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Background: How to ingeniously design multi-effect photosensitizers (PSs), including multimodal imaging and multi-channel therapy, is of great significance for highly spatiotemporal controllable precise phototherapy of malignant tumors., Methods: Herein, a novel multifunctional zinc(II) phthalocyanine-based planar micromolecule amphiphile ( ZnPc 1 ) was successfully designed and synthesized, in which N atom with photoinduced electron transfer effect was introduced to enhance the near-infrared absorbance and nonradiative heat generation. After simple self-assembling into nanoparticles (NPs), ZnPc 1 NPs would exhibit enhanced multimodal imaging properties including fluorescence (FL) imaging (FLI) /photoacoustic (PA) imaging (PAI) /infrared (IR) thermal imaging, which was further used to guide the combined photodynamic therapy (PDT) and photothermal therapy (PTT)., Results: It was that under the self-guidance of the multimodal imaging, ZnPc 1 NPs could precisely pinpoint the tumor from the vertical and horizontal boundaries achieving highly efficient and accurate treatment of cancer., Conclusion: Accordingly, the integration of FL/PA/IR multimodal imaging and PDT/PTT synergistic therapy pathway into one ZnPc 1 could provide a blueprint for the next generation of phototherapy, which offered a new paradigm for the integration of diagnosis and treatment in tumor and a promising prospect for precise cancer therapy., Competing Interests: The authors declare no conflicts of interest in this work., (© 2024 Sun et al.)

Zinc oxide nanoparticles (ZnO NPs) expedite the conversion of organic phosphorus (OP) into PO 4 -P (Pi), facilitating phosphorus (P) absorption by algae. Our study explored the mechanisms of converting OP (2-aminoethylphosphonic acid (AEP) and β-glycerol phosphate (β-GP)) into Pi in Chlorella pyrenoidosa under P deficiency with sunscreen and ZnO NPs. Cell density followed the order of K 2 HPO 4 > β-GP+ZnO > β-GP > AEP+ZnO > AEP > P-free. ZnO NPs promoted the conversion of β-GP, containing C-O-P bonds (0.028-0.041 mg/L), into Pi more efficiently than AEP, which possesses C-P bonds (0.022-0.037 mg/L). Transcriptomics revealed Pi transport/metabolism (phoB (3.99-12.01 fold), phoR (2.20-5.50 fold), ppa (4.49-10.40 fold), and ppk (2.50-5.40 fold)) and phospholipid metabolism (SQD1 (1.85-2.79 fold), SQD2 (2.60-6.53 fold), MGD (2.13-3.21 fold), and DGD (4.08-7.56 fold)) were up-regulated compared to K 2 HPO 4 . 31 P nuclear magnetic resonance spectroscopy identified intracellular P as polyphosphate, orthophosphate, and pyrophosphate. Synchrotron radiation-based X-ray near-edge structure spectroscopy indicated that K 2 HPO 4 and Zn 3 (PO 4 ) 2 in β-GP+ZnO were increased by 8.09% and 7.28% compared to AEP+ZnO, suggesting superior P storage in β-GP+ZnO. Overall, ZnO NPs improved photoinduced electron-hole pair separation and charge separation efficiency and amplified the ·OH and ·O 2 - levels, promoting OP photoconversion into Pi and algae growth.

Chemotherapy remains the primary treatment method for osteosarcoma after surgery. However, the lack of selectivity of chemotherapy for osteosarcoma leads to unpredictable therapeutic effects, undesirable side effects, and drug resistance. A platinum(IV) (Pt IV ) prodrug amphiphile (ALN-Pt IV -Lipo) covalently bound to alendronate (ALN) and a lipid tail is designed to overcome these limitations. ALN-Pt IV -Lipo can self-assemble into Pt IV lipid nanoparticles (APt IV ) for osteosarcoma targeting chemotherapy and bone destruction inhibition. It is demonstrated that APt IV achieved an eightfold increase in the eradication of osteosarcoma cells compared to cisplatin and threefold selective inhibition of osteosarcoma cells over breast cancer cells via APt IV in vitro. After intravenous injection, APt IV effectively accumulates at the osteosarcoma site in vivo, resulting in significantly suppressed primary osteosarcoma growth, and alleviation of bone destruction. Therefore, APt IV delivers a promising solution for enhanced chemotherapy targeting and bone destruction inhibition in osteosarcoma., (© 2023 Wiley-VCH GmbH.)

Cancers are fatal diseases that lead to most death of human beings, which urgently require effective treatments methods. Hyperthermia therapy employs magnetic nanoparticles (MNPs) as heating medium under external alternating magnetic field. Among various MNPs, ferrite nanoparticles (FNPs) have gained significant attention for hyperthermia therapy due to their exceptional magnetic properties, high stability, favorable biological compatibility, and low toxicity. The utilization of FNPs holds immense potential for enhancing the effectiveness of hyperthermia therapy. The main hurdle for hyperthermia treatment includes optimizing the heat generation capacity of FNPs and controlling the local temperature of tumor region. This review aims to comprehensively evaluate the magnetic hyperthermia treatment (MHT) of FNPs, which is accomplished by elucidating the underlying mechanism of heat generation and identifying influential factors. Based upon fundamental understanding of hyperthermia of FNPs, valuable insights will be provided for developing efficient nanoplatforms with enhanced accuracy and magnetothermal properties. Additionally, we will also survey current research focuses on modulating FNPs' properties, external conditions for MHT, novel technical methods, and recent clinical findings. Finally, current challenges in MHT with FNPs will be discussed while prospecting future directions., 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 B.V. All rights reserved.)

Endometriosis (EM) is a prevalent and debilitating gynecological disorder primarily affecting women of reproductive age. The diagnosis of EM is historically hampered by delays, owing to the absence of reliable diagnostic and monitoring techniques. Herein, it is reported that photoacoustic imaging can be a noninvasive modality for deep-seated EM by employing a hyaluronic-acid-modified polydopamine (PDA@HA) nanoparticle as the contrast agent. The PDA@HA nanoparticles exhibit inherent absorption and photothermal effects when exposed to near-infrared light, proficiently converting thermal energy into sound waves. Leveraging the targeting properties of HA, distinct photoacoustic signals emanating from the periphery of orthotopic EM lesions are observed. These findings are corroborated through anatomical observations and in vivo experiments involving mice with green fluorescent protein-labeled EM lesions. Moreover, the changes in photoacoustic intensity over a 24 h period reflect the dynamic evolution of PDA@HA nanoparticle biodistribution. Through the utilization of a photoacoustic ultrasound modality, in vivo assessments of EM lesion volumes are conducted. This innovative approach not only facilitates real-time monitoring of the therapeutic kinetics of candidate drugs but also obviates the need for the sacrifice of experimental mice. As such, this study presents a promising avenue for enhancing the diagnosis and drug-screening processes of EM., (© 2023 Wiley-VCH GmbH.)

Triptorelin is a first-line drug for assisted reproductive technology (ART), but the low bioavailability and frequent subcutaneous injection of triptorelin impair the quality of life of women preparing to become pregnant. We report silk fibroin (SF)-based microneedles (MNs) for transdermal delivery of triptorelin-loaded nanoparticles (NPs) to improve bioavailability and achieve safe and efficacious self-administration of triptorelin. Triptorelin was mixed into an aqueous solution of SF with shear force to prepare NPs to control the release and avoid the degradation of triptorelin by enzymes in the skin. Two-step pouring and centrifugation were employed to prepare nanoparticles-encapsulated polymeric microneedles (NPs-MNs). An increased β-sheet content in the conformation ensured that NPs-MNs had good mechanical properties to pierce the stratum corneum. Transdermal release of triptorelin from NPs-MNs was increased to ∼65%. The NPs-MNs exhibited a prolonged drug half-life and increased relative bioavailability after administration to rats. Surging levels of luteinizing hormone and estradiol in plasma and their subsequent prolonged downregulation indicate the potential therapeutic role of NPs-MNs in ART regimens. The triptorelin-loaded NPs-MNs developed in this study may reduce the physical and psychological burden of pregnant women using ART regimens.

