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Pancreatic ductal adenocarcinoma (PDAC) poses a challenge in oncology due to its high lethality and resistance to immunotherapy. Recently, emerging research on the stimulator of interferon gene (STING) pathway offers novel opportunities for immunotherapy. Although STING expression is retained in PDAC cells, the response of PDAC cells to STING agonists remains ineffective. Signal transducer and activator of transcription 3 (STAT3), a downstream pathway of STING, is notably overexpressed in pancreatic cancer and related to tumor survival and immune escape. We observed that inhibiting STAT3 signaling post-STING activation effectively suppressed tumor growth through signal transducer and activator of transcription 1 (STAT1)-mediated apoptosis but led to a potential risk of immune-related adverse events (irAEs). To address this issue, we designed a tumor-penetrating liposome for the codelivery of STING agonist and STAT3 inhibitor. These nanoparticles regulated the STING/STAT3 signaling axis and effectively inhibited the proliferation and survival of tumor. Simultaneously, we found a significant increase in the activation of NK cells and CD8 + T cells after treatment, leading to robust innate immunity and adaptive immune response. We highlight the potential of regulating the STING/STAT3 axis as a promising treatment for improving clinical outcomes in PDAC patients.

Bacterial infection, reactive oxygen species (ROS) accumulation, and persistent inflammation pose significant challenges in the treatment of periodontitis. However, the current single-modal strategy makes achieving the best treatment effect difficult. Herein, we developed a double-network hydrogel composed of Pluronic F127 (PF-127) and hyaluronic acid methacrylate (HAMA) loaded with spermidine-modified mesoporous polydopamine nanoparticles (M@S NPs). The PF-127/HAMA/M@S (PH/M@S) hydrogel was injectable and exhibited thermosensitivity and photocrosslinking capabilities, which enable it to adapt to the irregular shape of periodontal pockets. In vitro, the PH/M@S displayed multiple therapeutic effects, such as photothermal antibacterial activity, a high ROS scavenging capacity, and anti-inflammatory effects, which are beneficial for the multimodal treatment of periodontitis. The underlying anti-inflammatory mechanism of this hydrogel involves suppression of the extracellular regulated protein kinase 1/2 and nuclear factor kappa-B signalling pathways. Furthermore, in lipopolysaccharide-stimulated macrophage conditioned media, the PH/M@S effectively restored the osteogenic differentiation potential. In a rat model of periodontitis, the PH/M@S effectively reduced the bacterial load, relieved local inflammation and inhibited alveolar bone resorption. Collectively, these findings highlight the versatile functions of the PH/M@S, including photothermal antibacterial activity, ROS scavenging, and anti-inflammatory effects, indicating that this hydrogel is a promising multifunctional filling material for the treatment of periodontitis., 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.)

Efficient tumor-targeted drug delivery is still a challenging and currently unbreakable bottleneck in chemotherapy for tumors. Nanomedicines based on passive or active targeting strategy have not yet achieved convincing chemotherapeutic benefits in the clinic due to the tumor heterogeneity. Inspired by the efficient inflammatory-cell recruitment to acute clots, we constructed a two-component nanosystem, which is composed of an RGD-modified pyropheophorbide-a (Ppa) micelle (PPRM) that mediates the tumor vascular-targeted photodynamic reaction to activate local coagulation and subsequently transmits the coagulation signals to the circulating clot-targeted CREKA peptide-modified camptothecin (CPT)-loaded nanodiscs (CCNDs) for amplifying tumor targeting. PPRM could effectively bind with the tumor vasculature and induce sufficient local thrombus by a photodynamic reaction. Local photodynamic reaction-induced tumor target amplification greatly increased the tumor accumulation of CCND by 4.2 times, thus significantly enhancing the chemotherapeutic efficacy in the 4T1 breast tumor model. In other words, this study provides a powerful platform to amplify tumor-specific drug delivery by taking advantage of the efficient crosstalk between the PPRM-activated coagulation cascade and clot-targeted CCND.

