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Multi-functionalised nano-platforms based on persistent-luminescence nanoparticles (PLNPs) have attracted considerable attention for biomedical applications owing to their lack of background noise and suitability for in vivo imaging without the need for in situ excitation. However, nano-platforms based on PLNPs for continuous photodynamic therapy (PDT) are currently lacking. Herein, we report a nano-platform (LiGa 4.99 O 8 :Cr 0.01 /IrO 2 , LGO:Cr/IrO 2 ) prepared using PLNPs (LiGa 4.99 O 8 :Cr 0.01 , LGO:Cr) covalently bonded with iridium oxide nanoparticles (IrO 2 NPs), producing near-infrared (NIR) persistent luminescence, "afterglow" PDT and photo-thermal therapy (PTT) effects. The LGO:Cr/IrO 2 not only exhibits NIR-persistent luminescence at 719 nm and a PTT effect under 808 nm irradiation but also a continuous "afterglow" PDT effect without the need for in situ excitation owing to persistent energy transfer from LGO:Cr to the IrO 2 NPs, in turn generating reactive oxygen species (ROS). This multi-functional nano-platform is expected to further promote the application of PLNPs in tumour treatment.

Synergistic therapy is expected to be a promising strategy for highly effective cancer treatment. However, the rational design of a simple and multifunctional nanoplatform still remains a grand challenge. Considering the nature of weak acidic, hypoxic, and H 2 O 2 abundant tumor microenvironment, we constructed an indocyanine green (ICG) modified platinum nanoclusters (Pt NCs) decorated gold nanobipyramids (Au NBPs) to form the multifunctional nanocomposites (Au NBPs@Pt NCs-ICG) for multimodal imaging mediated phototherapy and chemodynamic cancer therapy. The photosensitizer ICG was covalently linked to Au NBPs@Pt NCs by bridging molecules of SH-PEG-NH 2 for both photodynamic therapy (PDT) and fluorescence imaging. Besides, Au NBPs@Pt NCs-ICG nanocomposites exhibited catalase- and peroxidase-like activities to generate O 2 and ·OH, which relieved the tumor hypoxia and upregulated antitumoral ROS level. Moreover, the combination of Au NBPs and ICG endowed the Au NBPs@Pt NCs-ICG with super photothermal conversion for effective photothermal imaging and therapy. In addition, the Au NBPs@Pt NCs-ICG nanoplatform displayed excellent X-ray computed tomography (CT) imaging ability due to the presence of high-Z elements (Au and Pt). Overall, our results demonstrated that Au NBPs@Pt NCs-ICG nanoplatform exhibited a multimodal imaging guided synergistic PTT/PDT/CDT therapeutic manners and held great potential as an efficient treatment for breast cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The development of a radioresponsive delivery platform has led to an innovative combination radioimmunotherapy strategy for treating tumors. However, controlling the release of immunomodulators by local radiotherapy in vivo remains a significant challenge in order to minimize off-target toxicity, reduce radiation-induced immunosuppression, and maximize synergistic radioimmunotherapy efficacy. In this study, we report the development of core-cross-linked diselenide nanoparticles (dSeNPs) as carriers for radioresponsive delivery of the toll-like receptors 7/8 agonist through systemic administration to achieve combined radioimmunotherapy of tumors. The dSeNPs were fabricated from a ring-opening reaction between 2,2'-diselenidebis(ethylamine) and the ethylene oxide group of an amphiphilic block copolymer. The diselenide bonds were naturally protected in the core of the self-assembled nanostructure, making the dSeNPs extremely stable in the physiological environment. However, they exhibited dose- and time-dependent radiosensitivity, meaning that X-ray irradiation could spatiotemporally control the release of R848 from the dSeNPs. In vivo results showed that local radioresponsive R848 release from dSeNPs greatly improved the synergistic efficacy of combined radioimmunotherapy via the programmed cooperative immune system activation process. This process included macrophage polarization, dendritic cell maturation, and cytotoxic T cell activation. Our findings suggest that core-cross-linked dSeNPs are a promising platform for combined radiotherapy due to their spatiotemporal controllability of radioresponsive drug release.

Chitosan (CS) based nanoparticles (NPs) were fabricated via an ionic gelation reaction modified by flaxseed gum (FG) or sodium tripolyphosphate (STPP). The average particle size, morphology, interfacial tension, and wettability of NPs were characterized. The particle size of CS-STPP-HA (hyaluronic acid)-FA (ferulic acid) NPs and CS-FG-HA-FA NPs was 400.8 nm and 262.4 nm, respectively under the optimized conditions of CS/STPP = 5:1 (w/w) or CS/FG = 1:1 (v/v) with HA concentration of 0.25 mg/mL and FA dosage of 25 μM. FG acted as a good alternative for STPP to form particles with CS in stabilizing Pickering emulsion with an internal diacylglycerol (DAG) phase of 50-80 % (v/v). The complex nanoparticles had high surface activity and contact angle close to 90 °C, being able to tightly packed at the droplet surface. The emulsions had high thermal, ionic and oxidative stability. With the aid of moisturizing polysaccharides and DAG oil, the emulsions had a good sustained-release ability for FA with deeper penetration and retention into the dermis of the skin. Thus, FG and HA-based NPs serve as green vehicles for the fabrication of novel Pickering emulsions and possess great potential to be applied as a delivery system for lipophilic active agents in functional food and cosmetic products., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2023. Published by Elsevier B.V.)

Secretory otitis media (SOM) is a clinical condition characterized by the accumulation of fluids and oxidative stress in the middle ear, leading to hearing impairment and infection complications. One potential solution for mitigating oxidative stress associated with SOM is the use of antioxidants such as astaxanthin. However, its effectiveness is limited due to its poor bioavailability and rapid oxidation. Herein, we developed a novel diselenium-crosslinked apotransferrin enriched with astaxanthin (AST@dSe-AFT) nanoparticles to augment the transport of astaxanthin across biological membranes, resulting in increased bioavailability and reduced oxidative stress in SOM. Our research demonstrated that AST@dSe-AFT efficiently accumulated in the middle ear, allowing for controlled delivery of astaxanthin in response to reactive oxygen species and reducing oxidative stress. Additionally, AST@dSe-AFT stimulated macrophages to polarize towards M2 phenotype and neutrophils to polarize towards N2 phenotype, thereby facilitating an anti-inflammatory response and tissue restoration. Importantly, AST@dSe-AFT exhibited no toxicity or adverse effects, suggesting its potential for safety and future clinical translation. Our findings suggested that AST@dSe-AFT represents a promising approach for the treatment of secretory otitis media and other oxidative stress-related disorders., Competing Interests: Declaration of Competing Interest The author has no other relevant affiliations or financial involvement with any organization or entity with financial interest in or financial conflict with the subject matter or materials discussed in the manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix flooded with immune suppressive cells, resulting in extremely poor clinical response to immunotherapy. It has been revealed that the activation of pancreatic stellate cells (PSCs) makes considerable contributions to the immunological "cold" tumor microenvironment (TME). Herein, we developed a polyamino acid-based nanodrug incorporating the PSC activation inhibitor calcipotriol and anti-CXCL12 siRNA. The nanodrug was easily prepared with a small particle size and is capable of penetrating pancreatic tumors to inactivate PSCs and downregulate CXCL12. The in vivo results of orthotopic pancreatic tumor treatment demonstrated that codelivery of calcipotriol and anti-CXCL12 siRNA remodeled the PDAC TME with reduced extracellular matrix and decreased immunosuppressive T cells. Eventually, the infiltration of cytotoxic T cells was increased, thereby acting with immune checkpoint blockade (ICB) therapy for immunologically "cold" pancreatic tumors. In the present study, we propose a promising paradigm to improve the immunotherapy outcome of PDAC using nanodrugs that synchronously inhibit PSC activation and regulatory T-cell infiltration. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes the tumor infiltration of therapeutic agents and cytotoxic T lymphocytes, resulting in a poor clinical response to immunotherapy. In the present study, we proposed a promising approach for enhanced immunotherapy of pancreatic cancer. Specifically, a nanodrug incorporating calcipotriol and anti-CXCL12 siRNA was synthesized to synchronously inactivate matrix-producing pancreatic stellate cells and suppress the infiltration of regulatory T cells. The reduced ECM removed the pathological barrier, preventing nanodrug penetration and effector T-cell infiltration, leading to a conversion of the immunosuppressive "cold" microenvironment to a "hot" microenvironment, which eventually boosted the immunotherapy of anti-PD-1 antibodies in pancreatic cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Low infiltration of cytotoxic T lymphocytes and their exhaustion manifest the two concurrent main hurdles for achieving effective tumor immunotherapy of triple-negative breast cancer. It is found that Galectin-9 blockage can revise the exhaustion of effector T cells, meanwhile the repolarization of protumoral M2 tumor-associated macrophages (TAMs) into tumoricidal M1-like ones can recruit effector T cells infiltrating into tumor to boost immune responses. Herein, a sheddable PEG-decorated and M2-TAMs targeted nanodrug incorporating Signal Transducer and Activator of Transcription 6 inhibitor (AS) and anti-Galectin-9 antibody (aG-9) is prepared. The nanodrug responds to acidic tumor microenvironment (TME) with the shedding of PEG corona and the release of aG-9, exerting local blockade of PD-1/Galectin-9/TIM-3 interaction to augment effector T cells via exhaustion reversing. Synchronously, targeted repolarization of M2-TAMs into M1 phenotype by AS-loaded nanodrug is achieved, which promotes tumor infiltration of effector T cells and thus synergizes with aG-9 blockade to boost the therapeutic efficacy. Besides, the PEG-sheddable approach endows nanodrug with stealth ability to reduce immune-related adverse effects caused by AS and aG-9. This PEG sheddable nanodrug holds the potential to reverse the immunosuppressive TME and increase effector T cell infiltration, which dramatically enhances immunotherapy in highly malignant breast cancer., (© 2023 Wiley-VCH GmbH.)