Metal-based nanoparticles (NPs) attract increasing concerns because of their adverse effects on aquatic ecosystems. However, their environmental concentrations and size distributions are largely unknown, especially in marine environments. In this work, environmental concentrations and risks of metal-based NPs were examined in Laizhou Bay (China) using single-particle inductively coupled plasma-mass spectrometry (sp-ICP-MS). First, separation and detection approaches of metal-based NPs were optimized for seawater and sediment samples with high recoveries of 96.7% and 76.3%, respectively. Spatial distribution results showed that Ti-based NPs had the highest average concentrations for all the 24 stations (seawater, 1.78 × 10 8 particles/L; sediments, 7.75 × 10 12 particles/kg), followed by Zn-, Ag-, Cu-, and Au-based NPs. For all the NPs in seawater, the highest abundance occurred around the Yellow River Estuary, resulting from a huge input from Yellow River. In addition, the sizes of metal-based NPs were generally smaller in sediments than those in seawater (22, 20, 17, and 16 of 22 stations for Ag-, Cu-, Ti-, and Zn-based NPs, respectively). Based on the toxicological data of engineered NPs, predicted no-effect concentrations (PNECs) to marine species were calculated as Ag at 72.8 ng/L < ZnO at 2.66 µg/L < CuO at 7.83 µg/L < TiO 2 at 72.0 µg/L, and the actual PNECs of the detected metal-based NPs may be higher due to the possible presence of natural NPs. Station 2 (around the Yellow River Estuary) was assessed as "high risk" for Ag- and Ti-based NPs with risk characterization ratio (RCR) values of 1.73 and 1.66, respectively. In addition, RCR total values for all the four metal-based NPs were calculated to fully assess the co-exposure environmental risk, with 1, 20, and 1 of 22 stations as "high risk", "medium risk", and "low risk", respectively. This study helps to better understand the risks of metal-based NPs in marine environments., 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. Published by Elsevier Ltd.)

Phototherapy is considered a promising alternative to conventional tumor treatments due to its noninvasive modality and effective therapeutic effect. However, designing a photosensitizer with satisfactory therapeutic effect and high security remains a considerable challenge. Herein, a series of dimeric heptamethine cyanine photosensitizers with an aromatic diphenol linker at the meso position is developed to improve the photothermal conversion efficiency (PCE). Thanks to the extended conjugate system and high steric hindrance, the screened 26NA-NIR and 44BP-NIR exhibit high PCE (≈35%), bright near-infrared (NIR) fluorescence, excellent reactive oxygen species (ROS) generation capability, and improved photostability. Furthermore, their outstanding performance on imaging-guided PDT-PTT synergistic therapy is demonstrated by in vivo and in vitro experiments. In conclusion, this study designs a series of dimeric heptamethine cyanine photosensitizers and presents two compounds for potential clinical applications. The strategy provides a new method to design NIR photosensitizers for imaging-guided cancer treatment., (© 2023 Wiley-VCH GmbH.)

Transcytosis is a crucial process that nanomedicines can experience in various delivery stages. However, little was known about whether it endows biofunctions to the nanomedicines. Here, we reported that transporting photodynamic nanoparticles across cancer cells via the endoplasmic reticulum (ER)-Golgi pathway formulated them with abundant neoantigens and damage-associated molecular patterns. The resultant nanoparticles (Tran-NPs) were potent in dendritic cell maturation and T cell activation. Meanwhile, the photodynamic Tran-NPs maintained their primary function of repolarizing immunosuppressive cells. The immune responses were observed in melanoma B16F10 tumor models. Our work suggested that the transcytosis process reprogrammed the nanoparticles with immunological properties, which might shed light on the design of nanomedicines.

The development of high-performance composite films using biomass materials have become a sought-after direction. Herein, a green method to fabricate strong, flexible and UV-shielding biological composite film from wood cellulose skeleton (WCS), lignin nanoparticles (LNPs) and polyvinyl alcohol (PVA) was described. In the work, WCS and LNPs were prepared by chemical treatment of wood veneer and Enzymatic lignin, respectively. Then, WCS was infiltrated with the LNPs/PVA mixtures and dried to obtain composite films. WCS enhanced the mechanical properties of the composite films, the tensile stress reached to 85.8 MPa and the tensile strain reached to 6.39 %. The composite films with LNPs blocked over 98 % of UV-light, the water absorption decreased by 30 %, and the thermal stabilities were also improved. These findings would provide some references for exploring high quality biological composite films., Competing Interests: Declaration of competing interest 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 © 2022. Published by Elsevier B.V.)

For the successful oral delivery of peptide drugs, considerable barriers created by the harsh environment of the gastrointestinal tract, mucus, and epithelial cells must be overcome. This study was to establish a core-shell structure with chitosan (CS) nanoparticles (NP) as the core and poly-N-(2-hydroxypropyl) methacrylamide (pHPMA) as the intelligent escape shell to overcome pH and mucus barriers and improve the delivery efficiency of peptide drugs. A core-shell system (COS) composed of pHPMA-AT-1002-cys-chitosan (LRA-PA-CNPs) was prepared and used for the treatment of type 2 diabetes mellitus with the large-molecule peptide drug liraglutide (LRA). The complete COS system was observed through electron microscopy; the particle size of the LRA-PA-CNPs was approximately 160 nm; the encapsulation efficiency was approximately 69% ± 5%; the zeta potential was close to neutral; the mucus and epithelial penetration of the COS system were increased; and animal experiments showed that the COS system enhanced the oral hypoglycaemic effect of LRA.HIGHLIGHTSIntelligent escape material of poly-N-(2-hydroxypropyl) methacrylamide as the shell.Core-shell nanoparticles penetrate the mucus layer and exposing the chitosan core.Overcome pH and mucus barriers to improve the delivery efficiency of peptide drugs.

A novel hyaluronic acid (HA)-modified hybrid nanocomplex HA-SeSe-COOH/siR-93C@PAMAM, which could efficiently deliver siRNA into tumor cells via a redox-mediated intracellular disassembly, was constructed for enhanced antitumor efficacy. Thereinto, siR-93C (siRNA) and positive PAMAM were firstly mixed into the electrostatic nano-intermediate, and then diselenide bond (-SeSe-)-modified HA was coved to shield excessive positive charges. This hybrid nanocomplex displayed uniform dynamic sizes, high stability, controlled zeta potential and narrow PDI distribution. Moreover, the -SeSe- linkage displayed GSH/ROS dual responsive properties, improving intracellular trafficking of siRNA. In vitro assays in A549 cell line presented that HA-SeSe-COOH/siR-93C@PAMAM has low cytotoxicity, rapid lysosomal escape and significant transfection efficiency; besides, an efficient proliferation inhibition ability and enhanced apoptosis. Furthermore, in animal studies, this negative-surfaced hybrid nanocomplex showed a prolonged circulation in blood and improved inhibition of tumor growth. All these results verified our hypothesis in this study that diselenide bonds-modified HA could promote not only stability and safety of nanoparticles in vivo but also intracellular behavior of siRNA via redox-dual sensitive properties; furthermore, this hybrid nanocomplex provided a visible potential approach for siRNA delivery in the antitumor field.

Cancer cells and their stromal microenvironment are mutually supportive. Either destroying cancer cells or damaging stromal components cannot guarantee a satisfactory outcome in the long-term treatment. Herein, we showed that the tumor-stroma crosstalk was disturbed by nanoparticle-based photodynamic therapy (PDT) in pancreatic tumor models, leading to the persistent inhibition of extracellular matrix (ECM) secretion and the enhanced therapeutic effect. By employing a conditioned medium method, we found that the nanoparticulate PDT at a sub-lethal dosage down-regulated TGFβ signaling pathways, leading to the decrease in drug resistance, proliferation, and migration of the cancer cells. Meanwhile, pancreatic stellate cells (PSCs) were inactivated by PDT, hindering the secretion of ECM. Combining the results that PDT indiscriminately killed PSCs and cancer cells, we showed that the mutual support between the cancer cells and the stroma was interrupted. We further presented the inhibition of the crosstalk persistently enhanced tumor penetration in stroma-rich pancreatic tumor models. The loosened stroma not only facilitated tumor eradication by subsequent therapy but also improved the efficiency of gemcitabine treatment on monthly later recurrent tumors. Therefore, our work may boost the potential of PDT to be a valuable individual or adjuvant treatment for desmoplastic cancers., 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 © 2022 Elsevier Ltd. All rights reserved.)