The problem of microplastics (MPs) contamination in food has gradually come to the fore. MPs can be transmitted through the food chain and accumulate within various organisms, ultimately posing a threat to human health. The concentration of nanoplastics (NPs) exposed to humans may be higher than that of MPs. For the first time, we studied the differences in toxicity, and potential toxic effects of different polymer types of NPs, namely, polyethylene terephthalate (PET), polyvinyl chloride (PVC), and polystyrene (PS) on HepG2 cells. In this study, PET-NPs, PVC-NPs, and PS-NPs, which had similar particle size, surface charge, and shape, were prepared using nanoprecipitation and emulsion polymerization. The results of the CCK-8 assay showed that the PET-NPs and PVC-NPs induced a decrease in cell viability in a concentration-dependent manner, and their lowest concentrations causing significant cytotoxicity were 100 and 150 μg/mL, respectively. Moreover, the major cytotoxic effects of PET-NPs and PVC-NPs at high concentrations may be to induce an increase in intracellular ROS, which in turn induces cellular damage and other toxic effects. Notably, our study suggested that PET-NPs and PVC-NPs may induce apoptosis in HepG2 cells through the mitochondrial apoptotic pathway. However, no relevant cytotoxicity, oxidative damage, and apoptotic toxic effects were detected in HepG2 cells with exposure to PS-NPs. Furthermore, the analysis of transcriptomics data suggested that PET-NPs and PVC-NPs could significantly inhibit the expression of DNA repair-related genes in the p53 signaling pathway. Compared to PS-NPs, the expression levels of lipid metabolism-related genes were down-regulated to a greater extent by PET-NPs and PVC-NPs. In conclusion, PET-NPs and PVC-NPs were able to induce higher cytotoxic effects than PS-NPs, in which the density and chemical structure of NPs of different polymer types may be the key factors causing the differences in toxicity., 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.)

Induction of pyroptosis can promote anti-PD-L1 therapeutic efficacy due to the release of pro-inflammatory cytokines, but current approaches can cause off target toxicity. Herein, a phthalocyanine-conjugated mesoporous silicate nanoparticle (PMSN) is designed for amplifying sonodynamic therapy (SDT) to augment oxidative stress and induce robust pyroptosis in tumors. The sub-10 nm diameter structure and c(RGDyC)-PEGylated modification enhance tumor targeting and renal clearance. The unique porous architecture of PMSN doubles ROS yield and enhances pyroptotic cell populations in tumors (25.0%) via a cavitation effect. PMSN-mediated SDT treatment efficiently reduces tumor mass and suppressed residual tumors in treated and distant sites by synergizing with PD-L1 blockade (85.93% and 77.09%, respectively). Furthermore, loading the chemotherapeutic, doxorubicin, into PMSN intensifies SDT-pyroptotic effects and increased efficacy. This is the first report of the use of SDT regimens to induce pyroptosis in liver cancer. This noninvasive and effective strategy has potential for clinical translation., (© 2023 Wiley-VCH GmbH.)

CaO 2 nanoparticles (CNPs) can produce toxic Ca 2+ and H 2 O 2 under acidic pH, which accounts for their intrinsic anticancer activity but at the same time raises safety concerns upon systemic exposure. Simultaneously realizing minimized Ca 2+ /H 2 O 2 production and enhanced anticancer activity poses a dilemma. Herein, we introduce a "crystallinity gradient-based selective etching" (CGSE) strategy, which is realized by creating a crystallinity gradient in a CNP formed by self-assembled nanocrystals. The nanocrystals distributed in the outer layer have a higher crystallinity and thus are chemically more robust than those distributed in the inner layer, which can be selectively etched. CGSE not only leads to CNPs with tailored single- and double-shell hollow structures and metal-doped compositions but more surprisingly enables significantly enhanced anticancer activity as well as tumor growth inhibition under limited Ca 2+ /H 2 O 2 production, which is attributed to an alkalinity-reinforced lysosome-dependent cell death pathway.