The hollow MCM-48 polyethyleneimine carboxyphenylboronic acid molecularly imprinted polymers (H-MPC@MIPs) were synthesized to efficiently and selectively separate and enrich the ovalbumin (OVA) in egg white samples. Polyethyleneimine contained enough active amino groups to increase the amount of boric acid molecules modified to silica nanoparticles. Meanwhile, the materials were etched to enhance the adsorption effect. The H-MPC@MIPs exhibited a rapid adsorption equilibrium rate (within 30 min) and outstanding adsorption capacity for OVA (1334.1 mg g -1 ). It possessed a good reusability after 5 cycles. In addition, both the high density and the imprinting action of boric acid were essential for enhancing the identification and binding of OVA. The OVA in egg white samples was successfully selectively enriched using this method., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cell encapsulation has been studied for various applications ranging from cell transplantation to biological production. However, current encapsulation technologies focus on cell protection rather than cell regulation that is essential to most if not all cell-based applications. Here we report a method for cell nanoencapsulation and regulation using an ultrathin biomimetic extracellular matrix as a cell nanocapsule to carry nanoparticles (CN 2 ). This method allows high-capacity nanoparticle retention at the vicinity of cell surfaces. The encapsulated cells maintain high viability and normal metabolism. When gold nanoparticles (AuNPs) are used as a model to decorate the nanocapsule, light irradiation transiently increases the temperature, leading to the activation of the heat shock protein 70 (HSP70) promoter and the regulation of reporter gene expression. As the biomimetic nanocapsule can be decorated with any or multiple NPs, CN 2 is a promising platform for advancing cell-based applications., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Tethering nanoparticles (NPs) onto the cell surface is critical to cellular hitchhiking applications, such as targeted NP delivery and enhanced cell therapy. While numerous methods have been developed to achieve NP attachment onto the cell membrane, they often face limitations such as the use of complicated cell surface modifications or low-efficiency NP attachment. The purpose of this work was to explore a DNA-based synthetic ligand-receptor pair for NP attachment to the surface of live cells. Polyvalent ligand mimics were used to functionalize NPs, while the cell membrane was functionalized with DNA-based cell receptor mimics. Base pair-directed polyvalent hybridization allowed the NPs to bind to the cells quickly and efficiently. Notably, the process of attaching NPs to cells did not require sophisticated chemical conjugation on the cell membrane or involve any cytotoxic cationic polymers. Therefore, DNA-based polyvalent ligand-receptor binding is promising to various applications ranging from cell surface engineering to NP delivery.

Bacterial prostatitis is a bacterial infection of the prostate gland presenting with lower quadrant abdominal pain, urination disorders and poor fertility. In recent years, reports have emerged on the significantly reduced efficacy of fluoroquinolone drugs attributed to multiple drug-resistant bacteria, emphasizing the need for new drugs. In this study, we designed a targeting drug delivery system via curcumin copper complex grafted with hyaluronic acid. Subsequently, the prepared system was characterized using FT-IR, XRD, SEM, XPS and 1 H NMR methods. In addition to the substantial improvement in the solubility of the carrier, its antibacterial performance and targeting ability were improved. Interestingly, the grafting of hyaluronic acid endowed the carrier with excellent CD44 receptor targeting function and good water solubility, and the complexation of copper ions greatly enhanced its antibacterial capability, especially the inhibitory effect on E. coli. The anti-prostatitis effect of the drug was evaluated comprehensively by establishing a bacterial prostatitis model infected by E. coli. Assessment of the anti-prostatitis effects in vivo indicated that the Cur-Cu@HA delivery system could effectively promote recovery from bacterial prostatitis by downregulating inflammation. In conclusion, our Cur-Cu@HA delivery system has great potential for treating bacterial prostatitis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Hepatocellular cancer stem cells (CSCs) play crucial roles in hepatocellular cancer initiation, development, relapse, and metastasis. Therefore, eradication of this cell population is a primary objective in hepatocellular cancer therapy. We prepared a nanodrug delivery system with activated carbon nanoparticles (ACNP) as carriers and metformin (MET) as drug (ACNP-MET), which was able to selectively eliminate hepatocellular CSCs and thereby increase the effects of MET on hepatocellular cancers., Methods: ACNP were prepared by ball milling and deposition in distilled water. Suspension of ACNP and MET was mixed and the best ratio of ACNP and MET was determined based on the isothermal adsorption formula. Hepatocellular CSCs were identified as CD133 + cells and cultured in serum-free medium. We investigated the effects of ACNP-MET on hepatocellular CSCs, including the inhibitory effects, the targeting efficiency, self-renewal capacity, and the sphere-forming capacity of hepatocellular CSCs. Next, we evaluated the therapeutic efficacy of ACNP-MET by using in vivo relapsed tumor models of hepatocellular CSCs., Results: The ACNP have a similar size, a regular spherical shape and a smooth surface. The optimal ratio for adsorption was MET: ACNP=1:4. ACNP-MET could target and inhibit the proliferation of CD133 + population and decrease mammosphere formation and renewal of CD133 + population in vitro and in vivo., Conclusion: These results not only suggest that nanodrug delivery system increased the effects of MET, but also shed light on the mechanisms of the therapeutic effects of MET and ACNP-MET on hepatocellular cancers. ACNP, as a good nano-carrier, could strengthen the effect of MET by carrying drugs to the micro-environment of hepatocellular CSCs., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Sun et al.)