Afterglow materials have drawn considerable attention due to their attractive luminescent properties. However, their low-efficiency luminescence in aqueous environment limits their applications in life sciences. Here, we developed a molecular fusion strategy to improve the afterglow efficiency of photochemical afterglow materials. By fusing a cache unit with an emitter, we obtained a blue afterglow system with a quantum yield up to 2.59 %. This is 162 times higher than that achieved with the traditional physical mixing system and more than an order of magnitude larger than that of the covalent coupling system. High-efficiency afterglow nanoparticles were obtained and utilized for bio-imaging with a high signal-to-noise ratio (SNR) of 131, and for the lateral flow immunoassay (LFIA) of β-hCG with a low limit of detection (LOD) of 0.34 mIU mL -1 . This paves a new way for the construction of high-efficiency afterglow materials and expands the number of luminescence reporter candidates for disease diagnosis and bio-imaging., (© 2022 Wiley-VCH GmbH.)

Electrochemical reduction of oxygen plays a critical role in emerging electrochemical energy technologies. Multiple electron transfer processes, involving adsorption and activation of O 2 and generation of protons from water molecules, cause the sluggish kinetics of the oxygen reduction reaction (ORR). Herein, a double-active-site catalyst of Fe 3 C nanoparticles coupled to paulownia wood-derived N-doped carbon (Fe 3 C@NPW) is fabricated via an active-site-uniting strategy. One site on Fe 3 C nanoparticles contributes to activating water molecules, while another site on N-doped carbon is responsible for activating oxygen molecules. Benefiting from the synergistic effect of double active sites, Fe 3 C@NPW delivers a remarkable catalytic activity for ORR with a half-wave potential of 0.87 V (vs. RHE) in alkaline electrolyte, outperforming commercial Pt/C catalyst. Moreover, zinc-air batteries (ZABs) assembled with Fe 3 C@NPW as a catalyst on cathode achieve a large specific capacity of 804.4 mA h g Zn -1 and a long-term stability of 780 cycles. The model solid-state ZABs also display satisfactory performances with an open-circuit voltage of 1.39 V and a high peak power density of 78 mW cm -2 . These outstanding performances reach the level of first-rank among the non-noble metal electrode materials. This work offers a promising approach to creating double-active-site catalysts by the active-site-uniting strategy for energy conversion fields., (© 2022 Wiley-VCH GmbH.)

Surface charge of biological and medical nanocarriers has been demonstrated to play an important role in cellular uptake. Owing to the unique physicochemical properties, charge-reversal delivery strategy has rapidly developed as a promising approach for drug delivery application, especially for cancer treatment. Charge-reversal nanocarriers are neutral/negatively charged at physiological conditions while could be triggered to positively charged by specific stimuli (i.e., pH, redox, ROS, enzyme, light or temperature) to achieve the prolonged blood circulation and enhanced tumor cellular uptake, thus to potentiate the antitumor effects of delivered therapeutic agents. In this review, we comprehensively summarized the recent advances of charge-reversal nanocarriers, including: (i) the effect of surface charge on cellular uptake; (ii) charge-conversion mechanisms responding to several specific stimuli; (iii) relation between the chemical structure and charge reversal activity; and (iv) polymeric materials that are commonly applied in the charge-reversal delivery systems., (© 2022. The Author(s).)

Prostate cancer is the second most frequently diagnosed cancer in the men population. Combination anticancer therapy using doxorubicin (DOX) and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, maximize the treatment effect, and overcome multi-drug resistance. The purpose of this study is to construct a drug delivery system for the co-delivery of DOX and tanshinones (TAN). Lipid nanoparticles loaded with DOX and TAN (N-DOX/TAN) were prepared by emulsification and solvent-diffusion method. PSMA targeted nanoparticles loaded with DOX and TAN (P-N-DOX/TAN) were synthesized by conjugating a PSMA targeted ligand to N-DOX/TAN. We evaluate the performance of this system in vitro and in vivo . P-N-DOX/TAN has a size of 139.7 ± 4.1 nm and a zeta potential of 11.2 ± 1.6 mV. The drug release of DOX and TAN from P-N-DOX/TAN was much faster than that of N-DOX/TAN. N-DOX/TAN presented more inhibition effect on tumor growth than N-DOX and N-TAN, which is consistent with the synergistic results and successfully highlighting the advantages of combing the DOX and TAN in one system. P-N-DOX/TAN achieved higher uptake by LNCaP cells (58.9 ± 1.9%), highest tumor tissue distribution, and the most significant tumor inhibition efficiency. The novel nanomedicine offers great promise for the dual drug delivery to prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.

Drug resistance remains the dominant impediment for cancer therapy, not only because compensatory drug resistance pathways are always activated, but also because of the cross-resistance of cancer cells to unrelated therapeutics. Herein, chemodrug-sensitive cancer cells, intrinsic drug-resistant cells, and acquired resistant cells were employed to uncover their biological response to a nanoparticle-based photodynamic method in tumoral, cellular, and molecular levels. We observed that nanoparticle-based photodynamic process with high therapeutic efficiency, intracellular delivery, and tumor penetration effect resulted in the indiscriminate and significant therapeutic outcome, in contrast to the diversiform effect of first-line chemo-drug, Temozolomide (TMZ). By real-time quantitative PCR array technique, we revealed that signals in classical resistance pathways were unaffected or downregulated, and photodynamic effect initiates cell apoptosis via downstream genes. The discovery that nanoparticulate photodynamic therapy bypasses the signals in multiple resistant pathways may imply an alternative route for combating drug resistance of cancer.

Metal-organic frameworks (MOFs) are useful as drug delivery carriers with high loading capacity and excellent biocompatibility. We fabricated a new drug carrier based on MIL-101(Cr) environmentally and loaded it with 47.2 wt% WR-1065 (active metabolite of amifostine). Moreover, the permeability and stability of these nanoparticles increased after PEGylation by the N-hydroxysuccinimide active ester protocol. Then, a "green" continuous-flow system equipped with an ultrasound applicator was newly designed to prepare the nanoparticles under the effect of acoustic cavitation. Response surface methodology (RSM) was used to optimize the large-scale process conditions with Box-Behnken design to obtain high space-time yield (5785 kg m -3  day -1 ). These less toxic MOFs nanoparticles increased cell viability by scavenging the accumulated reactive oxygen species and resisting DNA damage after irradiation. They are capable of mitigating radiation injury, achieving a 30-d survival rate of 90% in mice after lethal total body irradiation (8.0 Gy). This countermeasure significantly improved the peripheral blood cell count, hematopoietic stem and progenitor cells frequency, and clonogenic function of hematopoietic progenitor cells. It probably prevents irradiation-induced hematopoietic damage through the p53-dependent apoptotic pathway. Therefore, ultrasound-assisted continuous-flow synthesis is a sustainable method to produce MOFs on a large scale for radioprotection., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recently, more and more attention has been focused on silica nanoparticles (SiNPs) as they are increasingly used in various fields. Yet, their biological effects, especially on human beings, largely remain unknown. This study was implanted to assess the biological responses in vitro elicited by human macrophages exposed to the SiNPs and to explore its toxicity and fibrosis biomarker. We found that SiNPs suppressed the viability of THP-1 cells in a dose-dependent manner while they triggered apoptosis and promoted the secretion of inflammatory factors. Next, SiNPs-induced macrophage supernatant was used to act on fibroblast (MRC-5), indicating that the expression of hydroxyproline (Hyp), α-SMA, and collagonIin MRC-5 increased after SiNPs treatment. To further explore the biomarker of fibrosis, Liquid-mass spectrometry facilitated quantitative proteomics, identified 3247 proteins, of which 791 proteins were expressed differentially in human embryonic lung fibroblasts after treated with SiNPs. In conclusion, our observations suggest that SiNPs induced THP-1-derived macrophage damage and apoptosis. Moreover, SiNPs induced macrophages to secrete cytokines that promote fibroblasts' proliferation and differentiation and changed protein expression in MRC-5 cells, regulating biological processes such as apoptosis, protein synthesis, and cell growth. Among these results, our findings could provide a basis for determining fibrosis biomarkers of silica nanoparticle exposure., (Copyright © 2021. Published by Elsevier Ltd.)