Bacterial infection is a critical factor in wound healing. Due to the abuse of antibiotics, some pathogenic bacteria have developed resistance. Thus, there is an urgent need to develop a non-antibiotic-dependent multifunctional wound dressing for the treatment of bacteria-infected wounds. In this work, a multifunctional AOCuT hydrogel embedded with CuS@TA-Fe nanoparticles (NPs) through Schiff base reaction between gelatin quaternary ammonium salt - gallic acid (O-Gel-Ga) and sodium dialdehyde alginate (ADA) along with electrostatic interactions with CuS@TA-Fe NPs is prepared. These composite hydrogels possess favorable injectability, rapid shape adaptation, electrical conductivity, photothermal antimicrobial activity, and biocompatibility. Additionally, the doped NPs not only impart fast self-healing properties and excellent adhesion performance to the hydrogels, but also provide excellent peroxide-like properties, enabling them to scavenge free radicals and exhibit anti-inflammatory and antioxidant capabilities via photothermal (PTT) and photodynamic (PDT) effects. In an S. aureus infected wound model, the composite hydrogel effectively reduces the expression level of wound inflammatory factors and accelerates collagen deposition, epithelial tissue, and vascular regeneration, thereby promoting wound healing. This safe and synergistic therapeutic system holds great promise for clinical applications in the treatment of infectious wounds., (© 2023 Wiley-VCH GmbH.)

Ulcerative colitis (UC) is a chronic inflammatory illness affecting the colon and rectum, with current treatment methods being unable to meet the clinical needs of ulcerative colitis patients. Although nanomedicines are recognized as promising anti-inflammatory medicines, their clinical application is limited by their high cost and unpredictable safety risks. This study reveals that two natural phytochemicals, berberine (BBR) and hesperetin (HST), self-assemble directly to form binary carrier-free multi-functional spherical nanoparticles (BBR-HST NPs) through noncovalent bonds involving electrostatic interactions, π-π stacking, and hydrogen bonding. Because of their synergistic anti-inflammatory activity, berberine-hesperetin nanoparticles (BBR-HST NPs) exhibit significantly better therapeutic effects on UC and inhibitory effects on inflammation than BBR and HST at the same dose by regulating the immune microenvironment and repairing the damaged intestinal barrier. Furthermore, BBR-HST NPs exhibit good biocompatibility and biosafety. Thus, this study proves the potential of novel natural anti-inflammatory nanoparticles as therapeutic agents for UC, which could promote the progress of drug development for UC and eventually benefit patients who suffering from it., (© 2023 Wiley-VCH GmbH.)

Tumor infarction therapy is a promising antitumor strategy with the advantages of taking a short therapy duration, less risk of resistance, and effectiveness against a wide range of tumor types. However, its clinical application is largely hindered by tumor recurrence in the surviving rim and the potential risk of thromboembolic events due to nonspecific vasculature targeting. Herein, a neovasculature-targeting synthetic high-density lipoprotein (sHDL) nanodisc loaded with pyropheophorbide-a and camptothecin (CPN) was fabricated for photoactivatable tumor infarction and synergistic chemotherapy. By manipulating the anisotropy in ligand modification of sHDL nanodiscs, CPN modified with neovaculature-targeting peptide on the planes (PCPN) shows up to 7-fold higher cellular uptake compared with that around the edge (ECPN). PCPN can efficiently bind to endothelial cells of tumor vessels, and upon laser irradiation, massive local thrombus can be induced by the photodynamic reaction to deprive nutrition supply. Meanwhile, CPT could be released in response to the tumor reductive environment, thus killing residual tumor cells in the surviving rim to inhibit recurrence. These findings not only offer a powerful approach of synergistic cancer therapy but also suggest the potential of plane-modified sHDL nanodiscs as a versatile drug delivery nanocarrier.