Nanoparticles (NPs) derived from RNA interference (RNAi) are considered a potentially revolutionary technique in the field of plant protection in the future. However, the application of NPs in RNAi is hindered by the conflict between the high cost of RNA production and the large quantity of materials required for field application. This study aimed to evaluate the antiviral efficacy of commercially available nanomaterials, such as chitosan quaternary ammonium salt (CQAS), amine functionalized silica nano powder (ASNP), and carbon quantum dots (CQD), that carried double-stranded RNA (dsRNA) via various delivery methods, including infiltration, spraying, and root soaking. ASNP-dsRNA NPs are recommended for root soaking, which is considered the most effective method of antiviral compound application. The most effective antiviral compound tested was CQAS-dsRNA NPs delivered by root soaking. Using fluorescence, FITC-CQAS-dsCP-Cy3, and CQD-dsCP-Cy3 NPs demonstrated the uptake and transport pathways of dsRNA NPs in plants when applied to plants in different modes. The duration of protection with NPs applied in various modes was then compared, providing references for evaluating the retention period of various types of NPs. All three types of NPs effectively silenced genes in plants and afforded at least 14 days of protection against viral infection. Particularly, CQD-dsRNA NPs could protect systemic leaves for 21 days following spraying., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The dense extracellular matrix (ECM) is a key barrier to tumor infiltration of cytotoxic T lymphocytes (CTLs), which greatly compromises T cell-dependent immunotherapy of hepatocellular carcinoma (HCC). Herein, hyaluronidase (HAase), IL-12, and anti-PD-L1 antibody (αPD-L1) were co-delivered using a pH and MMP-2 dual-sensitive polymer/calcium phosphate (CaP) hybrid nanocarrier. The dissolution of CaP triggered by tumor acidity facilitated the release of IL-12 and HAase responsible for ECM digestion, enhancing the tumor infiltration and proliferation of CTLs. Furthermore, the in situ-released αPD-L1 inside tumor, as triggered by an overexpressed MMP-2, prevented the tumor cell from escaping the killing effects of CTLs. Such combination strategy induced a robust antitumor immunity for efficiently suppressing HCC growth in mice. Additionally, tumor acidity-sheddable polyethylene glycol (PEG) coating enhanced the tumor accumulation of nanocarrier and reduced the immune-related adverse events (irAEs) induced by on-target off-tumor αPD-L1. This dual-sensitive nanodrug demonstrates an effective immunotherapy paradigm for other dense ECM-characterized solid tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Introduction: Hydrogels offer a wide range of applications in the antithrombotic modification of biomedical devices. The functionalization of these hydrogels with potentially drug-laden nanoparticles in the context of deviceassociated turbulence is critically under-studied. Thus, the purpose of this study was to use a hydrogel-coating nitinol surface as a model to understand the functions of hydrogels and the capture of nanoparticles under clinically relevant flow conditions., Methods: Nitinol was coated by an oligonucleotide (ON) functionalized hydrogel. Nanoparticles were functionalized with complementary oligonucleotides (CONs). The capture of CONfunctionalized nanoparticles by the ON-functionalized hydrogel surfaces was studied under both static and dynamic attachment conditions. Fluorescent-labelling of nanoparticles was utilized to assess capture efficacy and resistance to removal by device-relevant flow conditions., Results: The specificity of the ON-CON bond was verified, exhibiting a dose-dependent attachment response. The hydrogel coating was resistant to stripping by flow, retaining >95% after exposure to one hour of turbulent flow. Attachment of nanoparticles to the hydrogel was higher in the static condition than under laminar flow (p < 0.01), but comparable to that of attachment under turbulent flow. Modified nitinol samples underwent one hour of flow treatment under both laminar and turbulent regimes and demonstrated decreased nanoparticle loss following static conjugation rather than turbulent conjugation (36.1% vs 53.8%, p < 0.05). There was no significant difference in nanoparticle functionalization by upstream injection between laminar and turbulent flow., Conclusion: The results demonstrate promising potential of hydrogelfunctionalized nitinol for capturing nanoparticles using nucleic acid hybridization. The hydrogel structure and ONCON bond integrity both demonstrated a resistance to mechanical damage and loss of biomolecular functionalization by exposure to turbulence. Further investigation is warranted to highlight drug delivery and antithrombogenic modification applications of nanoparticle-functionalized hydrogels., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.

Contrast agents for radiography and computed tomography (CT) scans are substances that can enhance the contrast of blood vessels and soft tissue with detailed imaging information of the diseased sites. However, the large doses, short circulation time and adverse effects are the intrinsic limitations of CT contrast agents, preventing their extended and safe use in the clinical setting. Bismuth nanoparticles (NPs) have gained attention for the high X-ray absorption of bismuth elements with acceptable biocompatibility, showing their potential to be translated into commercialized CT contrast agents. Compared with traditional iodine contrast agents, bismuth NPs are characterized by prolonged circulation time and enhanced contrast, largely due to the surface modification and enhanced permeability and retention effect of NPs. Bismuth NPs can also be flexibly upgraded into sophisticated nanoagents for multimodal imaging and therapeutic purposes by complexation with supporting chemicals, small molecule drugs, fluorescence labels, and other functional agents. Additionally, the affinity and retention of the bismuth NPs in the diseased sites can be further improved by modification of the targeting moiety on the NPs surface. However, a simple synthetic process and low complexity of bismuth NPs are highly recommended for scaling out and quality control of nanoagents with commercialization potential. Since product safety is a prerequisite for the translation of bismuth NPs from bench to the clinic, we focus on recent advances in the distribution, elimination, and toxicity of bismuth NPs previously reported. Finally, we delineate the associated mechanisms for nephrotoxicity and the strategy to reduce the toxicity of bismuth NPs. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials., (© 2022 Wiley Periodicals LLC.)

Chitosan (CS) based nanoparticles simultaneously loaded with (-)-epigallocatechin gallate (EGCG) and ferulic acid (FA) were fabricated via ionic gelation method modified by sodium tripolyphosphate and genipin (G-CS-EGCG-FA NPs). The particle size, morphology, entrapment efficiency, rheological properties, antioxidant and tyrosinase inhibitory activity of NPs were investigated. The G-CS-EGCG-FA NPs exhibited irregular ellipsoidal shape with average diameter of 412.3 nm and high DPPH and ABTS· + scavenging ability. The entrapment efficiency of EGCG and FA in NPs was 46.0 ± 1.3 % and 46.8 ± 1.6 %, respectively. CS-based NPs show no toxic effects on NIH 3 T3 cells and B16-F10 melanoma cells with concentration <200 μg/mL and 25 μg/mL, respectively and the cell viability ranged from 100 % to 118 %. Meanwhile, the oxidative repaired capacity of G-CS-EGCG-FA NPs (200 μg/mL) in H 2 O 2 -induced cells was over 100 %, higher than that of the same dose of free EGCG or FA. Moreover, the tyrosinase inhibition activity of G-CS-EGCG-FA NPs (25 μg/mL) (84.6 %) was more potent than that of free EGCG (55.3 %), free FA (47.1 %) and kojic acid, indicating the good skin repairing and whitening ability of G-CS-EGCG-FA NPs. Given these results, this research provides new insights for designing novel particles loaded with dual bioactive agents that possess synergistic benefits., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Achieving molecular sample capture at micro/nanoscales while integrating functions of controllable loading and real-time monitoring of cargo molecules is of great significance in the development of intelligent micro/nanorobots. Herein, we prepare a temperature-responsive microsampling nanorobot by encapsulating metal (Au) nanodots inside hollow mesoporous silica nanoparticles and grafting a temperature-responsive polymer, poly( N -isopropylacrylamide), on their external surface. The molecular gate of nanochannels accessing the internal hollow reservoir can be switched between "open" and "closed" states by regulating the temperature, allowing on-demand loading and releasing of small molecules. The internally embedded surface-enhanced Raman scattering hotspots of gold nanodots can serve as sensing probes for real-time detection of the molecular cargo load inside the hollow nanorobots. Furthermore, we demonstrate temperature-dependent self-propulsion behavior of the nanorobots driven by enzymatic reactions. The active motion behavior can favorably regulate the loading efficiency of molecular cargos. In addition, by further introducing the magnetic component Ni, the nanorobots can accomplish effective transportation of cargo molecules by magnetic guidance under real-time Raman monitoring. The current strategy is expected to provide a manipulable nanorobot platform for precise biomedical sampling, which holds promising potential for disease diagnosis or controlled drug delivery in precision medicine.