Radio-sensitization is highly desired to reduce side-effect of the harsh dose of radiation therapy (RT), for which nanoparticles with high atomic number elements provide a promising tool. However, insufficient knowledge on utilizing the interaction between nanoparticles and cancerous cells hampers the improvement of therapeutic outcome. We herein employed NaGdF 4 :Yb,Er nano-crystals as the sensitizer, and modified them with a tumor targeting agent and a mitochondria targeting moiety, separately and jointly, to achieve varied extent of mitochondrial accumulation. We observed that NaGdF 4 :Yb,Er nano-crystal, even unmodified with targeting ligands, is effective for radio-sensitization. Furthermore, the extent of mitochondrial targeting was responsible for sensitization efficiency both in vitro and in vitro. By RNA sequencing technique, the result was ascribed to the reactive oxygen species (ROS) mediated TNF-JNK pathway and cell cycle arrest besides breaking DNA, in contrast to only DNA damage only with those untargeted nanoparticles. Our work indicated that ROS generated by the irradiation can be utilized by activating an alternative apoptotic pathway with mitochondrial targeting nanoparticles, and therefore may suggest an approach for the enhancement of radio-sensitization. STATEMENT OF SIGNIFICANCE: Radiosensitization by nanoparticles could reduce the burden of cancer due to lowering the dose of radiation therapy and reducing side-effect. How to fully utilize the interactions of irradiation-nanoparticles-biotissues remains a challenge for improving the outcome of radiosensitization. In this manuscript, by modifying tumor-targeting and mitochondria-targeting ligands on nanoparticles, separately and jointly, we demonstrated that the radiosensitization efficiency of NaGdF 4 :Yb,Er nanoparticle depends on the extent of accumulation near mitochondria. By RNA-seq technique, the RT sensitization with mitochondrial targeting was ascribed to ROS-mediated TNF-JNK pathway and cell cycle arrest, in contrast to only DNA breaks with untargeted nanoparticles. The results suggested a strategy for better utilization of the energy of therapeutic irradiation and demonstrate that subcellular targeting is a potent factor for designing nanoparticulate radiosensitizers., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Combined photothermal therapy/chemotherapy by co-delivery of a photosensitizer (PS) and a chemotherapeutic drug has demonstrated great potential for cancer treatment. The intrinsic drawbacks of traditional drug delivery systems (DDSs), such as tedious synthetic procedures, side effects originated from the carrier materials, low loading efficiency, and uncontrolled drug release, however, have impaired their further advancement. On the other hand, enediyne antibiotics are highly cytotoxic toward cancer cells through the generation of lethal carbon radicals via thermal-induced cyclization, endowing them with great potential to achieve enhanced synergistic anticancer performance by incorporation with the photothermal effect of PS. To this end, a carrier-free and NIR/acid dual-responsive DDS was constructed for combined photothermal therapy/chemotherapy. The facile co-assembly of maleimide-based enediyne and PS IR820 was achieved in aqueous solution to give nanoparticles (EICN) with a hydrodynamic diameter of 90 nm and high stability. In vitro study confirmed the acid/NIR dual-responsive degradation and drug release, free radical generation and DNA-cleaving ability of EICN, which was accomplished by the corporation of enediyne and IR820 moieties. Further tests on HeLa cells verified the excellent synergistic anticancer performance of EICN including the improved cellular uptake, NIR-enhanced drug release, DNA damage and histone deacetylase inhibitor capacity. Overall, this carrier-free DDS with dual acid/NIR-responsivity would potentially provide new insights for the development of combined photothermal/chemotherapy.

Nano-graphene oxide (nGO), an effective drug nanocarrier, is used for simultaneous photothermal therapy (PTT) and near-infrared fluorescence imaging. Dacarbazine (DTIC) is used in the treatment of melanoma with limited clinical efficacy. PTT shows promise in the treatment of skin cancer. Herein, chitosan oligosaccharide (COS)-grafted nGO was further modified with CD47 antibody, and loaded DTIC was prepared using a versatile nanoplatform (nGO-COS-CD47/DTIC) for the treatment of melanoma as a synergistic targeted chemo-photothermal therapy. The in vitro results demonstrated that nGO-COS-CD47/DTIC nanocarriers have excellent biocompatibility, photothermal conversion efficiency, high targeting efficiency, fast drug release under NIR irradiation, and tumor cell killing efficiency. Notably, nGO-COS-CD47/DTIC plus NIR irradiation significantly promoted early cell apoptosis through the mitochondrial apoptosis pathway and exhibited a significant joint function of antitumor efficacy. The demonstrated nGO-COS-CD47/DTIC can provide a highly efficient malignant melanoma therapy using this multifunctional intelligent nanoplatform., (Copyright © 2021. Published by Elsevier B.V.)

Background: The use of drug nanocarriers to encapsulate drugs for oral administration may become an important strategy in addressing the challenging oral absorption of some drugs. In this study-with the premise of controlling single variables-we prepared model nanoparticles with different particle sizes, surface charges, and surface hydrophobicity/hydrophilicity. The two key stages of intestinal nanoparticles (NPs) absorption-the intestinal mucus layer penetration stage and the trans-intestinal epithelial cell stage-were decoupled and analyzed. The intestinal absorption of each group of model NPs was then investigated., Results: Differences in the behavioral trends of NPs in each stage of intestinal absorption were found to result from differences in particle properties. Small size, low-magnitude negative charge, and moderate hydrophilicity helped NPs pass through the small intestinal mucus layer more easily. Once through the mucus layer, an appropriate size, positive surface charge, and hydrophobic properties helped NPs complete the process of transintestinal epithelial cell transport., Conclusions: To achieve high drug bioavailability, the basic properties of the delivery system must be suitable for overcoming the physiological barrier of the gastrointestinal tract.

Background: The aim of this study is to develop a novel in situ gel of tacrolimus-loaded SLNs (solid lipid nanoparticles) for ocular drug delivery., Methods: The optimal formulation was characterized by surface morphology, particle size, zeta potential, entrapment efficiency, drug loading and in vitro release behavior. In vivo studies were also conducted to evaluate the pharmacokinetic and pharmacodynamic results., Results: In this study, TAC-SLNs ISG were prepared using homogenization followed by probe sonication method. The average particle size of TAC-SLNs ISG was observed to be 122.3±4.3 nm. Compared with TAC-SLNs, in situ gel did not increase particle size, and there was no significant difference between them. The results of viscosity measurement showed that TAC SLNs-ISG were typical of pseudo plastic systems and showed a marked increase in viscosity as temperature increased and ultimately formed a rigid gel (32°C). In vitro and in vivo studies illustrated the sustained release model of the drug from TAC-SLNs ISG. Animal model showed that TAC-SLNs ISG had good pharmacodynamics when compared with eye drops and SLNs., Conclusion: Our results demonstrated that TAC SLNs-ISG had the potential for being an ideal ocular drug delivery system., Competing Interests: The authors report no conflicts of interest for this work., (© 2021 Sun and Hu.)