Cadmium pollution in farmland has become a global environmental problem, threatening ecological security and human health. Biochar is effective in remediation of soil pollution. However, high concentrations of biochar can inhibit plant growth, and low concentrations of biochar have limited mitigation effect on cadmium toxicity. Therefore, the combination of low-concentration biochar and other amendments is a promising approach to alleviate cadmium toxicity in plants and improve the safety of edible parts. In this study, muskmelon was selected as the research object, and different concentrations of α-Fe 2 O 3 nanoparticles were used alone or combined with biochar to explore the effects of different treatments on muskmelon plants in cadmium-contaminated soil. The results showed that the combined application of 250 mg/kg α-Fe 2 O 3 nanoparticles and biochar had a good effect on the repair of cadmium toxicity in muskmelon plants. Compared with cadmium treatment, its application increased plant height by 32.53%, cadmium transport factor from root to stem decreased by 32.95%, chlorophyll content of muskmelon plants increased by 14.27%, and cadmium content in muskmelon flesh decreased by 18.83%. Moreover, after plant harvest, soil available cadmium content in 250 mg/kg α-Fe 2 O 3 nanoparticles and biochar combined treatment decreased by 31.18% compared with cadmium treatment. The results of this study provide an effective reference for the composite application of different exogenous amendments and a feasible idea for soil heavy metal remediation and mitigation of cadmium pollution in farmland., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Numerous positive effects have been attributed to lutein, a lipophilic nutrient, including resisting ultraviolet radiation and protecting retinal pigment epithelial (RPE) cells against blue light damage. It also has preventive effects against cardiovascular disease and cancer. However, its use could be limited by its poor stability and low bioaccessibility in the human digestive system. An encapsulation delivery system was therefore developed to resolve these limitations. In this study, chitosan-modified lutein nanoliposomes (CS-LNLs), chitosan-EGCG covalently modified lutein nanoliposomes (C-CS-EGCG-LNLs), and chitosan-EGCG noncovalently modified lutein nanoliposomes (non-C-CS-EGCG-LNLs) were designed. The average particle size, ζ-potential, and retention of lutein during storage were measured to indicate the physicochemical stability of the modified lutein nanoliposomes. The bioaccessibility of modified lutein nanoliposomes was also investigated to demonstrate the availability of lutein in the human digestive system., Results: First, Fourier-transform infrared spectroscopy (FTIR) verified that covalent bonds between chitosan and EGCG were formed. Subsequently, ζ-potential results revealed that C-CS-EGCG-LNLs had a relatively stable structure in comparison with lutein nanoliposomes (LNLs). The retention rate of lutein in CS-LNLs, C-CS-EGCG-LNLs, and non-C-CS-EGCG-LNLs was improved, especially in C-CS-EGCG-LNLs (at around 70% of lutein in initial system). An in vitro digestion experiment illustrated that CS-LNLs, C-CS-EGCG-LNLs, and non-C-CS-EGCG-LNLs presented relatively higher bioaccessibility, especially in C-CS-EGCG-LNLs (at around 33% of luein in initial system), which increased 2.5 and 1.65 times in comparison with free lutein and LNLs, respectively., Conclusion: Overall, the results showed that C-CS-EGCG-LNLs presented greater physicochemical stability and bioaccessibility than LNLs, CS-LNLs, and non-C-CS-EGCG-LNLs. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Cuproptosis, a newly identified form of regulated cell death that is copper-dependent, offers great opportunities for exploring the use of copper-based nanomaterials inducing cuproptosis for cancer treatment. Here, a glucose oxidase (GOx)-engineered nonporous copper(I) 1,2,4-triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], for starvation-augmented cuproptosis and photodynamic synergistic therapy is developed. Importantly, the catalytic activity of GOx is shielded in the nonporous scaffold but can be "turned on" for efficient glucose depletion only upon glutathione (GSH) stimulation in cancer cells, thereby proceeding cancer starvation therapy. The depletion of glucose and GSH sensitizes cancer cells to the GOx@[Cu(tz)]-mediated cuproptosis, producing aggregation of lipoylated mitochondrial proteins, the target of copper-induced toxicity. The increased intracellular hydrogen peroxide (H 2 O 2 ) levels, due to the oxidation of glucose, activates the type I photodynamic therapy (PDT) efficacy of GOx@[Cu(tz)]. The in vivo experimental results indicate that GOx@[Cu(tz)] produces negligible systemic toxicity and inhibits tumor growth by 92.4% in athymic mice bearing 5637 bladder tumors. This is thought to be the first report of a cupreous nanomaterial capable of inducing cuproptosis and cuproptosis-based synergistic therapy in bladder cancer, which should invigorate studies pursuing rational design of efficacious cancer therapy strategies based on cuproptosis., (© 2022 Wiley-VCH GmbH.)

