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Electrospun nanofibers have been frequently used for tissue engineering due to their morphological similarities with the extracellular matrix (ECM) and tunable chemical and physical properties for regulating cell behaviors and functions. However, most of the existing electrospun nanofibers have a closely packed two-dimensional (2D) membrane with the intrinsic shortcomings of limited cellular infiltration, restricted nutrition diffusion, and unsatisfied thickness. Three-dimensional (3D) electrospun nanofiber-based scaffolds can provide stem cells with 3D microenvironments and biomimetic fibrous structures. Thus, they have been demonstrated to be good candidates for in vivo repair of different tissues. This review summarizes the recent developments in 3D electrospun nanofiber-based scaffolds (ENF-S) for tissue engineering. Three types of 3D ENF-S fabricated using different approaches classified into electrospun nanofiber 3D scaffolds, electrospun nanofiber/hydrogel composite 3D scaffolds, and electrospun nanofiber/porous matrix composite 3D scaffolds are discussed. New functions for these 3D ENF-S and properties, such as facilitated cell infiltration, 3D fibrous architecture, enhanced mechanical properties, and tunable degradability, meeting the requirements of tissue engineering scaffolds were discovered. The applications of 3D ENF-S in cartilage, bone, tendon, ligament, skeletal muscle, nerve, and cardiac tissue regeneration are then presented with a discussion of current challenges and future directions. Finally, we give summaries and future perspectives of 3D ENF-S in tissue engineering and clinical transformation.

With the continuous development of the electronics industry, the energy density of modern electronic devices increases constantly, thus releasing a lot of heat during operation. Modern electronic devices take higher and higher request to the thermal interface materials. Achieving high thermal conductivity needs to establish an interconnecting thermal conductivity network in the matrix. For this purpose, the suspension of Al2O3 and curdlan was first foamed to construct a bubble-templated continuous ceramic framework. Owing to the rapid gelation property of curdlan, we can easily remove moisture by hot air drying. Finally, the high thermally conductive composites are prepared by vacuum impregnation of silicone rubber. The result showed that composites prepared by our method have higher thermal conductivity than the samples obtained by traditional method. The thermal conductivity of the prepared composite material reached 1.253 W·m−1·K−1 when the alumina content was 69.6 wt%. This facile method is expected to be applied to the preparation of high-performance thermal interface materials.

Chemiluminescence imaging is imperative for diagnostics and imaging due to its intrinsically high sensitivity. To improve in vivo detection of biomarkers, chemiluminophores that simultaneously possess near-infrared (NIR) emission and modular structures amenable to construction of activatable probes are highly desired; however, these are rare. Herein, we report two chemiluminophores with record long NIR emission (>750 nm) via integration of dicyanomethylene-4H-benzothiopyran or dicyanomethylene-4H-benzoselenopyran with dioxetane unit. Caging of the chemiluminophores with different cleavable moieties produces NIR chemiluminescence probes (NCPs) that only produce signals upon reaction with reactive oxygen species or enzymes, for example, β-galactosidase, with a tissue-penetration depth of up to 2 cm. Thus, this study provides NIR chemiluminescence molecular scaffolds applicable for in vivo turn-on imaging of versatile biomarkers in deep tissues. Ministry of Education (MOE) Nanyang Technological University This work was supported by Nanyang Technological University (Start-up Grant: M4081627) and Singapore Ministry of Education Academic Research Fund Tier 1 (2019-T1-002-045,RG125/19) and Tier 2 (MOE2018-T2-2-042)

Glucose oxidase (GOx)-mediated starvation therapy has demonstrated good application prospect in cancer treatment. However, the glucose- and oxygen-depletion starvation therapy still suffers from some limitations like low therapeutic efficiency and potential side effects to normal tissues. To overcome these disadvantages, herein a novel enzymatic cascade nanoreactor (Pd@Pt-GOx/hyaluronic acid (HA)) with controllable enzymatic activities was developed for high-efficiency starving-enhanced chemodynamic cancer therapy. The Pd@Pt-GOx/HA was fabricated by covalent conjugation of GOx onto Pd@Pt nanosheets (NSs), followed by linkage with hyaluronic acid (HA). The modification of HA on Pd@Pt-GOx could block the GOx activity, catalase (CAT)-like and peroxidase (POD)-like activities of Pd@Pt, reduce the cytotoxicity to normal cells and organs, and effectively target CD44-overexpressed tumors by active targeting and passive enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the intracellular hyaluronidase (Hyase) could decompose the outer HA and expose Pd@Pt-GOx for the enzymatic cascade reaction. The GOx on the Pd@Pt-GOx could catalyze the oxidation of intratumoral glucose by O2 for cancer starvation therapy, while the O2 produced from the decomposition of endogenous H2O2 by the Pd@Pt with the CAT-like activity could accelerate the O2-dependent depletion of glucose by GOx. Meanwhile, the upregulated acidity and H2O2 content in the tumor region generated by GOx catalytic oxidation of glucose dramatically facilitated the pH-responsive POD-like activity of the Pd@Pt nanozyme, which then catalyzed degradation of the H2O2 to generate abundant highly toxic •OH, thereby realizing nanozyme-mediated starving-enhanced chemodynamic cancer therapy. In vitro and in vivo results indicated that the controllable, self-activated enzymatic cascade nanoreactors exerted highly efficient anticancer effects with negligible biotoxicity.

Introduction Macleaya cordata (Willd) R. Br. (Papaveraceae family) is a well-known traditional Chinese medicine used to treat muscle pain, inflamed wounds, and bee bites. Benzo[c]phenanthridine alkaloids are the main active ingredients in M. cordata. In this work, sanguinarine and chelerythrine were efficiently extracted and purified by ultrahigh-pressure extraction (UHPE) technique and pH-zone-refining counter-current chromatography (PZRCCC) from M. cordata. Objective To develop an efficient UHPE method followed by an efficient separation technique using PZRCCC for benzo[c]phenanthridine alkaloids from the study plant species, and to evaluate the study samples for anti-breast cancer activity. Methodology The optimal extraction conditions were optimised as extraction pressure 200 MPa, extraction solvent 95% ethanol, solid-liquid ratio 1:30 (g/mL) and extraction time 2 min. A two-phase n-hexane/ethyl acetate/i-propanol/water (1:3:1.5:4.5, v/v) solvent system was optimised with 10 mmol triethylamine in the upper phase and 10 mmol trifluoroacetic acid in lower phase in PZRCCC. The sample loading was optimised as 2.50 g. Moreover, the samples were evaluated for anti-breast cancer activity later on. Results The 2.50 g sample loading yielded 0.45 g of sanguinarine and 0.59 g chelerythrine in one-step separation using PZRCCC. The anti-breast cancer activities of sanguinarine and chelerythrine were found stronger than positive control (vincristine 5.04 μg/mL) with half-maximal inhibitory concentration values of 0.96 and 3.00 μg/mL, respectively. Conclusion This study showed that the established methods were efficient in extraction (UHPE) and separation (PZRCCC) of the sanguinarine and chelerythrine from M. cordata.