Nanozymes that mimic peroxidase (POD) activity can convert H 2 O 2 into bactericidal free radicals, which is referred to as chemodynamic therapy (CDT). High glutathione (GSH) levels in the infectious tissue severely limit the performance of CDT. Herein, we report a near-infrared-controlled antibacterial nanoplatform that is based on encapsulating tungsten sulfide quantum dots (WS 2 QDs) and the antibiotic vancomycin in a thermal-sensitive liposome. The system exploits the photothermal sensitivity of the WS 2 QDs to achieve selective liposome rupture for the targeted drug delivery. We determined that WS 2 QDs show a strong POD-like activity under physiological conditions and the oxidase-like activity, which can oxidate GSH to further improve the CDT efficacy. Moreover, we found that increased temperature promotes multiple enzyme-mimicking activities of WS 2 QDs. This platform exerts antibacterial effects against Gram-positive Mu50 (a vancomycin-intermediate Staphylococcus aureus reference strain) and Gram-negative Escherichia coli and disrupts biofilms for improved penetration of therapeutic agents inside biofilms. In vivo studies with mice bearing Mu50-caused skin abscess revealed that this platform confers potent antibacterial activity without obvious toxicity. Accordingly, our work illustrates that the photothermal and nanozyme properties of WS 2 QDs can be deployed alongside a conventional therapeutic to achieve synergistic chemodynamic/photothermal/pharmaco therapy for powerful antibacterial effects.

Environmental pollution by heavy metals (HMs) has raised considerable attention due to their toxic impacts on plants, animals and human beings. Thus, the environmental cleanup of these toxic (HMs) is extremely urgent both from the environmental and biological point of view. To remediate HMs-polluted environment, several nanoparticles (NPs) such as metals and its oxides, carbon materials, zeolites, and bimetallic NPs have been documented. Among these, Fe-based NPs have emerged as an effective choice for remediating environmental contamination, due to infinite size, high reactivity, and adsorption properties. This review summarizes the utilization of various Fe-based NPs such as nano zero-valent iron (NZVI), modified-NZVI, supported-NZVI, doped-NZVI, and Fe oxides and hydroxides in remediating the HMs-polluted environment. It presents a comprehensive elaboration on the possible reaction mechanisms between the Fe-based NPs and heavy metals, including adsorption, oxidation/reduction, and precipitation. Subsequently, the environmental factors (e.g., pH, organic matter, and redox) affecting the reactivity of the Fe-based NPs with heavy metals are also highlighted in the current study. Research shows that Fe-based NPs can be toxic to living organisms. In this context, this review points out the environmental hazards associated with the application of Fe-based NPs and proposes future recommendations for the utilization of these NPs., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Biomimetic nanoparticles (NPs) coated with cell membranes show enhanced biocompatibility and specificity for homotypic cells, and have gained considerable attention for targeted anti-tumor therapy. We constructed cancer cell-macrophage hybrid membrane-coated near infrared (NIR)-responsive hollow copper sulfide nanoparticles encapsulating sorafenib and surface modified with anti-VEGFR (CuS-SF@CMV NPs). These CuS-SF@CMV NPs expressed the characteristic membrane proteins of both cancer cells and macrophages, and selectively accumulated in cancer cells in vitro and tumors in vivo, compared to the CuS NPs. In addition, the CuS-SF@CMV NPs achieved synergistic photo-thermal and chemotherapy in cancer cells upon NIR irradiation, with 94.3% inhibition of tumor growth in a murine hepatoma model. While the initial increase in temperature rapidly killed the tumor cells, sorafenib and the anti-VEGFR antibody sustained the tumor killing effect by respectively inhibiting tumor cell proliferation and angiogenesis via the Ras/Raf/MEK/ERK and PI3K/AKT pathways. Taken together, the CuS-SF@CMV NPs have immune evasion, tumor cell targeting and drug loading capacities, along with an inherent photo-thermal conversion ability, making them ideal for synergistic photo-thermal/chemo therapy against HCC. STATEMENT OF SIGNIFICANCE: We created cancer cell-macrophage hybrid membrane-coated hollow CuS NPs encapsulating sorafenib and surface modified with anti-VEGFR antibodies (CuS-SF@CMV). These CuS-SF@CMV NPs enhanced synergistic PTT and chemotherapy against hepatoma cells through homotypic cell targeting, immune escape and inhibition of a tumorigenic signaling pathway. A long-term inhibition of tumor growth and metastasis was achieved owing to the rapid destruction of the cancer cells through photo-thermal conversion by the CuS NPs, and sustained clearance of the tumor cells by sorafenib and anti-VEGFR antibodies. Our findings suggest that CuS-SF@CMV NPs present great treating effects in preclinical models of HCC, providing the framework for further study in clinical trials to improve patient outcome in hepatocellular carcinoma., 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 © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Nanozymes, which display the bifunctional properties of nanomaterials and natural enzymes, are useful tools for environmental remediation. In this research, nano-MnO 2 was selected for its intrinsic enzyme-like activity to remove 17β-estradiol (E2). Results indicated that nano-MnO 2 exhibited laccase-like activity (7.22 U·mg -1 ) and removed 97.3 % of E2 at pH 6. Humic acid (HA) impeded E2 removal (only 72.4 %) by competing with E2 for the catalytic sites of the MnO 2 nanozyme surface, and there was a good linear correlation between the kinetic constants and HA concentrations (R 2 = 0.9489). Notably, the phenolic -OH of E2 interacted with HA to yield various polymeric products via radical-driven covalent coupling, resulting in ablation of phenolic -OH but increase of ether groups in the polymeric structure. Intermediate products, including estrone, E2 homo-/hetero-oligomers, E2 hydroxylated and quinone-like products, as well as aromatic ring-opening species, were identified. Interestingly, HA hindered the extent of E2 oxidation, homo-coupling, and decomposition but accelerated E2 and HA hetero-coupling. A reasonable catalytic pathway of E2 and HA involving MnO 2 nanozyme was proposed. These findings provide novel insights into the influence of HA on MnO 2 nanozyme-driven E2 radical polymerization and decomposition, consequently favoring the ecological water restoration and the global carbon cycle., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epithelial cells are known to impede the oral delivery of polypeptides, and the accumulation of mucus and regular dynamic renewal also significantly impede drug absorption. In this work, we prepared a core-shell (COS) nanosystem using poly- N -(2-hydroxypropyl)methacrylamide (pHPMA)/chitosan (CTS). Liraglutide (NN2211) was isolated from the gastrointestinal environment and smoothly passes through the mucous layer. CSKSSDYQC (CSK) peptide and hemagglutinin-2 (HA 2 ) were introduced into the COS nanosystem to establish a complete path from the oral cavity to the epithelial basal side. The fate of nanocapsules in vivo was studied by fluorescence detection. The results showed that the nanocapsules escaped smoothly from the mucus. Taking into account the characteristics of CSK targeting goblet cells, we conducted cell-level studies, and the results showed that after the modification of CSK and pHPMA, more nanocapsules entered the cells. In vitro and in vivo evaluation results showed that the system successfully established a complete path from mucus to epithelial cells by responding to the gastrointestinal environment multiple times.

Trypsin-responsive near-infrared fluorescent (NIRF) and magnetic resonance (MR) dual-imaging composite nanoparticle/polypeptide coacervate nanoprobes with tunable sizes, have been constructed herein via electrostatic interaction-induced self-assembly. Considering the requirements of in vivo metabolism on nanoparticle size, three coacervate nanoprobes with diameters of around 100, 200, and 300 nm were fabricated with a polydispersity of around 0.2. These coacervate nanoprobes consist of Fe 3 O 4 magnetic nanoparticles surface-decorated with poly acrylic acid and Cy5.5-modified poly-l-lysine (PLL- g -Cy5.5) serving as MR imaging and trypsin-responsive substrate/NIRF agents, respectively. The notable fluorescence signal from PLL- g -Cy5.5 is self-quenched due to the short distances between the fluorescent Cy5.5 molecules after construction of the coacervate nanoprobes. Remarkably, coacervate nanoprobes with a diameter of around 100 nm are selectively disintegrated into fragmented segments upon the hydrolysis of PLL by trypsin, resulting in an 18-fold amplification of the NIRF intensity in comparison with the self-assembled coacervate nanoprobes in the quenched state. Moreover, the MR imaging enhancement is also related to the disintegration of the coacervate nanoprobes. Cellular experiments and in vivo studies demonstrate that the coacervate nanoprobes exhibit remarkable trypsin-sensitive NIRF and MR dual-imaging capabilities and thus have excellent potential to serve as dual-imaging nanoprobes for the efficient mapping of malignant tumors in which trypsin is often overexpressed. In consideration of their excellent capability to enrich charged molecules, the coacervate nanoprobes provide a conceptually novel and promising platform toward in vivo trypsin mapping and controlled delivery of targeted payloads.