Molecular resonance can be strengthened by charge transfer, profiting chemical mechanism (CM)-related surface-enhanced Raman scattering (SERS). Herein a supramolecular assembly enabled SERS system is established by functionalizing para -sulfonatocalix[4]arene (pSC 4 ) onto Au 3 Cu nanocrystals (NCs). Due to the cooperation of Au and Cu, pSC 4 is directionally assembled on the surface of Au 3 Cu NCs via van der Waals force, enabling photoinduced and hydrogen bond-induced charge transfer, which remarkably enhances the Raman scattering of methylene blue (MB) captured by pSC 4 . In particular, for the C-N and C-C stretching of MB, the contributions of resonance Raman scattering increase up to 80%. In addition, the SERS system is able to display affinities of different host-guest interactions, and further employed to evaluate effects of drugs for Alzheimer's disease. In this work, charge transfer is realized by performing supramolecular assembly on the surface of plasmonic nanomaterials, providing an avenue to design CM-related and reporter-tunable SERS systems.

The combination of various therapeutic modalities has received considerable attention for improving antitumor performance. Herein, an innovative nanohybrid, namely CaO 2 @FePt-DOX@PDA@CM (CFDPM), was developed for synergistic chemotherapy/chemodynamic therapy/Ca 2+ overloading-mediated amplification of tumor oxidative stress and photothermal enhanced cancer therapy. Camouflage of the 4T1 cell membrane enabled CFDPM to escape the immune surveillance and accumulate in the tumor tissue. Ca 2+ , released from CaO 2 , could lead to mitochondrial dysfunction and facilitate the production of reactive oxygen species to amplify intracellular oxidative stress. Meanwhile, the increase of H 2 O 2 concentration could enhance the efficiency of the chemodynamic therapy (CDT). Moreover, the hypoxic condition could be alleviated remarkably, which is attributed to the sufficient O 2 supply by CaO 2 , resulting in the suppression of drug resistance and promotion of the chemotherapeutic effect. The nanohybrids involving Ca 2+ overloading/CDT/chemotherapy could synergistically amplify the tumor oxidative stresses and remarkably aggravate the death of cancer cells. Significantly, the excellent photothermal conversion performance of CFDPM could further promote the tumoricidal effect. The in vitro and in vivo studies revealed that CFDPM could effectively advance the therapeutic efficiency via the cooperation of various therapeutic modalities to optimize their individual virtue, which would open a valuable avenue for effective cancer treatment.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by inflammatory micro-environments in the joints. Indomethacin (IND), a conventional nonsteroidal anti-inflammatory drug (NSAID), has been used for the therapy of RA. However, the poor solubility and serious side effects of oral administration of IND significantly limit its efficacy. In this study, we have synthesized biomimetic IND-loaded Prussian blue (PB) nanoparticles (IND@PB@M@HA) with hyaluronic acid (HA) modification for increasing the solubility and targeting the ability of IND to the inflamed joints. The application of hybrid cell membranes on the NPs endowed immune escape of IND@PB@M@HA NPs, which accordingly extended the circulation time in the blood. In vitro assay demonstrated that the combination of nanomedicine and photothermal therapy produced a powerful anti-inflammatory effect by reducing the levels of inflammatory factors and cell viability of activated macrophages and NPs possessed obvious pH-responsiveness. In vivo assay demonstrated that the nanomedicine for synergistic photothermal therapy exhibited desirable pharmacodynamics and pharmacokinetic properties at ultra-low drug dosage in a rat model of adjuvant-induced arthritis, which was confirmed by inflammatory suppression, bone erosion remission, and negligible adverse effects. In summary, the proposed nanomedicine has the potential role for targeted anti-inflammatory therapy of RA.