Type I photodynamic therapy (PDT) with less oxygen consumption shows great potential to overcome the malignant hypoxia in solid tumors. Herein, a novel meso phosphate-substituted pyronin PY-P and its nanoparticles (PY-P NPs) were prepared as an efficient type I organic photosensitizer. The in vivo data prove that PY-P NPs have outstanding low dark toxicity but high photocytotoxicity under hypoxia (<1% O 2 ).

Anthocyanins (ACNs) have attracted considerable research attention because of their excellent health benefits, but their low stability and bioavailability limit their applications. In this study, sinapic acid-grafted-chitosan (SA-g-CS) conjugate was synthesized by grafting SA onto CS via a free radical mediated method. Nanoparticles were prepared using casein (CA) together with SA-g-CS to improve the performance and sustained release of black rice anthocyanins (BRA). The results of UV-Vis, FTIR and 1 H NMR spectra for SA-g-CS conjugates demonstrated the successful grafting of SA onto CS. The results of DPPH, ABTS and ferric ion reducing antioxidant power assays showed that the SA-g-CS conjugates had strong antioxidant capacities, and the higher the pH of the grafting reaction system, the stronger the antioxidant capacity of the conjugates. X-ray diffraction and scanning electron microscopy analyses showed that the crystallographic property and microstructure of CS were improved by the grafting of SA. Compared with BRA loaded nanoparticles prepared with CA alone or the combination of CS and CA, the BRA loaded nanoparticles constructed by SA-g-CS and CA have smaller particle size, better dispersion, encapsulation efficiency and sustained-release property. These results provided great potential for the application of phenolic acid grafted CS in stabilizing ACNs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Self-assembly processes, while promising for enabling the fabrication of complexly organized nanomaterials from nanoparticles, are often limited in creating structures with multiscale order. These limitations are due to difficulties in practically realizing the assembly processes required to achieve such complex organizations. For a long time, a hierarchical assembly attracted interest as a potentially powerful approach. However, due to the experimental limitations, intermediate-level structures are often heterogeneous in composition and structure, which significantly impacts the formation of large-scale organizations. Here, we introduce a two-stage assembly strategy: DNA origami frames scaffold a coordination of nanoparticles into designed 3D nanoclusters, and then these clusters are assembled into ordered lattices whose types are determined by the clusters' valence. Through modulating the nanocluster architectures and intercluster bindings, we demonstrate the successful formation of complexly organized nanoparticle crystals. The presented two-stage assembly method provides a powerful fabrication strategy for creating nanoparticle superlattices with prescribed unit cells.

Nanovaccines have emerged as promising alternatives or complements to conventional cancer treatments. Despite the progresses, specific co-delivery of antigen and adjuvant to their corresponding intracellular destinations for maximizing the activation of antitumor immune responses remains a challenge. Herein, a lipid-coated iron oxide nanoparticle is delivered as nanovaccine (IONP-C/O@LP) that can co-deliver peptide antigen and adjuvant (CpG DNA) into cytosol and lysosomes of dendritic cells (DCs) through both membrane fusion and endosome-mediated endocytosis. Such two-pronged cellular uptake pattern enables IONP-C/O@LP to synergistically activate immature DCs. Iron oxide nanoparticle also exhibits adjuvant effects by generating intracellular reactive oxygen species, which further promotes DC maturation. IONP-C/O@LP accumulated in the DCs of draining lymph nodes effectively increases the antigen-specific T cells in both tumor and spleen, inhibits tumor growth, and improves animal survival. Moreover, it is demonstrated that this nanovaccine is a general platform of delivering clinically relevant peptide antigens derived from human papilloma virus 16 to trigger antigen-specific immune responses in vivo., (© 2022 Wiley-VCH GmbH.)

Detection of small biomolecules is critical for understanding molecular mechanisms in biological systems and performing in vitro diagnosis in clinics. Current antibody based detection methods face large challenges in detecting small biomolecules at low concentrations. We report a new method for detecting small biomolecules based on molecular recognition and nanoparticle (NP) counting. Aptamer-functionalized NPs are attached to complementary sequence (CS)-conjugated microparticle (MP) carriers. In the presence of target small biomolecules at ultra low concentrations, NPs would be released from the MP carriers. Coupled with a resistive pulse sensor (RPS) using a micropore that counts the released NPs, this method can measure the concentrations of target biomolecules at low concentrations with high sensitivity and high throughput. Adenosine was used as a model to demonstrate the feasibility of this method. It is demonstrated that this method can detect a wide range of adenosine concentrations with a low detection limit of 0.168 nM, which is 10 times lower than that of the ELISA kit. With its simple structure, high sensitivity, and high reproducibility, this detection method holds great potential for the ultrasensitive detection of low abundance small biomolecules., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Albumin-biomineralized copper sulfide nanoparticles (Cu 2-x S NPs) have attracted much attention as an emerging phototheranostic agent due to their advantages of facile preparation method and high biocompatibility. However, comprehensive preclinical safety evaluation is the only way to meet its further clinical translation. We herein evaluate detailedly the safety and hepatotoxicity of bovine serum albumin-biomineralized Cu 2-x S (BSA@Cu 2-x S) NPs with two different sizes in rats. Large-sized (LNPs, 17.8 nm) and small-sized (SNPs, 2.8 nm) BSA@Cu 2-x S NPs with great near-infrared absorption and photothermal conversion efficiency are firstly obtained. Seven days after a single-dose intravenous administration, SNPs distributed throughout the body are cleared primarily through the feces, while a large amount of LNPs remained in the liver. A 14-day subacute toxicity study with a 28-day recovery period are conducted, showing long-term hepatotoxicity without recovery for LNPs but reversible toxicity for SNPs. Cellular uptake studies indicate that LNPs prefer to reside in Kupffer cells, leading to prolonged and delayed hepatotoxicity even after the cessation of NPs administration, while SNPs have much less Kupffer cell uptake. RNA-sequencing analysis for gene expression indicates that the inflammatory pathway, lipid metabolism pathway, drug metabolism-cytochrome P450 pathway, cholesterol/bile acid metabolism pathway, and copper ion transport/metabolism pathway are compromised in the liver by two sizes of BSA@Cu 2-x S NPs, while only SNPs show a complete recovery of altered gene expression after NPs discontinuation. This study demonstrates that the translational feasibility of small-sized BSA@Cu 2-x S NPs as excellent nanoagents with manageable hepatotoxicity., (© 2022. The Author(s).)

