperative multimodal analgesia and intensive surgery. Since ERAS was introduced, many rehabilitation medicine teams have been deeply involved, including physical therapy, occupational therapy, nutrition therapy and psychological counseling. However, ERAS lacks several powerful means to address perioperative prognostic issues. Therefore, how to further improve the effects of ERAS, reduce perioperative complications and protect vital organ functions has become an urgent problem. With the continuous development of traditional Chinese medicine, electroacupuncture (EA) has been widely used in various clinical applications, and its efficacy and safety have been fully proved. Recent studies have shown that the application of EA in ERAS has had an important impact on rehabilitation researches. In terms of reducing complications, the therapeutic effects of EA treatment mainly include: reducing pain and the use of analgesics; Improvement of postoperative nausea and vomiting; Postoperative immune function treatment; Relieve anxiety and depression. In addition, EA also protects the recovery of physiological functions, including cardiovascular function, cerebrovascular function and gastrointestinal function, etc. To sum up, the complementary strengths of EA and ERAS will allow them to develop and combine. This review discusses the potential value and feasibility of EA in ERAS from the aspects of improving perioperative efficacy and protecting organ functions.

Integrating Network Pharmacology, Molecular Docking and Pharmacological Evaluation for Exploring the Polyrhachis vicina Rogers in Ameliorating Depression.

Purpose: To investigate the mechanisms of antidepressant action of active fraction of Polyrhachis vicina Rogers (AFPR) through network pharmacology, molecular docking and experimental validation. Methods: GC-MS was used to predict chemical compounds, corresponding databases were used to predict chemical compound targets and depression targets, Cytoscape software was used to construct and analyze the protein interaction network map, DAVID database was used to analyze gene ontology (GO) and KEGG signaling pathway, and AGFR software was used to perform molecular docking. Subsequently, the underlying action mechanisms of AFPR on depression predicted by network pharmacology analyses were experimentally validated in a CORT-induced depression model in vitro and in vivo. Results: A total of 52 potential targets of AFPR on antidepressant were obtained. GO is mainly related to chemical synaptic transmission, signal transduction and others. KEGG signaling pathways are mainly related to cAMP signaling pathway and C-type lectin receptor signaling pathway. The experiment results showed that AFPR significantly increased the expression of PRKACA, CREB and BDNF in mouse brain tissue and PC12 cells. Furthermore, after interfered of cAMP in PC12 cells, the decreased expression of PRKACA, CREB and BDNF was reversed by AFPR. Conclusion: AFPR may exert antidepressant effects through multiple components, targets and pathways. Furthermore, it could improve neuroplasticity via the cAMP signaling pathway to improve depression-like symptoms.

Rhinacanthin C Ameliorates Insulin Resistance and Lipid Accumulation in NAFLD Mice via the AMPK/SIRT1 and SREBP-1c/FAS/ACC Signaling Pathways.

Rhinacanthin C (RC) is a naphthoquinone ester with an anti-inflammatory activity extracted from Rhinacanthus nasutus (L.) Kurz (Rn). It has been proven to improve hyperglycemia and hyperlipidemia, but the prevention and mechanism of RC in nonalcoholic fatty liver disease (NAFLD) are not clear. In the current study, we first extracted RC from Rn using ethyl acetate and identified it by HPLC, MS, and NMR. At the same time, molecular docking analysis of RC with AMPK and SREBP-1c was performed using AutoDock software. In addition, the mouse model of NAFLD was induced by a high-fat diet in vivo, and low, medium, and high concentrations of RC were used for intervention. The results showed that RC significantly reduced the body mass and liver body coefficient of NAFLD mice, inhibited liver inflammation and fat accumulation, and improved insulin resistance. Further studies showed that RC significantly reduced the levels of serum leptin and resistin, upregulated the expression levels of adiponectin and adiponectin receptor in the liver, and inhibited the expression levels of MCP-1, TNF-α, and IL-6. In terms of mechanism, RC upregulates the expression of p-AMPK and SIRT1 and downregulates the expression of p-p65, SREBP-1c, Fas, Acc-α, PPAR-γ, and SCD1. These studies suggest that RC improves insulin resistance and lipid accumulation in NAFLD by activating the AMPK/SIRT1 and SREBP-1c/Fas/ACC pathways, respectively.

From single- to multi-omics: future research trends in medicinal plants.