Hypoxic tumor microenvironment and nonspecific accumulation of photosensitizers are two key factors that limit the efficacy of photodynamic therapy (PDT). Herein, a strategy of oxygen microbubbles (MBs) boosting photosensitizer micelles is developed to enhance PDT efficacy and inhibit tumor metastasis by self-assembling renal-clearable ultrasmall poly(ethylene glycol)-modified protoporphyrin IX micelles (PPM) and perfluoropentane (PFP)-doped oxygen microbubbles (OPMBs), followed by ultrasound imaging-guided OPMB destruction to realize the tumor-targeted delivery of PPM and oxygen in tumor. Doping PFP into oxygen MBs increases the production of MBs and stability of oxygen MBs, allowing for persistent circulation in blood. Following co-injection, destruction of OPMBs with ultrasound leads to ∼2.2-fold increase of tumor-specific PPM accumulation. Furthermore, the burst release of oxygen by MB destruction improves tumor oxygenation from 22 to 50%, which not only raises the production of singlet oxygen but also significantly reduces the expression of hypoxia-inducible factor-1 alpha and related genes, thus preventing angiogenesis and epithelial-mesenchymal transition. It is verified that this strategy effectively eradicates orthotopic breast cancer and inhibits lung metastasis. Furthermore, the survival rate of mice bearing orthotopic pancreatic tumor is significantly extended by such interventional PDT strategy. Therefore, the combination of ultrasmall PPM and OPMBs represents a simple but effective strategy in overcoming the limitations of PDT.

This work chemically modified short linear glucan (SLG) by introducing a surface carboxymethyl group to obtain carboxymethylated SLG (CMSLG), then prepared CMSLG-based ternary nanocomplex particles based on electrostatic interactions with sodium-caseinate (NaCas) and pectin. These nanocomplex particles are homogeneous, generally exhibiting sizes of <200 nm with spherical shape and negative surface charge. In addition, the results showed the increase in both the mass ratio of CMSLG and NaCas and the synthesis temperature can improve the colloidal stability of nanocomplex particles when they are exposed to simulated gastrointestinal fluids containing digestive enzymes. Moreover, nanocomplex particles have an exceptional capability to encapsulate curcumin, and this encapsulation efficiency increased as the mass ratios of CMSLG and NaCas were increased. The study also investigated the antioxidant activity and in vitro release properties of curcumin encapsulated by nanocomplex particles and found that CMSLG/NaCas/pectin had improved higher ABTS radical scavenging capacity and allowed for the controlled, sustained release of curcumin in simulated gastrointestinal fluid within 6 hours. Thus, this study provides new insights into the design of a CMSLG-based ternary nanocomplex and its use as a potential oral delivery system for lipophilic bioactive compounds. PRACTICAL APPLICATION: Curcumin, as a sort of natural polyphenolic compound, has many physiologic functions such as anti-oxidation, anticancer, and prevention of Alzheimer's disease. However, the application of the curcumin has been limited by its poor water solubility and unstable physicochemical property. To solve this problem, the nanotechnology has been used to prepare the nano-delivery carriers for curcumin. This work prepared a ternary nanoparticle based on the carboxymethyl short linear glucan, sodium-caseinate, and pectin. The ternary nanoparticle can achieve a higher encapsulation efficiency for curcumin. In addition, the ternary nanoparticle can enhance the ABTS radical scavenging capacity and provided control and sustained release of curcumin in the simulated gastrointestinal fluid., (© 2022 Institute of Food Technologists®.)