Background: Radioresistance inducing by hypoxic microenvironment of hepatocellular carcinoma is a major obstacle to clinical radiotherapy. Advanced nanomedicine provides an alternative to alleviate the hypoxia extent of solid tumor, even to achieve effective synergistic treatment when combined with chemotherapy or radiotherapy., Results: Herein, we developed a self-assembled nanoparticle based on hemoglobin and curcumin for photoacoustic imaging and radiotherapy of hypoxic hepatocellular carcinoma. The fabricated nanoparticles inhibited hepatoma migration and vascular mimics, and enhanced the radiosensitivity of hypoxic hepatoma cells in vitro via repressing cell proliferation and DNA damage repair, as well as inducing apoptosis. Benefit from oxygen-carrying hemoglobin combined with polyphenolic curcumin, the nanoparticles also effectively enhanced the photoacoustic contrast and the efficacy of radiotherapy for hepatocellular carcinoma in vivo., Conclusions: Together, the current study offered a radiosensitization platform for optimizing the efficacy of nanomedicines on hypoxic radioresistant tumor., (© 2022. The Author(s).)

Targeted cancer therapy has become one of the most important medical methods because of the spreading and metastatic nature of cancer. Based on the introduction of AS1411 and its four-chain structure, this paper reviews the research progress in cancer detection and drug delivery systems by modifying AS1411 aptamers based on graphene, mesoporous silica, silver and gold. The application of AS1411 in cancer treatment and drug delivery and the use of AS1411 as a targeting agent for the detection of cancer markers such as nucleoli were summarized from three aspects of active targeting, passive targeting and targeted nucleic acid apharmers. Although AS1411 has been withdrawn from clinical trials, the research surrounding its structural optimization is still very popular. Further progress has been made in the modification of nanoparticles loaded with TCM extracts by AS1411., (© 2022. The Author(s).)

Ovalbumin (OVA) is a model antigen commonly incorporated in smartly designed nanoparticles for delivery into antigen-presenting cells (APC), aiming to investigate the immune activity and therapeutic efficacy of nanoparticles that contain immunoregulatory compounds. However, the immunoresponse observed in nano-immunotherapy may unexpectedly arise from endotoxin impurity of OVA in the nanoparticles. Literature review shows that most researchers did not notice the importance of endotoxin-free OVA when used in nano-immunotherapy studies. Concentration at as low as 5 μg/ml OVA from Sigma-Aldrich (contains 0.625 ng/ml endotoxin) was able to activate APC such as dendritic cells and macrophages. Here, we proposed that the endotoxin impurity in OVA or the finished nanoproducts should be determined by both Limulus Amebocyte Lysate (LAL) and cell-based assay, to ensure the endotoxin-free quality of the nanoparticles. The endotoxin in OVA can be removed by endotoxin removal column and phase separation methods and endotoxin-free OVA can be purchased. This perspective alerts the researchers of endotoxin impurity of OVA that may transfer into the finished nanoparticles and introduce an unfavorable immunoregulatory function with false-positive results. OVA with minimal endotoxin level should be used in nano-immunotherapy studies to accurately reflect the true effects of nanoparticles on the immune system. This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials Nanotechnology Approaches to Biology > Nanoscale Systems in Biology., (© 2021 Wiley Periodicals LLC.)

As most of intracellular reactive oxygen species (ROS) is produced in the mitochondria, mitochondrial modulation of cancer cell is a promising strategy for maximizing the in situ-activable combination therapy of oxidative catastrophe and cascaded chemotherapy. Herein, a serum-stable polymer‑calcium phosphate (CaP) hybrid nanocapsule carrying siRNA against ADP-ribosylation factor 6 (Arf6) overexpressed in cancer cells and parent drug camptothecin (CPT), designated as PTkCPT/siRNA, was developed for the RNAi-induced oxidative catastrophe and cascaded chemotherapy. A copolymer of mPEG-P(Asp-co-TkCPT), covalently tethered with chemotherapeutic CPT via a ROS-labile dithioketal (Tk) linker, was synthesized and self-assembled into a PTkCPT micelle as a nanotemplate for the CaP mineralization. The as-prepared PTkCPT/siRNA nanoparticle showed a core-shell-distinct nanocapsule which was consisted of a spherical polymeric core enclosed within a CaP shell capable of releasing siRNA in response to lysosomal acidity. Blocking Arf6 signal pathway of cancer cells led to their mitochondrial aggregation and subsequently induced a burst of ROS for oxidative catastrophe, which further triggered the cascaded CPT chemotherapy via the breakage of ROS-labile dithioketal linker. This strategy of RNAi-induced oxidative catastrophe and cascaded chemotherapy resulted in a significant combination effect on cancer cell killing and tumor growth inhibition in mice with low side effects, and provided a promising paradigm for precise cancer therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A rapid and accurate diagnosis of mixed viral infections is important for providing timely therapeutic interventions. The aim of this study was to develop a highly sensitive and specific method for the simultaneous detection of canine distemper virus (CDV), canine parvovirus (CPV) and canine coronavirus (CCV) in mixed infections by combining the high specificity of a dual priming oligonucleotide (DPO) primer system with the high sensitivity of a nanoparticle-assisted PCR (nanoPCR) assay. Under the optimised assay conditions, the multiplex DPO-nanoPCR assay developed using DPO primers was 100-fold more sensitive than the multiplex PCR assay using conventional primers. The detection limits of the multiplex DPO-nanoPCR assay for the recombinant plasmids containing the cloned CDV, CPV and CCV target sequences were 5.4 × 10 2 , 6.5 × 10 2 and 1.6 × 10 2 copies in a 25 μL assay, respectively. No cross-reaction with other canine viruses was observed. This is the first reported use of a multiplex nanoPCR assay with the DPO primer system for the simultaneous detection of CDV, CPV and CCV in mixed infections. The high sensitivity and specificity of the assay indicated its potential for use in clinical diagnosis and field surveillance of animal epidemics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pickering water-in-oil (W/O) emulsions were fabricated by using medium-long chain diacylglycerol (MLCD)-based solid lipid nanoparticles (SLNs) and the connection between the characteristics of the SLNs and the colloidal stability of the emulsions was established. Via melt-emulsification and ultrasonication, MLCD-based SLNs with particle sizes of 120-300 nm were obtained with or without other surfactants. The particle size of the SLNs was influenced by the chemical properties of the surfactants, and surfactants decreased the contact angle of SLNs at the oil-water interface. Gelation was observed in SLNs modified by sodium stearoyl lactylate and lecithin, whereas the addition of Tween 20 resulted in a homogeneous SLN solution. The adsorption of surfactants onto SLN surfaces caused the production of higher amounts of α crystals accompanied by delayed crystallization onset which contributed to the reduction of particle size, interfacial tension and oil wetting ability. The W/O emulsions with higher rigidity and physical stability can be obtained by varying surfactant types and by increasing SLN mass ratios to 60%, whereby more SLNs are adsorbed at the droplet surface as a Pickering stabilizer. This study provides useful insights for the development of diacylglycerol-based SLNs and Pickering W/O emulsions which have great potential for food, cosmetic and pharmaceutical applications.