Chemodynamic therapy (CDT) that utilizes endogenous hydrogen peroxide (H2O2) to produce reactive oxygen species (ROS) to kill cancer cells has shown a promising strategy for malignant tumor treatment. Nevertheless, limited H2O2 levels in the tumor microenvironment often compromise the therapeutic benefits of CDT, leading to cancer recurrence and metastasis. Herein, a second near-infrared (NIR-II) photothermal Fenton nanocatalyst (PFN) was developed for activatable magnetic resonance imaging (MRI)-guided synergetic photothermal therapy (PTT) and CDT of pancreatic carcinoma. Such a PFN consists of manganese dioxide (MnO2), copper sulfide (CuS), and human serum albumin (HSA), which serve as the activatable imaging contrast agent, the NIR-II photothermal agent and Fenton catalyst, and the stabilizer, respectively. The acidic tumor microenvironment increased the relaxivity of PFN by 2.1-fold, allowing for improved imaging performance and monitoring of nanoparticle accumulation in tumors. Under NIR-II laser irradiation at 1064 nm, PFN generates local heat, which not only permits PTT but also enhances the nanocatalyst-mediated Fenton-like reaction. As such, PFN exerts a synergetic action to completely ablate xenografted tumor models in living animals, while the sole CDT fails to do so. This study thus provides an NIR-II photothermal nanocatalyst for potential treatment of deep-seated tumors.

Driven by increasingly severe cooling issue of modern electronic devices, the design of heat-dissipation films with ultrahigh in-plane thermal conductivity (TC) has achieved considerable development. However, the problems of the poor flexibility and low out-plane TC remain outstanding, significantly restricting the large-scale application of the films. Herein, we developed a novel GO-assisted gelation method combined with facile hot compression to fabricate the highly flexible rGO-BN-NR composite films with an outstanding heat dissipating performance. The as-prepared films, at a BN loading of 250phr, demonstrated both superior in-plane TC (16.0 W/(m·K)) and impressive elongation at break (113%). In addition, the composite films also exhibited excellent flame-retardant ability and pronounced antistatic performance. More importantly, to accommodate the applied characteristics of thermal interface materials, the orienting direction of the composites can be easily transferred to achieve a high vertical TC. The strong cooling capability of the rGO-BN-NR composite films was directly certified by thermal infrared imaging and finite element simulation, indicating a broad and bright application for thermal management in a variety of emerging electronic devices.

This study reports the development of iron-chelated semiconducting polycomplex nanoparticles (SPFeN) for photoacoustic (PA) imaging-guided photothermal ferrotherapy of cancer. The hybrid polymeric nanoagent comprises a ferroptosis initiator (Fe3+ ) and an amphiphilic semiconducting polycomplex (SPC ) serving as both the photothermal nanotransducer and iron ion chelator. By virtue of poly(ethylene glycol) (PEG) grafting and its small size, SPFeN accumulates in the tumor of living mice after systemic administration, which can be monitored by PA imaging. In the acidic tumor microenvironment, SPFeN generates hydroxyl radicals, leading to ferroptosis; meanwhile, under NIR laser irradiation, it generates localized heat to not only accelerate the Fenton reaction but also implement photothermal therapy. Such a combined photothermal ferrotherapeutic effect of SPFeN leads to minimized dosage of iron compared to previous studies and effectively inhibits the tumor growth in living mice, which is not possible for the controls. Ministry of Education (MOE) Nanyang Technological University K.P. thanks Nanyang Technological University (Start-Up grant: M4081627) and Singapore Ministry of Education Academic Research Fund Tier 1 (2017-T1-002-134 RG147/17 & 2019-T1-002-045 RG125/19) and Academic Research Fund Tier 2 (MOE2018-T2-2-042) for the financial support.

Real-time imaging of immunoactivation is imperative for cancer immunotherapy and drug discovery; however, most existing imaging agents possess "always-on" signals and thus have poor signal correlation with immune responses. Herein, renal-clearable near-infrared (NIR) fluorescent macromolecular reporters are synthesized to specifically detect an immunoactivation-related biomarker (granzyme B) for real-time evaluation of cancer immunotherapy. Composed of a peptide-caged NIR signaling moiety linked with a hydrophilic poly(ethylene glycol) (PEG) passivation chain, the reporters not only specifically activate their fluorescence by granzyme B but also passively target the tumor of living mice after systemic administration. Such granzyme B induced in vivo signals of the reporters are validated to correlate well with the populations of cytotoxic T lymphocytes (CD8⁺) and T helper (CD4⁺) cells detected in tumor tissues. By virtue of their ideal renal clearance efficiency (60% injected doses at 24 h postinjection), the reporters can be used for optical urinalysis of immunoactivation simply by detecting the status of excreted reporters. This study thus proposes a molecular optical imaging approach for noninvasive evaluation of cancer immunotherapeutic efficacy in living animals. Ministry of Education (MOE) Nanyang Technological University This work was supported by Nanyang Technological University (NTU-SUG: M4081627) and the Singapore Ministry of Education Academic Research Fund Tier 1 (2017-T1-002-134, RG147/17; 2019-T1-002-045, RG125/19) and Tier 2 (MOE2018-T2-2-042).

Cancer therapy is routinely performed in the clinic to cure cancer and control its progression, wherein therapeutic agents are generally used. To reduce side effects, protherapeutic agents that can be activated by overexpressed cancer biomarkers are under development. However, these agents still face certain extent of off-target activation in normal tissues, stimulating the interest to design external-stimuli activatable protherapeutics. In this regard, photoactivatable protherapeutic agents have been utilized for cancer treatments. However, because of the intrinsic features of photolabile moieties, most photoactivatable protherapeutic agents only respond to ultraviolet-visible light, limiting their in vivo applications. Thus, protherapeutic agents that can be activated by near-infrared (NIR) light with minimal phototoxicity and increased tissue penetration are highly desired.In this Account, we summarize our semiconducting polymer nanomaterials (SPNs) as NIR photoactivatable protherapeutic agents for cancer treatment. SPNs are transformed from π-conjugated polymers that efficiently convert NIR light into heat or singlet oxygen (¹O₂). With photothermal and photodynamic properties, SPNs can be directly used as photomedicine or serve as light transducers to activate heat or ¹O₂₋ responsive protherapeutic agents.The heat-activatable SPN-based protherapeutic agents are developed by loading or conjugating of SPNs with therapeutic agents (e.g., agonist, gene, and enzyme). For instance, photothermally triggered release of agonists specifically activates certain protein ion channels on the cellular membrane, leading to ion overinflux induced mitochondria dysfunction and consequently apoptosis of cancer cells. Moreover, photothermal activation of temperature-sensitive bromelain can promote the in situ degradation of collagens (the major components of extracellular matrix), resulting in an improved accumulation of agents in tumor tissues and thus amplified therapeutic outcome.The¹O₂₋ activatable SPN-based protherapeutic agents are constructed through covalent conjugation of SPNs with caged therapeutic agents via hypoxia- or ¹O₂₋ cleavable linkers. Upon NIR photoirradiation, SPNs consume oxygen to generate ¹O₂, which leads to photodynamic therapy (PDT), and meanwhile breaks hypoxia- or ¹O₂₋ cleavable linkers for on-demand release and in situ activation of caged protherapeutic molecules (e.g., chemodrug, enzyme, and inhibitor). Such remote activation of SPN-based protherapeutic agents can be applied to induce DNA damage, ribonucleic acid degradation, inhibition of protein biosynthesis, or immune system activation in tumors of living animals. By synergizing PDT with NIR photoactivation of those biological actions, these protherapeutic agents effectively eliminate tumors and even fully inhibit tumor metastasis.This Account highlights the potential of SPNs for construction of versatile NIR photoactivatable protherapeutics to treat cancer at designated times and locations with high therapeutic outcome and precision. Ministry of Education (MOE) Nanyang Technological University K.P. thanks Nanyang Technological University (Start-Up Grant: M4081627) and Singapore Ministry of Education Academic Research Fund Tier 1 (2017-T1-002-134, RG147/17) and Academic Research Fund Tier 2 (MOE2016-T2-1-098&MOE2018-T2-2-042) for the financial support.