Objectives: The objective of this study was to develop a novel nanostructured resin infiltrant containing nanoparticles of amorphous calcium phosphate (NACP) to treat enamel white spot lesions (WSLs). Physical properties and the therapeutic effect of the new resin infiltrant were investigated for the first time., Methods: NACP was incorporated into ICON (Icon caries infiltrant, DMG, Germany) with different mass fractions. Cytotoxicity, degree of conversion, surface hardness, calcium (Ca) and phosphorus (P) ions release concentrations were tested. After application to the demineralized enamel samples, the color changes were determined. Surface and cross-sectional hardness were measured, scanning electron microscopy (SEM) images were taken on the cross-section of samples to observe microstructure changes after 14-day pH cycling., Results: Incorporating 10%-30% of NACP did not compromise the biocompatibility and physical properties of the resin infiltrant. ICON + 30% NACP group had long-lasting and high level of Ca and P ion release. After 14-day pH cycling, enamel surface hardness of ICON + 30% NACP group was 1.83 ± 0.21 GPa, significantly higher than the control group (1.32 ± 0.18 GPa) (p < 0.05). ICON + 30NACP group had the highest cross-sectional enamel hardness among all groups (p < 0.05), especially at 50 μm and 100 μm depth. SEM images showed that apparent enamel prism and inter-prism gaps in negative control were masked by mineral deposition in ICON + 30% NACP group., Significance: The novel ICON+30% NACP infiltrant is promising to inhibit enamel WSLs, protect the enamel and increase its hardness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Immunogenic cell death (ICD) is a promising strategy in cancer immunotherapy to induce high immunogenicity and activate the immune system. However, its efficacy is counteracted by the concurrent exposure of phosphatidylserine (PS), an immunosuppressive signal on the surface of cancer cells. Here we report the synthesis of a bimetallic metal-organic framework (MOF) nanoparticle containing Gd 3+ and Zn 2+ (Gd-MOF-5) that can be used as an immunomodulator to downregulate the immunosuppressive PS signal and an ICD inducer to upregulate immunostimulatory signals. Gd 3+ inhibits PS externalization via inhibiting the activity of scramblase, an enzyme to transfer PS to the outer leaflet of plasma membrane. Moreover, intracellular Zn 2+ overload activates endoplasmic reticulum stress for ICD induction. In combination with an immune checkpoint inhibitor (PD-L1 antibody, denoted as aPDL1), Gd-MOF-5 activated potent immune response and effectively inhibited primary and distal tumor growth in a bilateral 4T1 tumor model. This work presents a new strategy using designed MOF materials to modulate the cell signalling and immunosuppressive microenvironment to improve the outcome of cancer immunotherapy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nanomaterials that combine multimodality imaging and therapeutic functions within a single nanoplatform have drawn extensive attention for molecular medicines and biological applications. Herein, we report a theranostic nanoplatform based on a relatively smaller (<20 nm) iron oxide loaded porphyrin-grafted lipid nanoparticles (Fe 3 O 4 @PGL NPs). The amphiphilic PGL easily self-assembled on the hydrophobic exterior surface of ultrasmall Fe 3 O 4 NPs, resulting in a final ultrasmall Fe 3 O 4 @PGL NPs with diameter of ∼10 nm. The excellent self-assembling nature of the as-synthesized PGL NPs facilitated a higher loading of porphyrins, showed a negligible dark toxicity, and demonstrated an excellent photodynamic effect against HT-29 cancer cells in vitro . The in vivo experimental results further confirmed that Fe 3 O 4 @PGL NPs were ideally qualified for both the fluorescence and magnetic resonance (MR) imaging guided nanoplatforms to track the biodistribution and therapeutic responses of NPs as well as to simultaneously trigger the generation of highly cytotoxic reactive oxygen species (ROS) necessary for excellent photodynamic therapy (PDT). After recording convincing therapeutic responses, we further evaluated the ability of Fe 3 O 4 @PGL NPs/Fe 3 O 4 @Lipid NPs for ferroptosis therapy (FT) via tumor microenvironment (TME) modulation for improved anticancer activity. We hypothesized that tumor-associated macrophages (TAMs) could significantly improve the efficacy of FT by accelerating the Fenton reaction in vitro . In our results, the Fe ions released in vitro directly contributed to the Fenton reaction, whereas the presence of RAW 264.7 macrophages further accelerated the ROS generation as observed by the fluorescence imaging. The significant increase in the ROS during the coincubation of NPs, endocytosed by HT-29 cells and RAW264.7 cells, further induced increased cellular toxicity of cancer cells.