Multifunctional nanodrugs have emerged as an effective platform to integrate multiple imaging and therapeutic functions for tremendous biomedical applications. However, the development of a simple potent theranostic nanoplatform is still an intractable challenge. Herein, a novel theranostic nanoplatform was developed by coupling prepared Au nanobipyramids with Gd 2 O 3 , Au nanoclusters and denatured bovine serum albumin (AuNBP-Gd 2 O 3 /Au-dBSA) for FL/MR dual-modal imaging guided photothermal therapy. AS1411 aptamers were conjugated to enhance its targetability towards breast cancer. The AS1411-AuNBP-Gd 2 O 3 /Au-dBSA suspension could be readily heated above 40 °C at a low concentration (2 mg/L) and NIR density (1 W/cm 2 ). The AS1411-AuNBP-Gd 2 O 3 /Au-dBSA revealed a fluorescence quantum yield of 4.2% and higher longitudinal relaxivity rate of 6.75 mM -1  s -1 compared to Gd-DTPA of 4.45 mM -1  s -1 . As a result, the AS1411-AuNBP-Gd 2 O 3 /Au-dBSA functions as a multimodal nanoprobe of photothermal, fluorescence and MR imaging for specific tumor diagnosis and guidance of therapy, which was validated via in vitro and in vivo tests. Moreover, AS1411-AuNBP-Gd 2 O 3 /Au-dBSA nanoparticles indicated excellent photothermal anticancer effect more than 95% in both in vitro and in vivo tests. Besides, the low toxicity of AS1411-AuNBP-Gd 2 O 3 /Au-dBSA nanocomposites was further confirmed in vitro and in vivo. Thus, these results demonstrated the AS1411-AuNBP-Gd 2 O 3 /Au-dBSA nanocomposites as a rational design of multifunctional nanoplatform to enable multimodal imaging guided photothermal therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

2D MXene, Ti 3 C 2 (TC), has displayed enormous potential in applications in photothermal therapy (PTT), attributing to its biocompatibility and outstanding photothermal conversion capability. However, some tumor ablations are difficult to be realized completely by monotherapy due to the essential defects of monotherapy and intricate tumor microenvironment (TME). In this work, the appropriate doped Fe 2+ ions are anchored into the layers of 2D ultrathin TC nanosheets (TC NSs) to synthesize a novel multifunctional nanoshell of Fe(II)-Ti 3 C 2 (FTC) through interlayer electrostatic adsorption. FTC possesses superior photothermal conversion efficiency (PTCE) than TC NSs, attributing to the enhanced conductivity promoted by interlaminar ferrous ion-channels. Moreover, Fenton reaction based on ferrous ions endows FTC the abilities of reactive oxide species (ROS) releasing and glutathione (GSH) suppression triggered by near-infrared (NIR) laser, featuring splendid biocompatibility and curative effect in hypoxic TME. Meanwhile, magnetic resonance imaging (MRI) responding in FTC reveals the potential as an integrated diagnosis and treatment nanoplatform. FTC could provide new insights into the development of multimoded synergistic nanoplatform for biological applications, especially breaking the shackles of MXenes merely used as a photo-thermal agent (PTA), adopting it to bioimaging sensor and drug loading., (© 2021 Wiley-VCH GmbH.)

Combination therapy provides significantly better outcomes than a single drug treatment and becomes an efficient strategy for cancer therapy at present. Owing to the advantages of improved drug bioavailability, decreased side effects, and drug codelivery properties, polymeric carrier-based nanodrugs show great application potential in combination therapy. In this study, a pH-responsive block polymer consisting of polyethylene glycol (mPEG) and poly(asparagyl diisopropylethylenediamine-co-phenylalanine) (P(Asp(DIP)-co-Phe)) is synthesized for drug delivery. The polymer self-assembles into nanovesicles and simultaneously encapsulates the hydrophilic hypoxia-activated prodrug tirapazamine (TPZ) and the hydrophobic photosensitizer dihydrogen porphin (chlorin e6, Ce6). The formed nanodrug can be triggered by near infrared irradiation to induce photodynamic therapy (PDT), resulting in a hypoxic tumor environment to activate the prodrug TPZ to achieve efficient chemotherapy. The cascade synergistic therapeutic effect is evaluated both in vitro and in vivo in a breast cancer mice model. This study reveals a potential strategy for efficient cancer therapy by using Ce6 and TPZ co-encapsulated nanovesicles.

Aim: To explore the hepatotoxicity of copper sulfide nanoparticles (CuSNPs) toward hepatocyte spheroids. Materials & methods: Other than the traditional agarose method to generate hepatocyte spheroids, we developed a multi-concave agarose chip (MCAC) method to investigate changes in hepatocyte viability, morphology, mitochondrial membrane potential, reactive oxygen species and hepatobiliary transporter by CuSNPs. Results: The MCAC method allowed a large number of spheroids to be obtained per sample. CuSNPs showed hepatotoxicity in vitro through a decrease in spheroid viability, albumin/urea production and glycogen deposition. CuSNPs also introduced hepatocyte spheroid injury through alteration of mitochondrial membrane potential and reactive oxygen species, that could be reversed by N-acetyl-l-cysteine. CuSNPs significantly decreased the activity of BSEP transporter by downregulating its mRNA and protein levels. Activity of the MRP2 transporter remained unchanged. Conclusion: We observed the hepatotoxicity of CuSNPs in vitro with associated mechanisms in an advanced 3D culture system.

Considering that pathological hallmarks are directly related to structural and chemical information of tumor, noninvasive, real-time, spatially resolved quantitative chemical imaging is significant for treatment decisions. The discovery of the transparency window of biological tissues and the advancement of near-infrared technology provide exciting prospects for in vivo imaging. Herein, an engineering apoferritin-conjugated cypate nanoprobe is fabricated for near-infrared photoacoustic imaging and fluorescence imaging in the first and second window. As the analogue of indocyanine green, dicarboxylic cypate is directly conjugated with the apoferritin molecules for forming assembly nanoprobes. Resulting from the intrinsic targeting and optical capacity of the nanoprobes, the triple near-infrared imaging can perform multimeasurements of the target analyte in real-time. This imaging methodology not only provides the structural background information of the tumor, each pixel also contains quantitative in situ information of the tumor. In particular, part of the absorbed light energy is released as heat energy in the near-infrared photoacoustic imaging process. The constructed triple near-infrared nanoprobes therefore naturally navigate the photothermal treatment plan of tumor and finally realize the efficient assistance of tumor photothermal ablation. The tumor metabolomics reveal that the nanoprobe-assisted tumor ablation has a potential mechanism toward glutamine- and phenylalanine-related metabolism perturbation and the disordered oxidative stress state. The tumor-specific bioconjugate nanoprobes hold great potential as a versatile theranostic platform for tumor imaging and therapy.

The development of a specific and noninvasive technology for understanding gastritic response together with efficient therapy is an urgent clinical issue. Herein, we fabricated a novel iodinated bovine serum albumin (BSA) nanoparticle based on gastritic microenvironment for computed tomography (CT) imaging and repair of acute gastritis. Derived from the characteristic mucosa defect and inflammatory cell (e.g., macrophage and neutrophil) infiltration in acute gastritis, the pH-sensitive nanoparticles can sedimentate under acidic conditions and be uniformly distributed in the defected mucosal via the phagocytosis of inflammatory cells. Hence, enhanced CT images can clearly reveal the mucosal morphology in the nanoparticle-treated gastritic rat over a long time window comparison with nanoparticle-treated healthy rats and clinical small-molecule-treated gastritic rat. In addition, we have discovered that nanoparticles can repair the atrophic gastric mucosa to a normal state. This repair process mainly stems from inflammatory immune response caused by phagocytized nanoparticles, such as the polarization of proinflammatory macrophages (M1) to anti-inflammatory macrophages (M2). The biocompatible nanoparticles that avoid the inherent defects of the clinical small molecules have great potential for accurate diagnosis and treatment of gastritis in the early stage.