Medicinal plants are the main source of natural metabolites with specialised pharmacological activities and have been widely examined by plant researchers. Numerous omics studies of medicinal plants have been performed to identify molecular markers of species and functional genes controlling key biological traits, as well as to understand biosynthetic pathways of bioactive metabolites and the regulatory mechanisms of environmental responses. Omics technologies have been widely applied to medicinal plants, including as taxonomics, transcriptomics, metabolomics, proteomics, genomics, pangenomics, epigenomics and mutagenomics. However, because of the complex biological regulation network, single omics usually fail to explain the specific biological phenomena. In recent years, reports of integrated multi-omics studies of medicinal plants have increased. Until now, there have few assessments of recent developments and upcoming trends in omics studies of medicinal plants. We highlight recent developments in omics research of medicinal plants, summarise the typical bioinformatics resources available for analysing omics datasets, and discuss related future directions and challenges. This information facilitates further studies of medicinal plants, refinement of current approaches and leads to new ideas.

CPT1A-mediated fatty acid oxidation promotes cell proliferation via nucleoside metabolism in nasopharyngeal carcinoma.

As the first rate-limiting enzyme in fatty acid oxidation (FAO), CPT1 plays a significant role in metabolic adaptation in cancer pathogenesis. FAO provides an alternative energy supply for cancer cells and is required for cancer cell survival. Given the high proliferation rate of cancer cells, nucleotide synthesis gains prominence in rapidly proliferating cells. In the present study, we found that CPT1A is a determining factor for the abnormal activation of FAO in nasopharyngeal carcinoma (NPC) cells. CPT1A is highly expressed in NPC cells and biopsies. CPT1A dramatically affects the malignant phenotypes in NPC, including proliferation, anchorage-independent growth, and tumor formation ability in nude mice. Moreover, an increased level of CPT1A promotes core metabolic pathways to generate ATP, inducing equivalents and the main precursors for nucleotide biosynthesis. Knockdown of CPT1A markedly lowers the fraction of 13C-palmitate-derived carbons into pyrimidine. Periodic activation of CPT1A increases the content of nucleoside metabolic intermediates promoting cell cycle progression in NPC cells. Targeting CPT1A-mediated FAO hinders the cell cycle G1/S transition. Our work verified that CPT1A links FAO to cell cycle progression in NPC cellular proliferation, which supplements additional experimental evidence for developing a therapeutic mechanism based on manipulating lipid metabolism.

De novo and comparative transcriptomic analysis explain morphological differences in Panax notoginseng taproots.

BACKGROUND: Panax notoginseng (Burk.) F. H. Chen (PN) belonging to the genus Panax of family Araliaceae is widely used in traditional Chinese medicine to treat various diseases. PN taproot, as the most vital organ for the accumulation of bioactive components, presents a variable morphology (oval or long), even within the same environment. However, no related studies have yet explained the molecular mechanism of phenotypic differences. To investigate the cause of differences in the taproot phenotype, de novo and comparative transcriptomic analysis on PN taproot was performed. RESULTS: A total of 133,730,886 and 114,761,595 paired-end clean reads were obtained based on high-throughput sequencing from oval and long taproot samples, respectively. 121,955 unigenes with contig N50 = 1,774 bp were generated by using the de novo assembly transcriptome, 63,133 annotations were obtained with the BLAST. And then, 42 genes belong to class III peroxidase (PRX) gene family, 8 genes belong to L-Ascorbate peroxidase (APX) gene family, and 55 genes belong to a series of mitogen-activated protein kinase (MAPK) gene family were identified based on integrated annotation results. Differentially expressed genes analysis indicated substantial up-regulation of PnAPX3 and PnPRX45, which are related to reactive oxygen species metabolism, and the PnMPK3 gene, which is related to cell proliferation and plant root development, in long taproots compared with that in oval taproots. Furthermore, the determination results of real-time quantitative PCR, enzyme activity, and H2O2 content verified transcriptomic analysis results. CONCLUSION: These results collectively demonstrate that reactive oxygen species (ROS) metabolism and the PnMPK3 gene may play vital roles in regulating the taproot phenotype of PN. This study provides further insights into the genetic mechanisms of phenotypic differences in other species of the genus Panax.

Electroacupuncture Pretreatment Mitigates Myocardial Ischemia/Reperfusion Injury via XBP1/GRP78/Akt Pathway.