Photothermal therapy (PTT) that utilizes hyperthermia to ablate cancer cells is a promising approach for cancer therapy, while the generated high temperature may lead to damage of surrounding normal tissues and inflammation. We herein report the construction of glucose oxidase (GOx)-loaded hydrogels with a pH-sensitive photothermal conversion property for combinational cancer therapy at mild-temperature. The hydrogels (defined as CAG) were formed via coordination of alginate solution containing pH-sensitive charge-transfer nanoparticles (CTNs) as the second near-infrared (NIR-II) photothermal agents and GOx. In the tumor sites, GOx was gradually released from CAG to consume glucose for tumor starvation and aggravate acidity in tumor microenvironment that could turn on the NIR-II photothermal conversion property of CTNs. Meanwhile, the released GOx could suppress the expression of heat shock proteins to enable mild NIR-II PTT under 1,064 nm laser irradiation. As such, CAG mediated a combinational action of mild NIR-II PTT and starvation therapy, not only greatly inhibiting the growth of subcutaneously implanted tumors in a breast cancer murine model, but also completely preventing lung metastasis. This study thus provides an enzyme loaded hydrogel platform with a pH-sensitive photothermal effect for mild-temperature-mediated combinational cancer therapy.

Background: With the technical development of counter-reconnaissance and antijamming, communication system becomes more and more complex, and therefore, the recognition of communication signal becomes a challenging task according to recent patents. In order to achieve successful recognition and classification of radiation source signal under variant SNR environment, the design and selection of classifier are one of the key points. Methods: Gray relation theory can solve the learning problem with a small number of samples and its algorithm is simple and can solve the issue of generality versus accuracy, which is very suitable for dealing with fuzzy mathematical problems. However, the selection of distinguishing coefficient has a direct effect on the recognition results by gray relation classifier. For conventional gray relation classifier, the distinguishing coefficient is usually set as a fixed value of 0.5, and for different types of signals, its recognition rate varies. Aiming at this issue, an improved adaptive gray relation classifier algorithm is proposed in the paper. Results: The simulation results show that the recognition rate can still reach more than 87% even at the SNR of 10dB. Conclusion: The proposed methods can improve the anti-jamming capability of the classifier, which can be widely used in the fields of electronic reconnaissance, fault diagnosis and image processing.

Vulnerable atherosclerotic plaques are responsible for most cardiovascular diseases (CVDs). Folate receptor (FR) positive activated macrophages were thought to be a prominent component in the development of vulnerable plaque. The objective of this study is to develop folate conjugated two-dimensional (2D) Pd@Au nanomaterials (Pd@Au-PEG-FA) for targeted multimodal imaging of the FRs in advanced atherosclerotic plaques. Pharmacokinetic and imaging studies (single photon emission computed tomography (SPECT), computed tomography (CT) and photoacoustic (PA) imaging) were performed to confirm the prolonged blood half-life and enrichment of radioactivity in atherosclerotic plaques. Strong signals were detected in vivo with SPECT, CT and PA imaging in heavy atherosclerotic plaques, which were significantly higher than those of the normal aortas after injection of Pd@Au-PEG-FA. Blocking studies with preinjection of excess FA could effectively reduce the targeting ability of Pd@Au-PEG-FA in atherosclerotic plaques, further demonstrating the specific binding of Pd@Au-PEG-FA for plaque lesions. Histopathological characterization revealed that the signal of probe was in accordance with the high-risk plaques. In summary, the Pd@Au-PEG-FA has favorable pharmacokinetic properties and provides a valuable approach for detecting high-risk plaques in the presence of FRs in atherosclerotic plaques.

Noninvasive regulation of CRISPR/Cas9 gene editing is conducive to understanding of gene function and development of gene therapy; however, it remains challenging. Herein, a photolabile semiconducting polymer nanotransducer (pSPN) is synthesized to act as the gene vector to deliver CRISPR/Cas9 plasmids into cells and also as the photoregulator to remotely activate gene editing. pSPN comprises a 1 O2 -generating backbone grafted with polyethylenimine brushes through 1 O2 -cleavable linkers. NIR photoirradiation spontaneously triggers the cleavage of gene vectors from pSPN, resulting in the release of CRISPR/Cas9 plasmids and subsequently initiating gene editing. This system affords 15- and 1.8-fold enhancement in repaired gene expression relative to the nonirradiated controls in living cells and mice, respectively. As this approach does not require any specific modifications on biomolecular components, pSPN represents the first generic nanotransducer for in vivo regulation of CRISPR/Cas9 gene editing.

Drug-induced acute kidney injury (AKI) with a high morbidity and mortality is poorly diagnosed in hospitals and deficiently evaluated in drug discovery. Here, we report the development of molecular renal probes (MRPs) with high renal clearance efficiency for in vivo optical imaging of drug-induced AKI. MRPs specifically activate their near-infrared fluorescence or chemiluminescence signals towards the prodromal biomarkers of AKI including the superoxide anion, N-acetyl-β-d-glucosaminidase and caspase-3, enabling an example of longitudinal imaging of multiple molecular events in the kidneys of living mice. Importantly, they in situ report the sequential occurrence of oxidative stress, lysosomal damage and cellular apoptosis, which precedes clinical manifestation of AKI (decreased glomerular filtration). Such an active imaging mechanism allows MRPs to non-invasively detect the onset of cisplatin-induced AKI at least 36 h earlier than the existing imaging methods. MRPs can also act as exogenous tracers for optical urinalysis that outperforms typical clinical/preclinical assays, demonstrating their clinical promise for early diagnosis of AKI. Chemiluminescent molecular renal probes have been developed and are shown to be capable of non-invasive real-time imaging of early-stage oxidative stress biomarkers of drug-induced acute kidney injury, and high renal clearance.

Polydopamine-coated magnetic mesoporous silica nanoparticles have been designed by loading ultrasmall iron oxide nanoparticles within hollow mesoporous silica nanopartricles and then coating polydopamine onto the particle surface. The developed nanoplatform displayed improved colloidal stability, enhanced r1 relaxivity and near infrared absorption feature, affording their use for multimodal cancer theranostics.

Malignant glioma remains incurable largely due to the aggressive and infiltrative nature, as well as the existence of blood–brain-barrier (BBB). Precise diagnosis of glioma, which aims to accurately delineate the tumor boundary for guiding surgical resection and provide reliable feedback of the therapeutic outcomes, is the critical step for successful treatment. Numerous imaging modalities have been developed for the efficient diagnosis of tumors from structural or functional aspects. However, the presence of BBB largely hampers the entrance of contrast agents (Cas) or probes into the brain, rendering the imaging performance highly compromised. The development of nanomaterials provides promising strategies for constructing nano-sized Cas or probes for accurate imaging of glioma owing to the BBB crossing ability and other unique advantages of nanomaterials, such as high loading capacity and stimuli-responsive properties. In this review, the recent progress of nanomaterials applied in single modal imaging modality and multimodal imaging for a comprehensive diagnosis is thoroughly summarized. Finally, the prospects and challenges are offered with the hope for its better development.