Ferroptosis is attracting significant attention due to its effectiveness in tumor treatment. The efficiency to produce toxic lipid peroxides (LPOs) at the tumor site plays a key role in ferroptosis. A hybrid PFP@Fe/Cu-SS metal organic framework (MOF) is synthesized and shown to increase intratumoral LPO content through redox reactions generating ·OH. In addition, glutathione (GSH) depletion through disulfide-thiol exchange leads to the inactivation of glutathione peroxide 4 (GPX4), which results in a further increase in LPO content. This MOF exhibits high inhibitory effect on the growth of xenografted Huh-7 tumors in mice. The coadministration of a ferroptosis inhibitor reduces the antitumor effect of the MOF, leading to a restoration of GPX4 activity and an increase in tumor growth. Moreover, the construction of Cu into mesoporous PFP@Fe/Cu-SS not only allows the MOF to be used as a contrast agent for T 1 -weighted magnetic resonance imaging, but also renders its photothermal conversion capacity. Thus, near-infrared irradiation is able to induce photothermal therapy and transform the encapsulated liquid perfluoropentane into microbubbles for ultrasound imaging., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Sorafenib (SF) is the first drug demonstrated to improve the survival of patients diagnosed with advanced-stage hepatocellular carcinoma (HCC). However, its clinical application is limited by the poor oral bioavailability and severe side effects. In this study, a multifunctional micellar nanodrug was developed for simultaneous HCC-targeted delivery of SF and tumor detection with magnetic resonance imaging (MRI). The micellar nanodrug incorporating SF and superparamagnetic iron oxide nanoparticles (SPIONs) was prepared from a diblock copolymer of monomethoxyl poly(ethylene glycol) and poly(N-(2-aminoethanethiol-co-2-aminoethyldiisopropylamine) aspartamide) and then decorated with anti-glypican-3 antibody (Ab GPC3 ). Owing to the small size, weak positive charge and Ab GPC3 -mediated active targeting to HCC cells, the nanodrug exhibited an easy cellular uptake and enhanced tumor accumulation. The prominent reduction and pH dual-sensitivity allowed the nanodrug to rapidly release SF inside cancer cells via responding to the cytoplasmic glutathione and lysosomal acidity. The nanodrug not only significantly improved the anticancer effects of SF in hepatoma treatment but also facilitated a noninvasive tumor detection and monitoring of in vivo drug delivery by MRI, which revealed its great potential as a promising theranostic system.

Many lanthanide ions-based probes have been widely used for detecting anthrax spores biomarker-dipicolinic acid (DPA). However, little work has realized detection of bacillus anthrax spores in real environmental samples. In this work, a novel ratiometric fluorescent nanoprobe based on europium (Eu)-doped silicon nanoparticles (Eu@SiNPs) was fabricated for the first time by one-pot method without post-modification for determination of the DPA in bacillus subtilis spores (simulant bacillus anthrax spores). Based on Eu(III) in the Eu@SiNPs could be sensitized by DPA to emit intrinsic fluorescence and the fluorescence intensity of SiNPs in the Eu@SiNPs almost remained stable, a new ratiometric fluorescent method for determination of micro DPA in bacillus subtilis spores and bacillus subtilis spores in real environmental samples, such as Yellow river water, tap water and soil was established. Under the optimum conditions, the limit of detection (LOD) of the method toward bacillus subtilis spores was as low as 2.38×10 4 spore/mL. Simple, fast and visual DPA and bacillus subtilis spores determination was also achieved by the Eu@SiNPs-based test paper. Therefore, the newly established method was expected to be a powerful tool for efficiently determination of bacillus anthrax spores to avoid anthrax threats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Hydrogels for biomedical applications such as controlled drug release are usually synthesized with the chemical or physical crosslinking of monomers or macromers. In this work, we used gelatin to prepare hydrogel nanoparticles and studied whether gelatin nanoparticles (GNPs) could assemble to form a solid biomaterial and whether this solid biomaterial was capable of transforming into a hydrogel upon introduction to a hydrated environment. The data show that GNPs with or without aptamer functionalization could form a nanoparticle-assembled porous solid biomaterial after freezing and lyophilization treatment. This formation did not need any additional crosslinking reactions. More importantly, this solid biomaterial could undergo solid-to-hydrogel transition after contacting a solution and this transformation was tunable to match different shapes and geometries of defined molds. The formed hydrogel could also sequester and release growth factors for the promotion of skin wound healing. Thus, GNP-assembled solid biomaterials hold great potential as an off-the-shelf therapy for biomedical application such as drug delivery and regenerative medicine., Competing Interests: Declaration of Competing Interest There are no conflicts to declare., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Forensic saliva identification represents an increasingly useful auxiliary means of crime investigations, particularly in sex crimes. Salivary bacteria detection techniques have been shown to be viable methods for identifying the presence of saliva. A one-pot method is described for the fabrication of bovine serum albumin-stabilized SiC nanoparticles (SiC@BSA NPs). The SiC@BSA NPs were conjugated to antibacterial peptide GH12 to allow for fluorometric detection and imaging of bacteria in saliva. More specifically, the nanoprobe, with fluorescence excitation/emission maxima at 320/410 nm, was used to detect the oral bacteria S. salivarius levels. The detection limit is 25 cfu·mL -1 , and the assay can be performed within 40 min. The nanoprobe was also used to detect bacteria in forensic body fluids including blood, urine, and semen. In all cases, positive results were obtained with (mixed) samples containing saliva, while other saliva samples without saliva showed negative results. Fluorescent images of S. salivarius cells were obtained by implementing a high-content image analysis system. These results suggest that this new nanoprobe can be applied to screen for forensic saliva stains. Graphical abstractSchematic representation of the preparation of SiC@BSA-GH12 nanoprobe for fluorometric detection and imaging of S. salivarius in saliva.

Combination of chemotherapeutics and immunomodulators can generate synergistic anticancer efficacy, exerting efficient chemoimmunotherapy for cancer treatment. Nanoparticulate delivery systems hold great promise to promote synergistic anticancer efficacy for the codelivery of drugs. However, there remain challenges to precisely coencapsulate and deliver combinational drugs at designed ratios due to the difference of compatibility between drugs and nanocarriers. In this study, coassembled nanoparticles of lipophilic prodrugs (LPs) were designed to codeliver chemotherapeutics and immunomodulators for cancer treatment. Such nanoassemblies (NAs) could act as platforms to ratiometrically coencapsulate chemotherapeutics and immunomodulators. Based on this method, NAs formed by the self-assembly of iRGD peptide derivatives, paclitaxel (PTX) LPs, and imiquimod (R837) LPs were demonstrated to target the tumor at unified pharmacokinetics, further inducing the effective tumor inhibition and tumor recurrence prevention. This work provided an alternative to prepare chemoimmunotherapeutic NAs with advantages of ratiometric drug coencapsulation and unified pharmacokinetics, which may advance the future cancer chemoimmunotherapy.

Combination therapy with multiple chemotherapeutic agents is the main approach for cancer treatment in the clinic. Polyphenol-based materials are found in our diet, demonstrate good biocompatibility, and prevent numerous diseases. In this study, we encapsulate two drugs in a single polyphenol-based polymer with Fe 3+ or Mn 2+ ions as the cross-linker for cancer therapy. The combination index of two drugs is an essential parameter to evaluate drug combinations. The amphiphilic polymer poly(ethylene glycol)-block-polydopamine (PEG-PDA) was prepared by RAFT polymerization. The nanoparticles were prepared via self-assembly with Fe 3+ or Mn 2+ ions. Both doxorubicin (DOX) and simvastatin (SV) were encapsulated in the core of the nanoparticles. The cell viability and combination index were evaluated in vitro. The tumor accumulation of the nanoparticles was investigated by positron-emission tomography (PET) and magnetic resonance (MR) imaging. The as-prepared nanoparticles exhibited high drug loading capacity. The drug loaded nanoparticles could kill cancer cells effectively with a combination index <1. Both PET and MRI revealed that the nanoparticles showed long blood circulation time and high tumor accumulation. The nanoparticles could inhibit tumor inhibition via intravenous injection of nanoparticles. The polyphenol-based nanoplatform may serve as a promising theranostic candidate for clinical application.