Background: The complex preparation procedures and severe toxicities are two major obstacles facing the wide use of chimeric antigen receptor-modified T (CAR-T) cells in clinical cancer immunotherapy. The nanotechnology-based T cell temporary CAR modification may be a potential approach to solve these problems and make the CAR-T cell-based tumor therapy feasible and broadly applicable., Methods: A series of plasmid DNA-loaded self-assembled nanoparticles (pDNA@SNPs x/y ) prepared from adamantane-grafted polyamidoamine (Ad-PAMAM) dendrimers of different generations (G1 or G5) and cyclodextrin-grafted branched polyethylenimine (CD-PEI) of different molecular weights (800, 2000, or 25,000 Da) were characterized and evaluated. The detailed physicochemical properties, cellular interaction, and cytotoxicity of selected pDNA@SNP G1/800 were systematically investigated. Thereafter, the epidermal growth factor receptor variant III (EGFRvIII) CAR-expression plasmid vector (pEGFRvIII-CAR) was constructed and encapsulated into SNP G1/800 . The resulting pEGFRvIII-CAR@SNP G1/800 was used for Jurkat cell transient transfection, and the EGFRvIII-CAR expressed in transfected cells was measured by flow cytometry and Western blot. Finally, the response of EGFRvIII CAR-positive Jurkat T cell to target tumor cell was evaluated., Results: The pDNA@SNP G1/800 showed the highest efficacy in Jurkat cell gene transfection and exhibited low cytotoxicity. pEGFRvIII-CAR@SNP G1/800 can efficiently deliver pEGFRvIII-CAR into Jurkat T cells, thereby resulting in transient EGFRvIII-CAR expression in transfected cells. EGFRvIII-CAR that is present on the cell membrane enabled Jurkat T cells to recognize and bind specifically with EGFRvIII-positive tumor cells., Conclusion: These results indicated that pEGFRvIII-CAR@SNP G1/800 can effectively achieve T-cell transient CAR modification, thereby demonstrating considerable potential in CAR-T cancer therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Yu et al.)

Efficient delivery of brain-targeted drugs is highly important for successful therapy in Parkinson's disease (PD). This study was designed to formulate borneol and lactoferrin co-modified nanoparticles (Lf-BNPs) encapsulated dopamine as a novel drug delivery system to achieve maximum therapeutic efficacy and reduce side effects for PD. Dopamine Lf-BNPs were prepared using the double emulsion solvent evaporation method and evaluated for physicochemical and pharmaceutical properties. In vitro cytotoxicity studies indicated that treatment with dopamine Lf-BNPs has relatively low cytotoxicity in SH-SY5Y and 16HBE cells. Qualitative and quantitative cellular uptake experiments indicated that Lf modification of NPs increased cellular uptake of SH-SY5Y cells and 16HBE cells, and borneol modification can promote the cellular uptake of 16HBE. In vivo pharmacokinetic studies indicated that AUC 0-12 h in the rat brain for dopamine Lf-BNPs was significantly higher ( p  < .05) than that of dopamine nanoparticles. Intranasal administration of dopamine Lf-BNPs effectively alleviated the 6-hydroxydopamine-induced striatum lesion in rats as indicated by the contralateral rotation behavior test and results for striatal monoamine neurotransmitter content detection. Taken together, intranasal administration of dopamine Lf-BNPs may be an effective drug delivery system for Parkinson's disease.

The diffusion of nanomedicines used to treat tumors is severely hindered by the microenvironment, which is a challenge that has emerged as a bottleneck for the effective outcome of nanotherapies. Classical strategies for enhancing tumor penetration rely on passive movement in the extracellular matrix (ECM). Here, we demonstrate that nanomedicine also penetrates tumor lesions via an active trans-cell transportation process. This process was discovered by directly observing the movement of nanoparticles between cells, evaluating the intracellular trafficking pathway of nanoparticles via Rab protein labeling, comparing endocytosis-exocytosis between nanoparticles administered with inhibitors, and correlating the transcytosis process with the micro-CT distribution of nanomedicines. We also demonstrated that enhanced tumor penetration promotes the therapeutic efficacy of a photodynamic therapeutic nanomedicine. Our research thus suggests that transcytosis could be an important positive factor for designing cancer nanomedicines.

Mesoporous silica nanoparticles (MSNs) have been widely studied as drug delivery systems in nanomedicine. Surface coating of MSNs have enabled them to perform efficiently in terms of bioavailability, biocompatibility, therapeutic efficacy and targeting capability. Recent studies have suggested the use of polydopamine (PDA) as a facilitative coating for MSNs that provides sustained and pH-responsive drug release, owing to the adhesive "molecular-glue" function of PDA. This further endows these hybrid MSN@PDA particles with the ability to carry large amounts of hydrophilic drugs. In this study, we expand the feasibility of this platform in terms of exploring its ability to also deliver hydrophobic drugs, as well as investigate the effect of particle shape on intracellular delivery of both a hydrophilic and hydrophobic anticancer drug. MSN@PDA loaded with doxorubicin (hydrophilic) and fingolimod (hydrophobic) was studied via a systematic in vitro approach (cellular internalization, intracellular drug distribution and cytotoxicity). To promote the cellular uptake of the MSN@PDA particles, they were further coated with a polyethylene imine (PEI)-polyethylene glycol (PEG) copolymer. Drug-loaded, copolymer-coated MSN@PDA showed effective cellular uptake, intracellular release and an amplified cytotoxic effect with both doxorubicin and fingolimod. Additionally, rods exhibited delayed intracellular drug release and superior intracellular uptake compared to spheres. Hence, the study provides an example of how the choice and design of drug delivery systems can be tuned by the need for performance, and confirms the PDA coating of MSNs as a useful drug delivery platform beyond hydrophilic drugs.

The oral absorption of exenatide, a drug for type 2 diabetes treatment, can be improved by using nanoparticles (NPs) for its delivery. To improve the mucus penetration and intestinal absorption of exenatide, we designed a block copolymer, CSKSSDYQC-dextran-poly(lactic-co-glycolic acid) (CSK-DEX-PLGA), and used it for the preparation of exenatide-loaded NPs. The functionalized exenatide-loaded NPs composed of CSK-DEX-PLGA were able to target intestinal epithelial cells and reduce the mucus-blocking effect of the intestine. Moreover, the CSK modification of DEX-PLGA was found to significantly promote the absorption efficiency of NPs in the small intestine based on in vitro ligation of the intestinal rings and an examination of different intestinal absorption sites. Compared to DEX-PLGA-NPs (DPs), the absorption of CSK-DEX-PLGA-NPs (CDPs) was increased in the villi, allowing the drug to act on gobletlike Caco-2 cells through clathrin-, caveolin-, and gap-mediated endocytosis. Furthermore, the enhanced transport ability of CDPs was observed in a study on Caco-2/HT-29-MTX cocultured cells. CDPs exhibited a prolonged hypoglycemic response with a relative bioavailability of 9.2% in diabetic rats after oral administration. In conclusion, CDPs can target small intestinal goblet cells and have a beneficial effect on the oral administration of macromolecular peptides as a nanometer-sized carrier.

Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.