As a promising treatment option for cancer, immunotherapy can eliminate local and distant metastatic tumors and even prevent recurrence through boosting the body’s immune system. However, immunotherapy often encounters the issues of limited therapeutic efficacy and severe immune-related adverse events in clinical practices, which should be mainly due to the non-specific accumulations of immunotherapeutic agents. Activatable immunomodulatory agents that are responsive to endogenous stimuli in tumor microenvironment can afford controlled immunotherapeutic actions, while they still face certain extent of off-target activation. Since light has the advantages of noninvasiveness, simple controllability and high spatio-temporal selectivity, therapeutic agents that can be activated by light, particularly near-infrared (NIR) light with minimal phototoxicity and strong tissue penetrating ability have been programmed for cancer treatment. In this mini review, we summarize the recent progress of NIR photoactivatable immunomodulatory nanoparticles for combinational cancer immunotherapy. The rational designs, constructions and working mechanisms of NIR photoactivatable agents are first briefly introduced. The uses of immunomodulatory nanoparticles with controlled immunotherapeutic actions upon NIR photoactivation for photothermal and photodynamic combinational immunotherapy of cancer are then summarized. A conclusion and discussion of the existing challenges and further perspectives for the development and clinical translation of NIR photoactivatable immunomodulatory nanoparticles are finally given.

The Chuan–Dian region, situated in the middle part of the north-south seismic zone of mainland China in a highly deformed area of the eastern margin of the Tibetan Plateau, is one of the principal areas for monitoring earthquake activities in China. In this study, the geochemical characteristics of soil degassing (of CH4, H2, CO2, Rn, and Hg) and, the relationship between degassing and fault activity, were investigated in the Xianshuihe–Xiaojiang fault system (XXFS) at the eastern boundary of the Chuan–Dian rhombic block. The mean soil-gas concentrations of CH4, H2, CO2, Rn, and Hg in the XXFS were 8.1 ppm, 9.9 ppm, 0.5%, 15.1 kBq/m3 and 12.9 ng/m3, respectively. The δ13CCO2 and δ13CCH4 values of the hot-spring gases varied from −11.9‰ to −3.7‰ and −62.5‰ to 17‰, respectively. The He-C isotopic ratios indicate that the carbon in the northern and middle parts of the XXFS may have originated from deep fluids, whereas the carbon in the southern part of the XXFS is of organic origin. The high concentrations of soil gas were distributed near the faults, indicating that the faults could act as channels for gas migration. The distributions of the high soil-gas concentrations in the XXFS coincide with the highest stress and maximum strain rates, indicating that the fault activity enhanced permeability and increased the emission rates of the gases. The results of this study will be helpful for degassing in active fault zones and earthquake monitoring.

Zhao Li,1,2 Iftikhar Ali,1,3 Jiying Qiu,4 Huanzhu Zhao,1 Wenya Ma,1,2 Aiying Bai,5 Daijie Wang,1 Jingchao Li1 1Shandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, People’s Republic of China; 2College of Life Science, Shandong Normal University, Jinan 250014, People’s Republic of China; 3Department of Chemistry, Karakoram International University, Gilgit 15100, Pakistan; 4Institute of Agro-Food Science and Technology, Shandong Academy of Agricultural Sciences, Jinan 250100, People’s Republic of China; 5Jinan Municipal Center for Disease Control and Prevention, Jinan 250001, People’s Republic of ChinaCorrespondence: Daijie Wang; Jingchao LiShandong Analysis and Test Center, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250014, People’s Republic of ChinaTel +86-53182605319Fax +86-0531-82964889Email wangdaijie@126.com; lijingchao888@sohu.comBackground: Dihydromyricetin (DMY), a natural flavonoid, has reportedly antibacterial, antioxidant, anticancer and other properties. In the present study, DMY was used as a reducing agent and stabilizer to synthesize silver nanoparticles (AgNPs), and the optimal conditions for its synthesis were studied. The DMY-AgNPs were investigated for their DPPH scavenging properties and their potential against human pathogenic and food-borne bacteria viz. Escherichia coli (E. coli), and Salmonella. In addition, DMY-AgNPs also showed excellent inhibitory effects on cancer Hela, HepG2 and MDA-MB-231 cell lines.Methods: The dihydromyricetin-mediated AgNPs (DMY-AgNPs) were characterized by ultraviolet-visible spectrophotometer (UV-Vis spectra), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and X-ray powder diffraction (XRD). Antioxidant activity of DMY-AgNPs was determined by 1.1-diphenyl-2-picrylhydrazyl (DPPH) scavenging. The antibacterial activity was determined by 96-well plate (AGAR) gradient dilution, while anticancer potential was determined by MTT assay.Results: The results showed that the dispersion of AgNPs had the maximum UV–visible absorption at about 410 nm. The synthesized nanoparticles were almost spherical. FTIR was used to identify functional groups that may lead to the transformation of metal ions into nanoparticles. The results showed that the prepared AgNPs were coated with biological molecules in the extraction solution. The biosynthesized DMY-AgNPs exhibited good antioxidant properties, at various concentrations (0.01– 0.1mg/mL), the free radical scavenging rate was about 56– 92%. Furthermore, DMY-AgNPs possessed good antibacterial properties against Escherichia coli (E. coli), and Salmonella at room temperature. The minimum inhibitory concentrations (MIC) were 10− 6 g/L, and 10− 4 g/L, respectively. The bioactivity of DMY-mediated AgNPs was studied using MTT assay against Hela, HepG2 and MDA-MB-231 cancer cell lines, and all showed good inhibitory effects.Conclusion: The present study provides a green approach for the synthesis of DMY-AgNPs which exhibited stronger antioxidant, antibacterial and anticancer properties compared to the dihydromyricetin. DMY-AgNPs can serve as an economical, efficient, and effective antimicrobial material for its applications in food and pharmaceutical fields.Keywords: natural flavonoid, DMY-AgNO3-NPs, green approach, DPPH, Escherichia coli, Salmonella, Hela, HepG2, MDA-MB-231

Immunotherapy has offered new treatment options for cancer; however, the therapeutic benefits are often modest and desired to be improved. A semiconducting polymer nanoadjuvant (SPNII R) with a photothermally triggered cargo release for second near-infrared (NIR-II) photothermal immunotherapy is reported here. SPNII R consists of a semiconducting polymer nanoparticle core as an NIR-II photothermal converter, which is doped with a toll-like receptor (TLR) agonist as an immunotherapy adjuvant and coated with a thermally responsive lipid shell. Upon NIR-II photoirradiation, SPNII R effectively generates heat not only to ablate tumors and induce immunogenic cell death (ICD), but also to melt the lipid layers for on-demand release of the TLR agonist. The combination of ICD and activation of TLR7/TLR8 enhances the maturation of dendritic cells, which amplifies anti-tumor immune responses. Thus, a single treatment of SPNII R-mediated NIR-II photothermal immunotherapy effectively inhibits growth of both primary and distant tumors and eliminates lung metastasis in a murine mouse model. This study thus provides a remote-controlled smart delivery system to synergize photomedicine with immunotherapy for enhanced cancer treatment. Ministry of Education (MOE) Nanyang Technological University J.L. and X.Y. contributed equally to this work. K.P. thanks Nanyang Technological University (Start-up Grant No. NTU-SUG: M4081627.120), Singapore Ministry of Education, Academic Research Fund Tier 1 (2017T1-002-134; 2019-T1-002-045), and Academic Research Fund Tier 2 (MOE2018-T2-2-042) for the financial support.