An efficient method for the highly sensitive and specific detection of cancer cells is crucial for the early diagnosis of cancer. In this work, we propose a one-pot approach to fabricating magnetic-fluorescent iron oxide-carbon hybrid nanomaterials (MCNP) with excellent stable, high quantum yield and excellent magnetic properties for breast cancer cells recognition and detection via magnetic resonance and multicolour fluorescence imaging. MCNPs were efficiently synthesised via one-pot, multi-component reactions of FeCl 3 , FeCl 2 •4H 2 O, citric acid and ethylenediamine in diethylene glycol. The MCNPs showed strong excitation wavelength-dependent fluorescence in the blue-red region with a high quantum yield of 58.4%, and they presented higher stability and T 2 relaxivity than pure iron oxide nanoparticles. After conjugating with CD44 monoclonal antibodies, the fabricated targeting nanoprobe, MCNPs-CD44, demonstrated a specific fluorescence/MRI dual imaging contrast effect in 4T1 breast cancer cells. Biological transmission electron microscope imaging showed a significant preferential uptake of the nanoparticle conjugates by the 4T1 cells. By taking advantage of the high binding affinity and specificity of the CD44 antibodies to the overexpressed CD44 on the cancer cell surface, the developed MCNPs-CD44 probe distinguished 4T1 breast cancer cells from normal cells and detected as low as a few hundred cancer cells, thus indicating the potential application of multifunctional nanocomposites in the MR diagnosis and fluorescence positioning of breast cancer at cellular-level resolution., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Early stage exposure of foodborne substances, such as brightening agent titanium dioxide nanoparticles (TiO 2 NPs), can cause long-term effects in adulthood. We aimed to explore the potential adverse effect of long-term dietary intake of TiO 2 NPs. After feeding for 2-3 months from weaning, TiO 2 NPs-exposed mice showed lower body weight and induced intestinal inflammation. However, this phenomenon was not observed in gut microbiota-removed mice. TiO 2 NPs exposure rarely affected the diversity of microbial communities, but significantly decreased the abundance of several probiotic taxa including Bifidobacterium and Lactobacillus . Additionally, TiO 2 NPs aggravated DSS-induced chronic colitis and immune response in vivo, and reduced the population of CD4+T cells, regulatory T cells, and macrophages in mesenteric lymph nodes. Therefore, dietary TiO 2 NPs could interfere with the balance of immune system and dynamic of gut microbiome, which may result in low-grade intestinal inflammation and aggravated immunological response to external stimulus, thus introducing potential health risk.

Minimal drug leakage during blood circulation and intracellular drug delivery in tumor sites are of great significance in chemotherapeutics. Herein we propose an interlayer crosslinked polymeric micelle with tumor acidity and reduction dual sensitivity for highly efficient drug delivery to cancer cells. A novel copolymer mPEG-C[double bond, length as m-dash]N-PAsp(MEA)-CA was synthesized and self-assembled into a dual-sensitive interlayer-crosslinked micelle (ICM). The micelle was composed of a tumor acidity sheddable PEG outer layer, a reduction-sensitive disulfide-crosslinked interlayer (PAsp(MEA)) and a hydrophobic core of cholic acid (CA) for doxorubicin (DOX) delivery. The nano-sized ICM was stable and showed little drug leakage in a neutral physiological environment. In tumor microenvironments (TMEs) with mild acidity, the PEG outer layer was readily detached due to the hydrolysis of the Schiff base linker, and the surface of the ICM was switched to positively charged to enhance the cellular uptake. Furthermore, inside tumor cells DOX was rapidly released due to the reduction of disulfide bonds by glutathione (GSH). The DOX-loaded ICM exhibited an effective anticancer effect against C6 glioma and reduced side effects both in vitro and in vivo. The study reveals that this pH and reduction dual-sensitive micelle may have great potential to mediate effective anticancer therapy.

Radiotherapy is a traditional method for cancer therapy but may become ineffective likely due to the radiation-induced immunosuppression. Instead of simply increasing the radiation dose, reactivation of immunosuppression in the tumor microenvironment is an alternative strategy for successful cancer treatment. In this work, we synthesized bismuth sulfide nanoparticles (BiNP) and conjugated with immunoactive Ganoderma lucidum polysaccharide (GLP). GLP-BiNP were able to increase the sensitivity of radiotherapy, attributing to the efficient X-ray absorption of bismuth element. BiNP alone can mildly activate dendritic cells (DC) in vitro, while GLP-BiNP further enhanced the level of DC maturation, shown as the increase in phenotypic maturation markers, cytokine release, acid phosphatase activity, and T cell proliferation in DC/T cell co-culture. Compared to BiNP, GLP-BiNP altered the tissue distribution with faster accumulation in the tumor. Meanwhile, mature DC greatly increased in both tumor and spleen by GLP-BiNP within 24 h. GLP-BiNP combination with radiation achieved remarkable inhibition of tumor growth through apoptosis. Alternatively, lung metastasis was largely prohibited by GLP-BiNP, shown as a reduced amount of tumor nodules and cancer cell invasion by pathological findings. Mechanistically, GLP-BiNP altered the tumor immunosuppression microenvironment by preferably increasing the number of intratumor CD8 + T cell proliferation, as well as the improved immunobalance shown as the increased serum interferon-γ/interleukin-4 ratio. Specifically, GLP conjugation seemed to protect the kidney from injury occasionally introduced by bare BiNP. As a result, GLP-BiNP play a dual role in tumor treatment through radiosensitization and immunoactivities.

The physical properties of nanoparticles (NPs), such as size, surface chemistry, elasticity, and shape, have exerted a profound influence on tumor penetration. However, the effect of shape on cellular uptake and tumor penetration is still unclear because of the different chemical compositions and shapes of tested particles and the use of inapposite cellular models. To discover the effect of NP shapes on cellular uptake and tumor penetration and bridge the gap between models in vivo and in vitro, elongated polystyrene (PS) NPs with a fixed volume, an identical chemical composition, and the same zeta potential, but with different aspect ratios (ARs), were generated. The physical properties, cellular uptake, tumor penetration, and corresponding mechanisms of these NPs were thoroughly investigated. We discovered that the elongated PS particles with higher ARs had lower uptake rates in the 2-dimensional cell monolayer culture model in vitro, but they showed optimal ARs in the evaluated three-dimensional spheroid model. Although the elongated PS particles had a similar tumor penetration mechanism (mainly through extracellular pathways), the percentage of penetration using these mechanisms was strongly dependent on the ARs. As an alternative model for studies in vivo, spheroids were used instead of the cell monolayer for the development of drug delivery systems. In addition, the physicochemical properties of NPs must be delicately balanced and adjusted to achieve the best therapeutic outcomes.

The current study reports on a cross-priming amplification (CPA) scheme that utilizes antarctic thermal sensitive uracilDNA-glycosylase (AUDG) for simultaneous detection of nucleic acids and prevention of carryover contamination. Amplification products were applied in a nanoparticle-based lateral flow biosensor (LFB). The method shows attractive features in that it only requires the use of a labeled primer, eliminating the use of labeled probes. Thus, it is able to remove false-positive results yielded by undesired hybridization between two labeled primers or between a probe and labeled primer. CPA amplification and AUDG cleavage are carried out in a single pot, and the use of a closed-vessel reaction eliminates unwanted results due to carryover contamination. Then, the assay devised in this report was applied to the detection of the hospital-acquired pathogen Klebsiella pneumoniae in pure cultures and artificial sputum samples. This biosensor can detect K. pneumoniae in pure cultures with a 100 fg · μ L -1 detection limit, and in artificial sputum samples with a 520 cfu · mL -1 detection limit. The whole procedure, including specimen processing (20-min), CPA amplification (60-min), AUDG digestion (5-min) and result indicating (within 2-min), can be completed within 1.5 h. As a proof-of-concept technique, this method can be used for detecting a wide variety of other targets if the specific CPA primer set is available.