Myocardial ischemia/reperfusion injury is a common clinical problem and can result in severe cardiac dysfunction. Previous studies have demonstrated the protection of electroacupuncture against myocardial ischemia/reperfusion injury. However, the role of X-box binding protein I (XBP1) signaling pathway in the protection of electroacupuncture was still elusive. Thus, we designed this study and demonstrated that electroacupuncture significantly improved cardiac function during myocardial ischemia/reperfusion injury and reduced cardiac infarct size. Electroacupuncture treatment further inhibited cardiac injury manifested by the decrease of the activities of serum lactate dehydrogenase and creatine kinase-MB. The results also revealed that electroacupuncture elevated the expressions of XBP1, glucose-regulated protein 78 (GRP78), Akt, and Bcl-2 and decreased the Bax and cleaved Caspase 3 expressions. By using the inhibitor of XBP1 in vitro, the results revealed that suppression of XBP1 expression could markedly increase the activities of lactate dehydrogenase and creatine kinase-MB and cell apoptosis, thus exacerbating stimulated ischemia/reperfusion-induced H9c2 cell injury. Compared with stimulated ischemia/reperfusion group, inhibition of XBP1 inhibited the downstream GRP78 and Akt expressions during stimulated ischemia/reperfusion injury. Collectively, our data demonstrated that electroacupuncture treatment activated XBP1/GRP78/Akt signaling to protect hearts from myocardial ischemia/reperfusion injury. These findings revealed the underlying mechanisms of electroacupuncture protection against myocardial ischemia/reperfusion injury and may provide novel therapeutic targets for the clinical treatment of myocardial ischemia/reperfusion injury.

Structure and Function of Rhizosphere Soil and Root Endophytic Microbial Communities Associated With Root Rot of Panax notoginseng.

Panax notoginseng (Burk.) F. H. Chen is a Chinese medicinal plant of the Araliaceae family used for the treatment of cardiovascular and cerebrovascular diseases in Asia. P. notoginseng is vulnerable to root rot disease, which reduces the yield of P. notoginseng. In this study, we analyzed the rhizosphere soil and root endophyte microbial communities of P. notoginseng from different geographical locations using high-throughput sequencing. Our results revealed that the P. notoginseng rhizosphere soil microbial community was more diverse than the root endophyte community. Rhodopseudomonas, Actinoplanes, Burkholderia, and Variovorax paradoxus can help P. notoginseng resist the invasion of root rot disease. Ilyonectria mors-panacis, Pseudomonas fluorescens, and Pseudopyrenochaeta lycopersici are pathogenic bacteria of P. notoginseng. The upregulation of amino acid transport and metabolism in the soil would help to resist pathogens and improve the resistance of P. notoginseng. The ABC transporter and gene modulating resistance genes can improve the disease resistance of P. notoginseng, and the increase in the number of GTs (glycosyltransferases) and GHs (glycoside hydrolases) families may be a molecular manifestation of P. notoginseng root rot. In addition, the complete genomes of two Flavobacteriaceae species and one Bacteroides species were obtained. This study demonstrated the microbial and functional diversity in the rhizosphere and root microbial community of P. notoginseng and provided useful information for a better understanding of the microbial community in P. notoginseng root rot. Our results provide insights into the molecular mechanism underlying P. notoginseng root rot and other plant rhizosphere microbial communities.

SO2 prodrug doped nanorattles with extra-high drug payload for "collusion inside and outside" photothermal/pH triggered - gas therapy.

Recent years have witnessed the blooming of gas therapy nanoplatforms, which emerged as a promising area for cancer therapy. However, uncontrolled or inadequate generation of gas and unclear therapeutic mechanisms, which were still regarded as big challenges to apply gas therapy into clinical. Here in, a gas treatment based on sulfur dioxide (SO2) prodrug doped nanorattles was explored, which could not only inhibit superficial tumor but also deep tumor. A Benzothiazole sulfinate (BTS, a water-soluble SO2 prodrug) doped rattle-structured rough nanocapsule with high drug payload (~80%) composed of gold nanorods cores and polydopamine (PDA) shell (GNRs@PDA-BTS, GPBRs) has been prepared. Taking advantages of excellent photothermal conversion ability as well as acidic condition in the tumor sites, SO2 gas release could be precisely controlled by both photothermal and pH, thus realizing "collusion inside" gas therapy and "outside" photothermal therapy. In addition, the cytotoxic SO2 was found to induce cell apoptosis accompanied by the upregulation of intracellular reactive oxygen species (ROS) levels and modulation of apoptosis-relative proteins such as p53, bcl-2, Bax and caspase-3. Such photothermal/pH triggered SO2 gas therapy may provide an effective strategy to stimulate further development of deep tumor therapy.