Drug delivery systems (DDSs) based on nanomaterials have shown a promise for cancer chemotherapy; however, it remains a great challenge to localize on-demand release of anticancer drugs in tumor tissues to improve therapeutic effects and minimize the side effects. In this regard, photoresponsive DDSs that employ light as an external stimulus can offer a precise spatiotemporal control of drug release at desired sites of interest. Most photoresponsive DDSs are only responsive to ultraviolet-visible light that shows phototoxicity and/or shallow tissue penetration depth, and thereby their applications are greatly restricted. To address these issues, near-infrared (NIR) photoresponsive DDSs have been developed. In this review, the development of NIR photoresponsive DDSs in last several years for cancer photo-chemotherapy are summarized. They can achieve on-demand release of drugs into tumors of living animals through photothermal, photodynamic, and photoconversion mechanisms, affording obviously amplified therapeutic effects in synergy with phototherapy. Finally, the existing challenges and further perspectives on the development of NIR photoresponsive DDSs and their clinical translation are discussed.

Immunotherapy that harnesses the power of the immune system to eliminate malignant cells has offered an effective approach for cancer treatment. However, limited patient response rates and potential immune-related adverse events exist as two major issues for cancer immunotherapy. In parallel, a variety of electromagnetic nanomaterials that generate heat and/or reactive oxygen species triggered by electromagnetic energy have been applied for magnetic hyperthermia therapy, sonodynamic therapy, photothermal therapy, photodynamic therapy, and radiotherapy, which have the ability to induce immunogenic cell death. This review summarizes the recent development of electromagnetic nanomedicines in combinational cancer immunotherapy. The mechanisms of electromagnetic nanomedicines in reprogramming the immunosuppressive tumor microenvironment and sensitizing tumors for cancer immunotherapy are highlighted. Furthermore, potential challenges and perspectives of electromagnetic nanomedicines for combinational cancer immunotherapy are discussed.

Despite its growing promise in cancer treatment, ferrotherapy has low therapeutic efficacy due to compromised Fenton catalytic efficiency in tumor milieu. We herein report a hybrid semiconducting nanozyme (HSN) with high photothermal conversion efficiency for photoacoustic (PA) imaging-guided second near-infrared photothermal ferrotherapy. HSN comprises an amphiphilic semiconducting polymer as photothermal converter, PA emitter and iron-chelating Fenton catalyst. Upon photoirradiation, HSN generates heat not only to induce cytotoxicity but also to enhance Fenton reaction. The increased ·OH generation promotes both ferroptosis and apoptosis, oxidizes HSN (42 nm) and transforms it into tiny segments (1.7 nm) with elevated intratumoral permeability. The non-invasive seamless synergism leads to amplified therapeutic effects including a deep ablation depth (9 mm), reduced expression of metastasis-related proteins and inhibition of metastasis from primary tumor to distant organs. Thereby, our study provides a generalized nanozyme strategy to compensate both ferrotherapy and phototherapeutics for complete tumor regression., Due to tumour microenvironment, Fenton reactions have low therapeutic efficiency. Here the authors report on the application of NIR-II hybrid semiconducting nanozymes for combined photothermal therapy and enhanced ferrotherapy with photoacoustic imaging and show application in vivo in tumour models.

Sub-10 nm gold nanoparticles (Au NPs) have attracted extensive attention for different biomedical applications because of their small size. However, the influence of small NPs on the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) is unclear. In this study, 4 nm small Au NPs (Au4-mPEG NPs) were synthesized to investigate their influence on the osteogenic and adipogenic differentiation of hMSCs and 40-nm counterparts (Au40-mPEG NPs) were used for comparison. Different from Au40-mPEG NPs, Au4-mPEG NPs reduced the ALP activity, calcium deposition and osteogenic marker gene expression, while increased the oil droplet formation and adipogenic marker gene expression in hMSCs. The mechanism study indicated that Au4-mPEG NP treatment did not affect the cellular mechanical property significantly but induced a high level of reactive oxygen species (ROS). The results provide some insights into the influence of sub-10 nm Au NPs on the stem cell functions and applications of these small particles for tissue engineering.

Encapsulation of single mammalian cells with biocompatible and protective materials has important applications in biomedical and single-cell biology research. To date, single mammalian cells have generally been encapsulated by physical approaches including hydrophobic and electrostatic interactions. However, the cytotoxicity of the used materials, short sustained period, and especially loose structure of the encapsulation layer have limited the application of the encapsulated cells. Here, we show a novel strategy based on in situ polymerization for encapsulation of single mammalian cells with a network structure of the polymeric shell under mild conditions. Using the present strategy, the encapsulated mammalian cells, HeLa cells, hMSCs, and BACs showed high viability. Furthermore, the encapsulation shell was able to prevent the penetration of macro-external entities, while maintaining the free exchange of smaller molecules. This work provides a new and versatile method for single mammalian cell encapsulation.

In this work, a novel nanoplatform based on Pd corolla-human serum albumin-indocyanine green (PdCs-HSA-ICG) was developed for cancer photothermal/photodynamic combination therapy. Pd corollas (denoted as PdCs) with good near-infrared photothermal conversion efficiency (η≈ 37%) were first prepared and modified with human serum albumin (HSA) and indocyanine green (ICG) to get the PdCs-HSA-ICG nanocomposite. The prepared PdCs-HSA-ICG not only improves the colloid and thermal stability of ICG, but also shows a higher temperature increase than that of PdCs and free ICG as well as a comparable singlet oxygen (1O2) generation capability to that of free ICG. Upon single 808 nm laser irradiation, the photothermal (PTT)/photodynamic (PDT) combined therapeutic efficacy of PdCs-HSA-ICG at both cellular and animal levels was superior to PdCs-HSA (PTT) or free ICG (PTT and PDT), respectively. Thus, the designed PdCs-HSA-ICG nanocomposite holds great potential as a new class of photosensitive agent for cancer phototherapy.

Drug-induced kidney injury (DIKI) is a significant contributor of both acute and chronic kidney injury and remains a major concern in drug development and clinical care. However, current clinical diagnostic methods often fail to accurately and timely detect nephrotoxicity. This study reports the development of activatable molecular urinary reporters (MURs) that are able to specifically detect urinary biomarkers including γ-glutamyl transferase (GGT), alanine aminopeptidase (AAP), and N-acetyl-β-d-glucosaminidase (NAG). By virtue of their discrete absorption and emission properties, the mixture of MURs can serve as a cocktail sensor for multiplex optical urinalysis in the mouse models of drug-induced acute kidney injury (AKI) and chronic kidney disease (CKD). The MURs cocktail not only detects nephrotoxicity earlier than the tested clinical diagnostic methods in drug-induced AKI and CKD mice models, but also possesses a higher diagnostic accuracy. Therefore, MURs hold great promise for detection of kidney function in both preclinical drug screening and clinical settings. Ministry of Education (MOE) Nanyang Technological University K.P. thanks the Nanyang Technological University (Start-Up grant: M4081627), Singapore Ministry of Education Academic Research Fund Tier 1 (2017-T1-002-134, RG147/17; 2019-T1-002-045, and RG125/19), and Academic Research Fund Tier 2 (MOE2018-T2-2-042) for financial support.