A novel core-shell type nanoparticle (CSNP) was designed here to target co-delivery of doxorubicin (DOX) and photosensitizer indocyanine green (ICG) to tumor sites by the aid of NIR induced photothermal conversion effect for the purpose of synergistic chemo-photothermal cancer therapy. The electrostatically self-assembled CSNPs were prepared by amino-functionalized mesoporous silica nanoparticles (MSN-NH 2 ) as the positive inner core and DSPE-PEG 2000 -COOH and DSPE-PEG 2000 -FA modified lecithin as the negative outer shell. The obtained CSNPs were nanospheres with a uniform size of 47 nm, which were kept stable at 4 °C in PBS (pH = 7). Research on the release of NIR stimulus (808 nm, 1.54 W cm -2 , 6 min) manifested that the release property of the CSNPs was controllable under low pH conditions. In addition, specific concentration (40 μg ml -1 ) ICG-loaded CSNPs, achieving an appropriate temperature up to 45 °C, indicated a desired photothermal conversion efficiency. For targeting the folate receptor, the folate modified CSNPs enabled us to reach a higher cellular uptake by the mean fluorescence intensity. In vitro cell assay, the prepared CSNPs showed outstanding inhibitory efficiency (2.07% cell viability and 91.8% cell apoptosis) on MCF-7 cells for 24 h when irradiated by an 808 nm laser with a power of 1.54 W cm -2 for 6 min. Our research highlights that the prepared nanoparticles hold potential promise for cancer treatment based on photothermal conversion performance and FA-targeted delivery.

Lymph metastasis is a vital pathway of cancer cell dissemination, and insidious lymph node metastasis increases the risk of distant cancer metastasis. Current therapies for lymph metastasis are largely restricted by limited targeting and penetration capacity. Herein, we report that an r9 cell-penetrating peptide-based cabazitaxel nanovehicle (r9-CN) displays prominent lymph metastasis targeting and deep penetration ability after intravenous injection for effective anti-metastasis therapy. Methods: The r9-CN and CN nanovehicles were prepared by thin film dispersion, using DSPE-PEG2000 as the nano-carrier material and cabazitaxel as the model drug to fabricate r9-modified nano-micelles by self-assembly. The morphology, size, and stability in physiological solutions of r9-CN and CN were characterized. The targeting, biodistribution, deep penetration, and therapeutic efficacy of r9-CN and CN were systematically explored in vitro and in vivo. Results: The r9-CN nanovehicle consists of homogeneous particles with a mean diameter of 13 nm and zeta potential of +0.75 mV. Compared with the nanovehicle lacking the r9 peptide (CN), r9-CN exhibits long retention and deep penetration in the tumor mass, and considerably enhances accumulation and flexible permeation in metastatic lymph nodes, thereby notably suppressing primary tumor growth, lymph node metastasis, and distant lung metastasis. Conclusion: The cumulative findings reveal that r9-CN offers a promising delivery platform, enabling efficient lymph metastasis targeting and deep penetration for effective anti-metastasis therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Gliomas are the most common malignant brain tumor, but treatment is limited by the blood-brain barrier (BBB), especially for chemotherapeutic drugs. Although some chemotherapy drugs can pass through the BBB, many of these agents are toxic to normal brain tissue. To maximize therapeutic effects, chemotherapeutic drugs must accumulate at the glioma site. In this study, a specific ligand (the RVG29 peptide) that can combine with acetylcholine receptors was conjugated to polyethylene glycol-modified poly-(d,l-lactide-co-glycolide) (PEG-PLGA) to develop a targeted carrier; preparation of the targeted docetaxel nanoparticles (DTX-NPs) was performed by the nanoprecipitation method. The NPs were approximately 110 nm and had smooth surfaces. Enzyme-linked immunoassay results showed that the amount of receptor on the surface of glioma cells was 2.04-fold higher than that of nonmalignant cells, which may promote accumulation of RVG29-modified NPs at the targeting site. NPs showed targeting properties for glioma cells compared with the non-targeting NPs in an in vitro cellular uptake test. Targeted NPs also showed better BBB penetration in an in vitro model. In vivo tests indicated that RVG29-PEG-PLGA-NPs could selectively accumulate in intracranial glioma tissue. In conclusion, these results indicated that the RVG29-modified NPs have potential efficacy for glioma therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab' (antigen-binding fragments cut from TMAB)-modified NPs (Fab'-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells., Material and Methods: The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab'-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: The release kinetics showed that both Fab'-Cur-NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab'-Cur-NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab'-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2-) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration-time curve (AUC0-t) of Fab'-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab'-Cur-NPs was higher than that of TMAB-Cur-NPs., Conclusion: Fab' fragment has greater capacity than the intact antibody to achieve tumor targeting through NP-based delivery., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Nanomedicine, which is the application of nanotechnology in medicine to make medical diagnosis and treatment more accurate, has great potential for precision medicine. Despite some improvements in nanomedicine, the lack of efficient and low-toxic vectors remains a major obstacle., Objective: The aim of this study was to prepare an efficient and low-toxic vector which could deliver astrocyte elevated gene-1 ( AEG-1 ) small interfering RNA (siRNA; siAEG-1) into osteosarcoma cells effectively and silence the targeted gene both in vitro and in vivo., Materials and Methods: We prepared a novel polysaccharide derivative by click conjugation of azidized chitosan with propargyl focal point poly (L-lysine) dendrons (PLLD) and subsequent coupling with folic acid (FA; Cs-g-PLLD-FA). We confirmed the complexation of siAEG-1and Cs-g-PLLD or Cs-g-PLLD-FA by gel retardation assay. We examined the cell cytotoxicity, cell uptake, cell proliferation and invasion abilities of Cs-g-PLLD-FA/siAEG-1 in osteosarcoma cells. In osteosarcoma 143B cells tumor-bearing mice models, we established the therapeutic efficacy and safety of Cs-g-PLLD-FA/siAEG-1., Results: Cs-g-PLLD-FA could completely encapsulate siAEG-1 and showed low cytotoxicity in osteosarcoma cells and tumour-bearing mice. The Cs-g-PLLD-FA/siAEG-1 nanocomplexes were capable of transferring siAEG-1 into osteosarcoma cells efficiently, and the knockdown of AEG-1 resulted in the inhibition of tumour cell proliferation and invasion. In addition, caudal vein injecting of Cs-g-PLLD-FA/siAEG-1 complexes inhibited tumor growth and lung metastasis in tumor-bearing mice by silencing AEG-1 and regulating MMP-2/9., Conclusion: In summary, Cs-g-PLLD-FA nanoparticles are a promising system for the effective delivery of AEG-1 siRNA for treating osteosarcoma., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Safe and effective delivery of therapeutic drugs to the brain is important for successful therapy of Alzheimer's disease (AD)., Purpose: To develop Huperzine A (HupA)-loaded, mucoadhesive and targeted polylactide-co-glycoside (PLGA) nanoparticles (NPs) with surface modification by lactoferrin (Lf)-conjugated N-trimethylated chitosan (TMC) (HupA Lf-TMC NPs) for efficient intranasal delivery of HupA to the brain for AD treatment., Methods: HupA Lf-TMC NPs were prepared using the emulsion-solvent evaporation method and optimized using the Box-Behnken design. The particle size, zeta potential, drug entrapment efficiency, adhesion and in vitro release behavior were investigated. The cellular uptake was investigated by fluorescence microscopy and flow cytometry. MTT assay was used to evaluate the cytotoxicity of the NPs. In vivo imaging system was used to investigate brain targeting effect of NPs after intranasal administration. The biodistribution of Hup-A NPs after intranasal administration was determined by liquid chromatography-tandem mass spectrometry., Results: Optimized HupA Lf-TMC NPs had a particle size of 153.2±13.7 nm, polydispersity index of 0.229±0.078, zeta potential of +35.6±5.2 mV, drug entrapment efficiency of 73.8%±5.7%, and sustained release in vitro over a 48 h period. Adsorption of mucin onto Lf-TMC NPs was 86.9%±1.8%, which was significantly higher than that onto PLGA NPs (32.1%±2.5%). HupA Lf-TMC NPs showed lower toxicity in the 16HBE cell line compared with HupA solution. Qualitative and quantitative cellular uptake experiments indicated that accumulation of Lf-TMC NPs was higher than nontargeted analogs in 16HBE and SH-SY5Y cells. In vivo imaging results showed that Lf-TMC NPs exhibited a higher fluorescence intensity in the brain and a longer residence time than nontargeted NPs. After intranasal administration, Lf-TMC NPs facilitated the distribution of HupA in the brain, and the values of the drug targeting index in the mouse olfactory bulb, cerebrum (with hippocampus removal), cerebellum, and hippocampus were about 2.0, 1.6, 1.9, and 1.9, respectively., Conclusion: Lf-TMC NPs have good sustained-release effect, adhesion and targeting ability, and have a broad application prospect as a nasal drug delivery carrier., Competing Interests: Disclosure Aipang Wang is affiliated with Shandong Luye Pharmaceutical Co., Ltd. The authors report no conflicts of interest in this work.