Drug resistance of healthcare-associated pathogenic bacteria and carbapenem-resistant Acinetobacter baumannii homology in the general intensive care unit.

BACKGROUND: The objective of this study was to understand the distribution and drug resistance of healthcare-associated infection (HAI) pathogens in an intensive care unit (ICU) of a general tertiary hospital in Inner Mongolia, and to classify carbapenem-resistant Acinetobacter baumannii (CR-AB) in ICU patients and environmental samples. Additionally, this study aimed to provide scientific evidence for the use of clinical antibiotics and effective prevention and control measures for CR-AB outbreak. METHODS: The distribution and drug resistance of pathogens isolated from patient's samples in the ICU of 12 Hospitals from January to May 2019 were retrospectively analyzed. Meanwhile, CR-AB isolated from patients and environmental samples were collected and classified by pulsed-field gel electrophoresis (PFGE). RESULTS: The pathogens isolated from ICU samples, mainly Gram-negative bacteria (63.07%), were CR-AB, Klebsiella pneumoniae, and Pseudomonas aeruginosa; the main Gram-positive bacteria (22.13%) were Enterococcus faecium and Staphylococcus aureus; and fungi accounted for the remaining (14.80%). The samples mainly came from sputum (41.09%). Among non-fermenting bacteria, the resistance rates of CRAB to piperacillin, piperacillin/tazobactam, and other treatments were higher than those of Pseudomonas aeruginosa (P<0.05). Meanwhile, the resistance rates to ampicillin/sulbactam and compound sulfamethoxazole were lower than those of Pseudomonas aeruginosa (P<0.05). The resistance rates of Klebsiella pneumoniae to piperacillin/tazobactam, ceftazidime, and others were higher than those of Escherichia coli (P<0.05). Among Gram-positive bacteria, the resistance rates of Enterococcus faecium to erythromycin, clindamycin, and other treatment were higher than those of Staphylococcus aureus (P<0.05). A total of 62 bands were obtained from 63 strains of CR-AB by electrophoresis. Also, 16 clusters (A-P) were obtained with a 74% similarity coefficient, among which K, L, and N types (more than 9 strains) were more common. CONCLUSIONS: Gram-negative bacteria were the primary pathogens of HAI in the ICU, and their drug resistance was serious. There is homology in the PFGE typing of CR-AB. Therefore, hospitals should strengthen the surveillance of drug-resistant pathogenic bacteria. Additionally, further cleaning and disinfection measures are needed to improve environmental hygiene and prevent outbreaks of HAI.

Ultra-small Bi2S3 nanodot-doped reversible Fe(ii/iii)-based hollow mesoporous Prussian blue nanocubes for amplified tumor oxidative stress-augmented photo-/radiotherapy.

Improving the generation of reactive oxygen species (ROS) while consuming glutathione (GSH) is the main method for amplifying intracellular oxidative stress. However, in previous studies, it was normally necessary to combine two or more materials to achieve the effect of destroying the intracellular redox homeostasis. This made the preparation process relatively complicated. Herein, we designed ultra-small bismuth sulfide quantum dot (Bi2S3 QD)-doped hollow mesoporous Prussian blue (HMPB) (HMPB/Bi2S3) nanocubes for amplified tumor oxidative stress to augment photo-/radiotherapy. In addition to being photothermal materials, Prussian blue can be used as both a catalyst for the Fenton reaction and a consumer of GSH due to the multivalent state of iron. Ferrous ions (Fe(ii)) can produce toxic ROS-hydroxyl radicals (˙OH) with abundant hydrogen peroxide in the tumor cells by the Fenton reaction. Meanwhile, ferric ions (Fe(iii)) can oxidize the intracellular GSH to GSSG, thus depleting the concentration of GSH inside tumors. As a result, oxidative stress imbalance could be induced by the reversible redox property of Fe(ii/iii), thereby causing DNA damage and increasing the cell membrane permeability to realize enhanced photo-/radiotherapy. As a sensitizer for radiotherapy, ultra-small Bi2S3 QDs (3-5 nm) are doped in HMPB, thus improving the therapeutic effect by prolonging blood circulation and reducing systemic toxicity via kidney metabolism. Therefore, such a reversible HMPB/Bi2S3 nanocube is a promising therapeutic agent for amplified tumor oxidative stress to augment photo-/radiotherapy, which might show further applications in nanomedical science.