In recent decade, palladium-based (Pd-based) nanomaterials have shown significant potential for biomedical applications because of their unique optical properties, excellent biocompatibility and high stability in physiological environment. Compared with other intensively studied noble nanomaterials, such as gold (Au) and silver (Ag) nanomaterials, research on Pd-based nanomaterials started late, but the distinctive features, such as high photothermal conversion efficiency and high photothermal stability, have made them getting great attention in the field of nanomedicine. The goal of this review is to provide a comprehensive and critical perspective on the recent progress of Pd-based nanomaterials as imaging contrast agents and therapeutic agents. The imaging section focuses on applications in photoacoustic (PA) imaging, single-photon emission computed tomography (SPECT) imaging, computed tomography (CT) imaging and magnetic resonance (MR) imaging. For treatment of cancer, single photothermal therapy (PTT) and PTT combined with other therapeutic modalities will be discussed. Finally, the safety concerns, forthcoming challenges and perspective of Pd-based nanomaterials on biomedical applications will be presented.

In this paper, we assume the security level of a system is a quantifiable metric and apply the insurance company ruin theory in assessing the defense failure frequencies. The current security level of an information system can be viewed as the initial insurer surplus; defense investment can be viewed as premium income resulting in an increase in the security level; cyberattack arrivals follow a Poisson process, and the impact of attacks is modeled as losses on the security level. The occurrence of cyber breach is modeled as a ruin event. We use this framework to determine optimal investment in cyber security that minimizes the total cyber costs. We show by numerical examples that there is an optimal allocation of total cyber security budget to (1) IT security maintenance/upkeep spending versus (2) external cyber risk transfer. Published version

In this paper, we study some state-specific one-sided exit probabilities in a Markov-modulated risk process including the probability that ruin occurs without or with the surplus visiting certain states; the probability that ruin occurs without or with a claim occurring in certain states; the probability that the surplus attains a target level without or with visiting certain states; and the probability that the surplus attains a target level without or with a claim occurring in certain states. We also investigate the corresponding two-sided first exit probabilities without (or with) the surplus visiting certain states or without (or with) claims occurring in certain states. All these probabilities can be expressed elegantly in terms of some modified matrix scale functions which are easily computable.

Nanotechnology is being utilized to develop advanced concepts in drug delivery systems including production of nanodrugs such as, nanocrystals and nanosuspensions. Continuous crystallization methods are of increasing interest and porous hollow fiber membrane (HFM) based modules have been recently utilized as an anti-solvent crystallizer. The porous hollow fiber anti-solvent crystallizer (PHFAC) based method has been modified here to produce continuously nanocrystals of Griseofulvin (GF). In the PHFAC device, deionized water introduced from the HFM bore into the shell side is used as the anti-solvent; acetone containing dissolved GF is introduced into the shell side of the HFM module as the drug solution. Water, the anti-solvent, mixed vigorously with the drug solution leading to drug crystallization and the drug crystals were separated by vacuum filtration and freeze-dried. The experimental conditions were varied to control the particle size, size distribution and the appearance of the nanoparticles. The properties of the drug nanocrystals were characterized via Transmission Electron Microscopy (TEM), Scanning Electron Microscope (SEM), Dynamic Light Scattering (DLS), Raman Spectroscopy, Energy Dispersive X-rays Spectroscopy (EDX), Differential Scanning Calorimetry (DSC), FT-IR Spectrometer, X-ray Diffraction (XRD); drug dissolution tests were also implemented. Drug nanocrystals as small as 86.4 nm were produced under modest pressure and temperature conditions in a controllable and continuous manner.

We present a convenient method to immobilize Au/Ag nanoparticles (NPs) within electrospun polyvinyl alcohol (PVA)/polyethylenimine (PEI) nanofibers by in-situ reduction for catalytic applications. Water-stable electrospun PVA/PEI nanofibers were initially fabricated by crosslinking with glutaraldehyde (GA) vapor. Then, the nanofibers were used as a nanoreactor to bind Au salt via electrostatic interaction with the free PEI amines, followed by NaBH4 reduction to form Au NPs. The formed Au NP-containing nanofibers were then used to bind Ag+ ions via chelation with the free PEI amines, followed by reduction with ascorbic acid to form the Au/Ag NP-loaded PVA/PEI nanofibers. The small size (4.9 ± 1.8 nm) and narrow size distribution of the immobilized Au/Ag NPs reveal that the nanofibrous structure is able to efficiently prevent the aggregation of the NPs. We then evaluated the catalytic activity and reusability of Au/Ag NP-immobilized PVA/PEI nanofiers by catalytic transformation of 4-nitrophenol to 4-aminophenol in aqueous solution. The material exhibited excellent catalytic efficiency and reusability. The developed approach could be applied to create other bimetallic NP-incorporated nanofibers for catalysis, tissue engineering, and environmental remediation applications.

Extracellular matrix (ECM) plays a very important role in regulating cell function and fate. It is highly desirable to fabricate biomimetic models to investigate the role of ECM in stem cell differentiation. In this study, arginine–glycine–aspartate (RGD)-modified gold nanoparticles (Au NPs) with tunable surface ligand density were prepared to mimic the ECM microenvironment. Their effect on osteogenic and adipogenic differentiation of human mesenchymal stem cells (MSCs) was investigated. The biomimetic Au NPs were taken up by MSCs in a ligand density-dependent manner. The biomimetic NPs with a high RGD density had an inhibitive effect on the alkaline phosphatase (ALP) activity, calcium deposition, and osteogenic marker gene expression of MSCs. Their effect on oil droplet formation and adipogenic marker gene expression was negative when RGD density was low, while their effect was promotive when RGD density was high. The biomimetic Au NPs regulated the osteogenic and adipogenic differentiation of MSCs mainly through affecting the focal adhesion and cytoskeleton. This study highlights the roles of biomimetic NPs on stem cell differentiation that could provide a meaningful strategy in fabricating functional biomaterials for tissue engineering and biomedical applications.

Carbon nanotube bundles (CNTB) with one-dimensional orientation arrangement structure were grafted a layer of polyacrylic acid (PAA) through plasma induced polymer grafting in this study. Thus, we blended these modified CNTB (CNTB-PAA) into natural rubber (NR) matrix through the silane in-situ modification-dispersion technique achieved by mechanical blending method. In this process, carboxyl groups in large quantities distributed in the surface of CNTB-PAA could be subjected to dealcoholization reaction with silicon hydroxyl (Si-OH) generated from the hydrolysis of silane coupling agent (Si69), and a single sulfur bond of Si69, meanwhile, could participate in the curing reaction of rubber. The ultimate nanocomposites had a significantly decreased network effect of fillers and an improved interfacial bonding between CNTB and rubber matrix. The tensile and dynamic-mechanical tests revealed a strong enhancement in the tensile stress and a marked reduction in the dynamic hysteresis loss of the nanocomposites.

Breast cancer is a major public health issue, whose morbidity and mortality are increasing across the world. It is still a challenge to completely ablate breast tumor cells and reconstruct tumor-initiated breast defects after surgical resection. Porous scaffolds with hyperthermal and tissue regeneration functions are a desirable option to achieve these effects. In this study, bifunctional composite porous scaffolds of gold nanorods (AuNRs) and gelatin with well controlled pore structures were prepared by introducing AuNRs into the porous matrices of gelatin and using ice particulates as a porogen material. The AuNRs-gelatin composite scaffolds exhibited a high photothermal conversion effect, whose photothermal temperature could be modulated by the amount of incorporated AuNRs, NIR laser power intensity and irradiation time. The AuNRs-gelatin composite scaffolds exhibited an excellent photothermal ablation capacity toward breast tumor cells in vitro and in vivo. Furthermore, the AuNRs-gelatin porous scaffolds supported cell adhesion and promoted the proliferation and adipogenic differentiation of human bone-marrow derived mesenchymal stem cells (hMSCs). Consequently, the AuNRs-gelatin scaffolds could not only provide photothermal therapy for breast tumors but also promote the adipogenic differentiation of stem cells for adipose tissue regeneration.