To improve the oral efficiency of exenatide, we prepared polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) NPs modified with Fc (NPs-Fc) for exenatide oral delivery. Exenatide was encapsulated into the NPs by the w/o/w emulsion-solvent evaporation method. The particle size of the NPs-Fc was approximately 30 nm larger than that of the unmodified NPs with polydispersity indices in a narrow range (PDIs; PDI < 0.3) as detected by DLS, and the highest encapsulation efficiency of exenatide in the NPs was greater than 80%. Fc-conjugated NPs permeated Caco-2 cells faster and to a greater extent compared to unmodified NPs, as verified by CLSM and flow cytometry. Hypoglycemic effect studies demonstrated that oral administration of exenatide-loaded PEG-PLGA NPs modified by an Fc group extended the hypoglycemic effects compared with s.c. injection of the exenatide solution. Fluorescence-labeled NPs were used to investigate the effects of Fc targeting, and the results demonstrated that the NPs-Fc stayed in the gastrointestinal tract for a longer time in comparison with the unmodified NPs, as shown by the whole-body fluorescence images and fluorescence images of the dissected organs detected by in vivo imaging in live mice. Therefore, Fc-targeted nano-delivery systems show great promise for oral peptide/protein drug delivery.

Viscoelastic properties are central for gels and other materials. Simultaneously, high storage and loss moduli are difficult to attain due to their contrarian requirements to chemical structure. Biomimetic inorganic nanoparticles offer a promising toolbox for multiscale engineering of gel mechanics, but a conceptual framework for their molecular, nanoscale, mesoscale, and microscale engineering as viscoelastic materials is absent. Here we show nanoparticle gels with simultaneously high storage and loss moduli from CdTe nanoparticles. Viscoelastic figure of merit reaches 1.83 MPa exceeding that of comparable gels by 100-1000 times for glutathione-stabilized nanoparticles. The gels made from the smallest nanoparticles display the highest stiffness, which was attributed to the drastic change of GSH configurations when nanoparticles decrease in size. A computational model accounting for the difference in nanoparticle interactions for variable GSH configurations describes the unusual trends of nanoparticle gel viscoelasticity. These observations are generalizable to other NP gels interconnected by supramolecular interactions and lead to materials with high-load bearing abilities and energy dissipation needed for multiple technologies.

Introduction: Efficient delivery of rotigotine into the brain is crucial for obtaining maximum therapeutic efficacy for Parkinson's disease (PD). Therefore, in the present study, we prepared lactoferrin-modified rotigotine nanoparticles (Lf-R-NPs) and studied their biodistribution, pharmacodynamics, and neuroprotective effects following nose-to-brain delivery in the rat 6-hydroxydopamine model of PD., Materials and Methods: The biodistribution of rotigotine nanoparticles (R-NPs) and Lf-R-NPs after intranasal administration was assessed by liquid extraction surface analysis coupled with tandem mass spectrometry. Contralateral rotations were quantified to evaluate pharmacodynamics. Tyrosine hydroxylase and dopamine transporter immunohistochemistry were performed to compare the neuroprotective effects of levodopa, R-NPs, and Lf-R-NPs., Results: Liquid extraction surface analysis coupled with tandem mass spectrometry analysis, used to examine rotigotine biodistribution, showed that Lf-R-NPs more efficiently supplied rotigotine to the brain (with a greater sustained amount of the drug delivered to this organ, and with more effective targeting to the striatum) than R-NPs. The pharmacodynamic study revealed a significant difference ( P <0.05) in contralateral rotations between rats treated with Lf-R-NPs and those treated with R-NPs. Furthermore, Lf-R-NPs significantly alleviated nigrostriatal dopaminergic neurodegeneration in the rat model of 6-hydroxydopamine-induced PD., Conclusion: Our findings show that Lf-R-NPs deliver rotigotine more efficiently to the brain, thereby enhancing efficacy. Therefore, Lf-R-NPs might have therapeutic potential for the treatment of PD., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Conventional photodynamic therapy is severely constrained by the limited light-penetration depth in tissue. Here, we show efficient photodynamic therapy (PDT) mediated by bioluminescence resonance energy transfer (BRET) that overcomes the light-penetration limitation. The photosensitizer Rose Bengal (RB) was loaded in biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles, which were then conjugated with firefly luciferase. Spectroscopic characterizations indicated that BRET effectively activated RB to generate reactive oxygen species (ROS). In vitro studies of the cellular cytotoxicity and photodynamic effect indicated that cancer cells were effectively destroyed by BRET-PDT treatment. In vivo studies in a tumor-bearing mouse model demonstrated that tumor growth was significantly inhibited by BRET-PDT in the absence of external light irradiation. The BRET-mediated phototherapy provides a promising approach to overcome the light-penetration limitation in photodynamic treatment of deep-seated tumors.

In this research, Rapeseed dregs (RDs), as a byproduct of agriculture (derived from processing of rapeseed for oil production), were originally employed asa new carbonaceous precursor to synthesize hierarchically porous and heteroatom-doped activated carbons (ACs) with the activation of ZnCl 2 at various high temperatures. A variety of measurements have been adopted to systemically characterize the RD-derived ACs. The micro-morphology, pore structures and surface chemistry property were fully investigated by SEM, TEM, XRD, Raman, N 2 adsorption-desorption analysis, XPS and IR, respectively. The RD-derived ACs possess as large specific surface area as up to 1416.966m 2 g -1 and the pore size distribution concentrates on 1-2, 2-5, 5-15 and 25-35nm, indicating their hierarchically porous structures. Furthermore, electrochemical measurements including electrochemical impedance spectroscopy (EIS), galvanostatic charge/discharge (GCD) and cyclic voltammetry (CV) were conducted to estimate RDAC's supercapacitive performance and rate capability. The investigations illustrated that RD derived ACs reached as high specific capacitance as 170.5 and 153.2Fg -1 at a scan rate of 5mVs -1 in 1M H 2 SO 4 and 1M Et 4 NBF 4 /AN, respectively. In addition, the RD-derived ACs demonstrated good long-term cycling stability and more than 90% initial capacity have been retained after 6400 cycles at a large current density of 1Ag -1 ., (Copyright © 2017 Elsevier Inc. All rights reserved.)

A tunable coffee-ring effect (CRE) that enables the patterned deposition of nanoparticles (NPs) is obtained on a designed superhydrophilic and superhydrophobic composite surface of a titanium substrate. Low-adhesion superhydrophobic surfaces with picosecond laser-induced periodic surface structure and micro-nano hierarchical structure are investigated. The NPs are not only deposited in a small area of 0.045  mm 2 , which is 265.56 times smaller than that of the original hydrophilic surface, but also in various patterns such as triangular, rectangular, and ecliptical besides the traditional circular shape. This controllable morphology of the CRE indicates a maneuvering capability of NPs in their common preservation form of suspension turbid liquid, even when the solution concentration reaches 1 mg/mL, which is promising for NP-printed circuit boards and site-specific delivery drugs.

Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly(d,l-lactide-co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas., Competing Interests: Disclosure The authors report no conflicts of interest in this work.