Rod-shape MSN@MoS2 Nanoplatform for FL/MSOT/CT Imaging-Guided Photothermal and Photodynamic Therapy.

Rod-shape nanoplatform have received tremendous attention owing to their enhanced ability for cell internalization and high capacity for drug loading. MoS2, widely used in electronic devices, electrocatalysis, sensor and energy-storage, has been studied as photothermal agents over the years. However, the efficacy of rod-shape MoS2 based photothermal agents for photothermal therapy has not been studied before. Here, a near-infrared (NIR) light-absorbing MoS2 nanosheets coated mesoporous silica nanorods with human serum albumin (HSA) modifying and Ce6 loading (MSNR@MoS2-HSA/Ce6) were constructed for combined photothermal and photodynamic therapy. Methods: The near-infrared (NIR) light was used to trigger the synergistic anti-tumor therapy. In addition, breast cancer cell line was applied to evaluate the in vitro anti-tumor activity. The multi-modal imaging capacity and tumor-killing efficiency of the designed nanocomposites in vivo was also demonstrated with the 4T1 tumor-bearing mouse model. Results: These nanocomposites could not only perform NIR light triggered photodynamic therapy (PDT) and photothermal therapy (PTT), but also achieve in vivo fluorescence (FL) /multispectral optical tomography (MSOT)/X-ray computed tomography (CT) triple-model bioimaging. What's more, the rod-shape nanoplatform could be endowed with better anti-tumor ability based on the EPR effect and HSA-mediated active tumor targeting. At the same time, the hyperthermia generated by MoS2 could synergistically improve the PDT effect with the acceleration of the blood flow, leading to the increase of the oxygen level in tumor tissue. Conclusion: MSNR@MoS2-HSA/Ce6 proves to be a promising multi-functional nanoplatform for effective treatment of tumor.

Glutathione-Mediated Clearable Nanoparticles Based on Ultrasmall Gd2O3 for MSOT/CT/MR Imaging Guided Photothermal/Radio Combination Cancer Therapy.

Recently, multifunctional clearable inorganic theranostic nanoparticles have been attracting more and more attention. Protein-based nanoparticles can be cleared by the hepatobiliary system efficiently. In this work, ultrasmall gadolinium oxide (Gd2O3) nanoparticles, which possess the advantage of high longitudinal relaxation rate, were coated with bovine serum albumin (BSA). After the Gd2O3/BSA nanoparticles were linked with two-dimensional photothermal MoS2 nanomaterials, the nanoparticles were also modified with hyaluronic acid (HA) through the disulfide bonds for tumor-targeting effect. As indicated by in vitro and in vivo studies, these Gd2O3/BSA@MoS2-HA nanoparticles could be rapidly degraded and excreted after reacting with glutathione (GSH) by the redox response, thus avoiding long-term toxicity. In addition, the cellular uptake study and in vivo multispectral optoacoustic tomography (MSOT), X-ray computed tomography (CT), and magnetic resonance (MR) triple-modal images demonstrated that Gd2O3/BSA@MoS2-HA nanoparticles exhibited a high tumor uptake effect after intravenous injection. Consequently, such clearable theranostic nanoparticles with multiple functions, which are applicable in multimodal imaging-guided cancer therapy, might show promise for applications in nanomedical science.

Testing and using complete plastomes and ribosomal DNA sequences as the next generation DNA barcodes in Panax (Araliaceae).

Complete plastid genome (plastome) sequences and nuclear ribosomal DNA (nrDNA) regions have been proposed as candidates for the next generation of DNA barcodes for plant species discrimination. However, the efficacy of this approach still lacks comprehensive evaluation. We carried out a case study in the economically important but phylogenetically and taxonomically difficult genus Panax (Araliaceae). We generated a large data set of plastomes and nrDNA sequences from multiple accessions per species. Our data improved the phylogenetic resolution and levels of species discrimination in Panax, compared to any previous studies using standard DNA barcodes. This provides new insights into the speciation, lineage diversification and biogeography of the genus. However, both plastome and nrDNA failed to completely resolve the phylogenetic relationships in the Panax bipinnatifidus species complex, and only half of the species within it were recovered as monophyletic units. The results suggest that complete plastome and ribosomal DNA sequences can substantially increase species discriminatory power in plants, but they are not powerful enough to fully resolve phylogenetic relationships and discriminate all species, particularly in evolutionarily young and complex plant groups. To gain further resolving power for closely related species, the addition of substantial numbers of nuclear markers is likely to be required.