Radiolabeled nanoparticles (NPs), taking advantage of nanotechnology and nuclear medicine, have shown attractive potential for cancer diagnosis and therapy. However, the high background signal in the liver and long-term toxic effects of radioisotopes caused by the nonselective accumulation of radiolabeled nanoparticles in organs have become the major challenges. Here, we report a pH-sensitive multifunctional theranostic platform with radiolabeled Pd nanosheets through a simple mixture of ultra-small Pd nanosheets and radioisotopes utilizing the strong adsorption of 131I and 125I on their surfaces (denoted as 131I-Pd-PEG or 125I-Pd-PEG). Systematic studies reveal that the labeling efficiency is higher than 98% and the adsorption of radioiodine is more stable in an acidic environment. In vivo studies further validate the pH-dependent behavior of this platform and the enhanced retention of radioisotopes in tumors due to the acidic microenvironment. Single photon emission computed tomography (SPECT) images with zero background were successfully achieved in a subcutaneous 4T1 tumor model, an orthotopic LM3 tumor model, and even in a Mst1/2 double-knockout hepatoma model. Moreover, the application of radiolabeled Pd nanosheets for photoacoustic (PA) imaging, and combined photothermal and radiotherapy was also explored. Therefore, this study provides a simple and efficient strategy to solve the critical high background issue of radiolabeled nanoparticles and shows enormous potential for clinical applications.

Introducing three-dimensional (3D) conductive network in polymer composites is a greatly potential way for acquiring desirable electromagnetic interference (EMI) shielding capacity to satisfy the requirements of next-generation mobile electronics devices. However, facile and scale production to achieve rational design of the microstructure of 3D conductive framework is still remain challenging. Here, we reported a facile foaming route to construct the bubble-templated 3D graphene network, which endow the polydimethylsiloxane (PDMS) rubber composites with excellent EMI-shielding effectiveness of ~86 dB at a thickness of 2 mm. The superior EMI-shielding property is ascribed to the abundant closed pore structures to reflect and absorb electromagnetic waves and high electrical conductivity from interconnected 3D graphene networks. Meanwhile, owing to the low filler loading content of only 18.1 wt%, the density of the obtained composite is just 1.1 g/cm3, which is about 200% lower than those of the commercial products with a similar EMI SE value. Moreover, this composites also have a high thermal conductivity of above 3 W/(m·K), showing great promise for applications of EMI shielding and efficient thermal management in aerospace, telecommunications, and mobile electronics devices.

Controlling the differentiation of human mesenchymal stem cells (hMSCs) shows a great potential in regenerative medicine. Because overproduced reactive oxygen species (ROS) have an obvious inhibitory effect on the differentiation and functions of hMSCs, it is highly desirable to develop an effective strategy for ROS scavenging and stem cell differentiation controlling. In this study, gold nanoparticles (Au NPs) with an average size of 40 nm were conjugated with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) to endow them with ROS-scavenging capacity while holding the beneficial effect of Au NPs. The TEMPO-conjugated Au NPs (Au-PEG-TEMPO NPs) were used for the culture of hMSCs to investigate their effect on ROS scavenging, proliferation, and osteogenic and adipogenic differentiation of hMSCs. The Au-PEG-TEMPO NPs had a negligible influence on cell viability and proliferation of hMSCs and could effectively reduce the ROS level of hMSCs under H2O2-exposed conditions because of their excellent cellular uptake. ...

Nanoencapsulation of individual mammalian cells has great potential in biomedical, biotechnological and bioelectronic applications. However, existing techniques for cell nanoencapsulation generally yield short sustaining period and loose structure of encapsulation shell, which fails to meet the long-term cytoprotection and immunosuppression requirements. Here, we report a mild method to realize the nanoencapsulation of individual mammalian cells by layer-by-layer (LbL) assembly of gelatin inner layer and cross-linking of poly(ethylene glycol) (PEG) outer layer through thiol-click chemistry. With the present method, the encapsulated individual HeLa cells showed a high viability, long persistence period and effective resistance against macro external entities and high physical stress. Moreover, on-demand cell release could also be achieved by selective cleavage of succinimide thioether linkage in the outer PEG layer. The approach presented here may provide a new and versatile method for the cleavable nanoencapsulation of individual mammalian cells.

As an earliest known and readily available osteogenic inducer for stem cells, dexamethasone (DEX) plays a key role in affecting cell functions and cellular processes, especially for cell proliferation and differentiation. However, the clinical application of DEX has been limited because of its uncontrolled release. An ideal carrier is desired to control the DEX release for the osteogenic differentiation of stem cells and bone tissue engineering. Biphasic calcium phosphate nanoparticles (BCP-NPs) should be potential carriers for DEX due to their osteoconductive properties and good biocompatibility as a bone graft biomaterial. In this study, DEX-loaded BCP-NPs were prepared by two methods: (1) immersion of BCP-NPs in a DEX solution (denoted DEX/BCP-NPs), (2) DEX incorporation during BCP-NP formation in a calcifying solution (denoted DEX@BCP-NPs). The DEX@BCP-NPs showed a higher DEX loading amount and more sustainable DEX release than did the DEX/BCP-NPs. The DEX@BCP-NPs were used for the culture of human bone marrow-derived mesenchymal stem cells (hMSCs) and showed a promotive effect on the proliferation of hMSCs. Furthermore, the DEX@BCP-NPs significantly increased the alkaline phosphatase (ALP) activity, calcium deposition and gene expressions of the osteogenic markers of hMSCs when compared to BCP-NPs without DEX loading. The results demonstrated BCP-NPs were good carriers for DEX loading and the DEX@BCP-NPs should be useful for bone tissue engineering.

Nanoparticles (NPs) have provided new opportunities to diagnose and treat various types of cancers, while it still remains a great challenge to develop novel and effective nanoscale platforms for these applications. In this study, we report a facile hydrothermal route to generate size- and shape-controlled gadolinium hydroxide (Gd(OH)3) NPs and polyethylenimine (PEI)-stabilized Gd(OH)3@Au core/shell nanostars (NSs). We show that Gd(OH)3 NPs with controlled size and shape can be synthesized through varying the stabilizer, reaction time and solvent. The formed Gd(OH)3 nanorods can be transformed into rice-shaped counterparts in the presence of trisodium citrate dehydrate. Furthermore, the introduction of PEI does not alter the morphology, rather have an impact on the size of the products. This facile synthetic route can also be utilized to synthesize Gd(OH)3@Au nanocomposite particles that can act as seeds to form Gd(OH)3@Au NSs in the Au growth solution. Further modification of PEI endows these NSs with excellent water-solubility and colloidal stability. Due to the strong surface plasmon resonance peak in the near-infrared region, the as-prepared Gd(OH)3@Au-PEI NSs display a high photothermal conversion efficiency under laser irradiation. The developed size- and shape-controlled Gd(OH)3 NPs and PEI-stabilized Gd(OH)3@Au core/shell NSs may be further developed as theranostic agents for various biomedical applications.

Multifunctional nanoparticles (NPs) have been widely used in biomedical applications because of their versatile properties. The properties of NPs should be well designed and controlled according to various applications because they may directly affect the functions and performances of NPs in biological systems. Cellular uptake is a prerequisite for the success of NP-based biomedical applications. However, the internalized NPs inside cells may have some adverse effects. Therefore, the interactions between NPs and cells should be thoroughly investigated and elucidated. This review summarizes the latest advances in NP-cell interactions. Especially the effects of NP properties including size, shape, shell structure, surface chemistry and protein corona formation on cellular uptake and cytotoxicity are highlighted in detail. Their effects on cell proliferation, differentiation and cellular mechanics are also discussed. These insights into NP-cell interactions should provide useful information for the preparation of highly functional NPs and their biomedical applications.

Photothermal therapy (PTT) has been extensively investigated as a promising strategy for cancer therapy. For successful application of this technique, various nanomaterials have been explored as photothermal conversion agents. Gold nanoparticles (AuNPs), especially Au nanorods and Au nanostars, have received much attention for photothermal therapy because of their facile preparation and high photothermal conversion efficiency. Due to the limited accumulation and easy diffusion of free nanoparticles, incorporation of nanoparticles into scaffolds for direct implantation has been demonstrated as an attractive way for cancer therapy applications. In this study, composite porous scaffolds of gelatin and AuNPs were prepared by introducing Au nanorods and Au nanostars with average sizes of around 35.0, 65.0 and 115.0 nm in gelatin scaffolds. The composite scaffolds were used for the localized PTT application of cancer cells. Gel/AuNP composite scaffolds supported cell adhesion and showed good biocompatibility. Temperature in the composite scaffolds increased quickly upon NIR laser irradiation. Photothermal efficiency and cancer cell killing efficiency were dependent on the shape, size and amount of AuNPs in the composite scaffolds. The composite scaffolds prepared with 65.0 nm Au nanorods showed the highest photothermal efficiency and cell killing efficiency. The results indicated the importance of the shape and size modulation of AuNPs for photothermal therapy applications.

Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize responsive exosome nano-bioconjugates for cancer therapy. Azide-modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne-modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH-sensitive linkers. After systemic administration, the nano-bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic-imine bonds of the nano-bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished "don't eat me" signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro-tumoral M2 to anti-tumoral M1. This work was supported by the National Natural Science Foundation of China (No.81571813 and No.21874011), National Science and Technology Major Project (No. 2018ZX 10301405-001).

Real-time imaging of kidney function is important to assess the nephrotoxicity of drugs and monitor the progression of renal diseases; however, it remains challenging because of the lack of optical agents with high renal clearance and high signal-tobackground ratio (SBR). Herein, a second near-infrared (NIR-II) fluorescent molecular semiconductor (CDIR2) is synthesized for realtime imaging of kidney dysfunction in living mice. CDIR2 not only has a high renal clearance efficiency (~90% injection dosage at 24 h postinjection), but also solely undergoes glomerular filtration into urine without being reabsorbed and secreted in renal tubules. Such a unidirectional renal clearance pathway of CDIR2 permits real-time monitoring of kidney dysfunction in living mice upon nephrotoxic exposure. Thus, this study not only introduces a molecular renal probe but also provides useful molecular guidelines to increase the renal clearance efficiency of NIR-II fluorescent agents. MOE (Min. of Education, S’pore) Accepted version

Real-time multiplex imaging is imperative to biology and diagnosis but remains challenging for optical modality. Herein, a unimolecular chemo-fluoro-luminescent reporter (CFR) is synthesized for duplex imaging of drug-induced hepatotoxicity (DIH), a long-term medical concern. CFR simultaneously detects superoxide anion (O2•-) and caspase-3 (casp3) through respective activation of its independent chemiluminescence and near-infrared fluorescence channels. Such a crosstalk-free duplex imaging capability of CFR enables longitudinal measurement of two correlated biomolecular events (oxidative stress and cellular apoptosis) during the progression of DIH, identifying O2•- as an earlier biomarker for detection of DIH both in vitro and in vivo. Moreover, CFR detects DIH 17.5 h earlier than histological changes. Thus, our study not only develops a sensitive optical reporter for early detection of DIH but also provides a general molecular design strategy for duplex imaging.

In this study, an organic semiconducting pro-nanostimulant (OSPS) with a near-infrared (NIR) photoactivatable immunotherapeutic action for synergetic cancer therapy is presented. OSPS comprises a semiconducting polymer nanoparticle (SPN) core and an immunostimulant conjugated through a singlet oxygen (1 O2 ) cleavable linkers. Upon NIR laser irradiation, OSPS generates both heat and 1 O2 to exert combinational phototherapy not only to ablate tumors but also to produce tumor-associated antigens. More importantly, NIR irradiation triggers the cleavage of 1 O2 -cleavable linkers, triggering the remote release of the immunostimulants from OSPS to modulate the immunosuppressive tumor microenvironment. Thus, the released tumor-associated antigens in conjunction with activated immunostimulants induce a synergistic antitumor immune response after OSPS-mediated phototherapy, resulting in the inhibited growth of both primary/distant tumors and lung metastasis in a mouse xenograft model, which is not observed for sole phototherapy.

Photoregulation, which utilizes light to remotely control biological events, provides a precise way to decipher biology and innovate in medicine; however, its potential is limited by the shallow tissue penetration and/or phototoxicity of ultraviolet (UV)/visible light that are required to match the optical responses of endogenous photosensitive substances. Thereby, biologically friendly near‐infrared (NIR) light with improved tissue penetration is desired for photoregulation. Since there are a few endogenous biomolecules absorbing or emitting light in the NIR region, the development of molecular transducers is essential to convert NIR light into the cues for regulation of biological events. In this regard, optical nanomaterials able to convert NIR light into UV/visible light, heat, or free radicals are suitable for this task. Here, the recent developments of optical nanotransducers for NIR‐light‐mediated photoregulation in medicine are summarized. The emerging applications, including photoregulation of neural activity, gene expression, and visual systems, as well as photochemical tissue bonding, are highlighted, along with the design principles of nanotransducers. Moreover, the current challenges and perspectives in this field are discussed. MOE (Min. of Education, S’pore) Accepted version

Therapeutic enzymes hold great promise for cancer therapy; however, in vivo remote control of enzymatic activity to improve their therapeutic specificity remains challenging. This study reports the development of an organic semiconducting pro-nanoenzyme (OSPE) with a photoactivatable feature for metastasis-inhibited cancer therapy. Upon near-infrared (NIR) light irradiation, this pro-nanoenzyme not only generates cytotoxic singlet oxygen (1O2) for photodynamic therapy (PDT), but also triggers a spontaneous cascade reaction to induce the degradation of ribonucleic acid (RNA) specifically in tumor microenvironment. More importantly, OSPE-mediated RNA degradation is found to downregulate the expression of metastasis-related proteins, contributing to the inhibition of metastasis after treatment. Such a photoactivated and cancer-specific synergistic therapeutic action of OSPE enables complete inhibition of tumor growth and lung metastasis in mouse xenograft model, which is not possible for the counterpart PDT nanoagent. Thus, our study proposes a phototherapeutic-proenzyme approach toward complete-remission cancer therapy. MOE (Min. of Education, S’pore) Accepted version