Transcriptome analyses of Paris polyphylla var. chinensis, Ypsilandra thibetica, and Polygonatum kingianum characterize their steroidal saponin biosynthesis pathway.

Steroidal saponins, one of the most diverse groups of plant-derived natural products, elicit biological and pharmacological activities; however, the genes involved in their biosynthesis and the corresponding biosynthetic pathway in monocotyledon plants remain unclear. This study aimed to identify genes involved in the biosynthesis of steroidal saponins by performing a comparative analysis among transcriptomes of Paris polyphylla var. chinensis (PPC), Ypsilandra thibetica (YT), and Polygonatum kingianum (PK). De novo transcriptome assemblies generated 57,537, 140,420, and 151,773 unigenes from PPC, YT, and PK, respectively, of which 56.54, 47.81, and 44.30% were successfully annotated, respectively. Among the transcriptomes for PPC, YT, and PK, we identified 194, 169, and 131; 17, 14, and 26; and, 80, 122, and 113 unigenes corresponding to terpenoid backbone biosynthesis; sesquiterpenoid and triterpenoid biosynthesis; and, steroid biosynthesis pathways, respectively. These genes are putatively involved in the biosynthesis of cholesterol that is the primary precursor of steroidal saponins. Phylogenetic analyses indicated that lanosterol synthase may be exclusive to dicotyledon plant species, and the cytochrome P450 unigenes were closely related to clusters CYP90B1 and CYP734A1, which are UDP-glycosyltransferases unigenes homologous with the UGT73 family. Thus, unigenes of ß-glucosidase may be candidate genes for catalysis of later period modifications of the steroidal saponin skeleton. Our data provide evidence to support the hypothesis that monocotyledons biosynthesize steroidal saponins from cholesterol via the cycloartenol pathway.

MSOT/CT/MR imaging-guided and hypoxia-maneuvered oxygen self-supply radiotherapy based on one-pot MnO2-mSiO2@Au nanoparticles.

Radiotherapy (RT) is one of the most widely applied treatments for cancer therapy in clinics. Herein, we constructed innovative multifunctional nanotheranostic MnO2-mSiO2@Au-HA nanoparticles (MAHNPs) based on one-pot MnO2-mSiO2 nanohybrids (MNHs) and gold nanoparticles (AuNPs) for multispectral optoacoustic tomography (MSOT)/computed tomography (CT) and magnetic resonance (MR) imaging-guided hypoxia-maneuvered radiotherapy. The MNHs were prepared via a facile one-pot approach, which avoided the leakage of MnO2 nanoparticles and increased the synthetic efficiency. The Mn2+ ions triggered the breakdown of endogenous H2O2 to generate O2 to convert the hypoxic tumor micro-environment (TME), thus enhancing radiotherapy by self-supply oxygen. In addition, hyaluronic acid (HA) was employed to modify the surface of the MnO2-mSiO2@Au nanoparticles to improve their biocompatibility and cellular uptake. The well-designed nanoparticles could perform remarkable photothermal therapy (PTT) and hypoxia-maneuvered radiotherapy (RT) simultaneously and MSOT/CT/MR imaging. The in vivo studies showed that the MAHNPs achieved almost total suppression of tumor growth without observable recurrence, which raises new possibilities for clinical nanotheranostics with multimodal diagnostic and therapeutic coalescent design.

Rodlike MSN@Au Nanohybrid-Modified Supermolecular Photosensitizer for NIRF/MSOT/CT/MR Quadmodal Imaging-Guided Photothermal/Photodynamic Cancer Therapy.

Recently, rodlike nanomaterials with specific aspect ratio for efficient cellular uptake have received enormous attention. For functional nanomaterials, such as photothermal agents, large surface areas for their rod-shaped exterior that increase the amount of light absorbed would lead to a higher absorption coefficient as well as drug-loading property. In this project, we coated rodlike mesoporous silica with gold nanoshells (MSNR@Au hybrid), modifying them with ultrasmall gadolinium (Gd)-chelated supramolecular photosensitizers, TPPS4 (MSNR@Au-TPPS4(Gd)), which could be applied to near-infrared fluorescence/multispectral optoacoustic tomography/computed tomography/magnetic resonance imaging and imaging-guided remotely controlled photothermal (PTT)/photodynamic (PDT) combined antitumor therapy. Gold nanoshells, as a perfect PTT agent, were used to assemble the rodlike mesoporous silica nanoparticles with larger superficial area and higher drug loading, thus obtaining the MSNR@Au hybrid. HS-ß-CD, which was used as the host, was adsorbed on the gold nanoshell (MSNR@Au-ß-CD) to link TPPS4(Gd) through the host-guest reaction, thus forming CD-TPPS4 supramolecular photosensitizers (supraPSs). Compared with conventional PSs, supraPSs have host screens, which could reduce the self-aggregation of TPPS4, and consequently generate 1O2 with high efficiency. The in vivo quadmodal imaging of MSNR@Au-TPPS4(Gd) nanoparticles revealed an intensive tumor uptake effect after injection. The in vivo antitumor efficacy further testified that the synergistic therapy, which was more efficient than any other monotherapy, exhibited an excellent tumor inhibition therapeutic effect. As a result, this encourages to further explore multifunctional theranostic nanoparticles based on gold shells for combined cancer therapy.

Ultrasmall MoS2 Nanodots-Doped Biodegradable SiO2 Nanoparticles for Clearable FL/CT/MSOT Imaging-Guided PTT/PDT Combination Tumor Therapy.

Recently, we developed ultrasmall molybdenum disulfide (MoS2) quantum dots for computed tomography (CT) and multispectral optoacoustic tomography (MSOT) imaging-guided photothermal therapy (PTT). But, due to rapid body elimination and limited blood circulation time, the tumor uptake of the dots is low. In our study, this problem was solved via designing an amino-modified biodegradable nanomaterial based on MoS2 quantum-dots-doped disulfide-based SiO2 nanoparticles (denoted MoS2@ss-SiO2) for multimodal application. By integrating the MoS2 quantum dots into clearable SiO2 nanoparticles, this nanoplatform with an appropriate particle size can not only degrade and excrete in a reasonable period induced by redox responsiveness of glutathione but also exhibit a high tumor uptake due to the longer blood circulation time. Moreover, hyaluronic acid and chlorin e6 (Ce6) were adsorbed on the outer shell for tumor-targeting effect and photodynamic therapy, respectively. So, this biodegradable and clearable theranostic nanocomposite, which is applicable in integrated fluorescence/CT/MSOT imaging-guided combined photothermal therapy (PTT) and photodynamic therapy, is very promising in biomedical applications in the future.

Photothermally activatable PDA immune nanomedicine combined with PD-L1 checkpoint blockade for antimetastatic cancer photoimmunotherapy.

Photothermal therapy (PTT) has shown promising potential and bright prospects in damaging primary tumors; however, it is limited to metastatic and recrudescent tumors as PTT requires straightforward light irradiation. Moreover, metastatic and recrudescent tumor immunosuppression due to host T-cell antitumor activity is dramatically impeded because of programmed cell death 1 ligand (PD-L1) and programmed cell death receptor 1 (PD-1) pathways and immune checkpoint blockade (ICB) therapy. In this work, we demonstrate that PTT combined with ICB could not only eliminate primary tumors, but also prevent tumor metastasis to the lungs/liver. In particular, we have designed immunoadjuvant nanomedicine carriers on the basis of polydopamine (PDA) simultaneously loaded with resiquimod (R848)-a kind of toll-like receptor 7 (TLR7) agonist-and carbon dots (CDs)-a fluorescent agent. This nanomedicine is defined as PDA-PEG-R848-CD nanoparticle (NP). The multitasking PDA-PEG-R848-CD NPs can destroy 4T1 breast tumors by PTT under near-infrared laser irradiation in addition to generating tumor-associated antigens. Moreover, the PTT effect triggered the release of R848, thereby inducing a strong antitumor immune response. Meanwhile, this synergistic therapy also shows the abscopal effects by completely inhibiting the growth of untreated distant tumors by effectively triggering the tumors infiltrated by CD3/CD8. Such findings suggest that PDA-PEG-R848-CD NPs could significantly potentiate the systemic therapeutic efficiency of PD-L1 checkpoint blockade therapy by activating both innate and adaptive immune systems in the body.