Ascorbic acid (AA) and glutathione (GSH), the most abundant intracellular reductive substances, have been widely used as biomarkers for cancer cells identification. The current methods relying on imaging of AA or GSH alone to identify cancer cells may cause systematic errors, since a mutual conversion relationship exists between AA and GSH. In this work, we propose a fluorescent nanosensor for the simultaneous imaging of intracellular reductive substances including AA and GSH. Biocompatible fluorescent silicon nanoparticles (SiNPs) with rich surface amine and carboxyl groups were synthesized. The fluorescence of the SiNP was initially quenched by chelation of Fe 3+ ions, forming SiNP/Fe 3+ complex as the fluorescent nanosensor. Upon the redox reaction with reductive substances, the nanosensor showed sensitively fluorescent recovery. Moreover, benefited from the efficient cellular uptake of the SiNP/Fe 3+ and the overexpressed intracellular reductive substances in cancer cells, the fluorescent nanosensor was used to accurately identify the human breast carcinoma (MCF-7) cells from normal mammary epithelial (MCF-10A) cells by imaging of intracellular AA and GSH simultaneously. This strategy would be promising in imaging-guided precision cancer diagnosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Nanomaterial-based on-off-on fluorescence sensing strategies are significant particularly in intracellular nucleic acids imaging assay. There still remains challenge to rationally balance fluorescence quenching efficiency and recovery dynamics. We assume that the performance of on-off-on fluorescence sensing strategy can be fundamentally improved on small zero-dimensional (0D) nanomaterial with precisely modulated surface charge. For a proof-of-concept demonstration, silicon nanoparticle (SiNP) with ~4 nm was synthesized and used as the quencher model, of which the surface charge density was modulated by modification of triphenylphosphonium (TPP). The influence of particle size, surface charge and charge density of the nanomaterials on sensing performance was systematically investigated. The strategy showed a low limit of detection (LOD) as 26 pM for target model miR-494, which is one of the lowest in nanomaterial-based on-off-on sensing platforms. And the LOD is even comparable to amplification-based methods in a greatly shortened assay time (2.5 h). The miR-494 expresses in cancerous and normal living cells of human cervical carcinoma (HeLa), human lung carcinoma (A549), human breast cancer (MCF-7), and normal human mammary epithelial (MCF-10A) cells were imaged and localized with significantly improved sensitivity and specificity. These excellent performances insure it a promising candidate as convenient and non-enzymatic sensing platform for miRNA-associated disease detection and early diagnosis., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The conventional anti-caries agents exhibit many shortcomings such as poor stability, low efficacy or short residence time in the oral environment, it is urgent to develop efficacy treatments to prevent dental caries. As the most active polyphenols from tea, Epigallocatechin gallate (EGCG) shows remarkable anti-cariogenic bioactivity. However, the poor stability and low bioavailability of EGCG limit its potential application. This study aimed to fabricate nanovesicles in-situ gel based on EGCG phospholipid complex in order to increase its stability and efficacy. The formation of EGCG phospholipid complex was characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The ethanol injection method was used to prepare the EGCG-loaded nanovesicles, an optimal ratio of Poloxamer407 (P407) and Poloxamer188 (P188) as in-situ gel matrix was selected to fabricate oral nanovesicles in-situ gel. EGCG-loaded nanovesicle in-situ gel based on the phospholipid complex had uniform spherical shape without any agglomeration. The discrete nanoparticle with a size (131.44 ± 4.24 nm) and a negative zeta potential value at -30.7 ± 0.5 mV possessed good physical stability and high entrapment efficiency (83.66 ± 3.2%). The formulation exhibited a strong antibacterial activity on S. mutans, which could reduce acid production and tooth surface adhesion. In addition, EGCG formulation could inhibit the formation of glucan and biofilm from S. mutans by suppressing the activity of glycosyltransferase enzymes (GTF). In conclusion, the EGCG-loaded nanovesicle in-situ gel holds great promise as an efficient anti-cariogenic formulation for topical oral delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

As a novel noninvasive therapeutic modality combining low-intensity ultrasound and sonosensitizers, sonodynamic therapy (SDT) is promising for clinical translation due to its high tissue-penetrating capability to treat deeper lesions intractable by photodynamic therapy (PDT), which suffers from the major limitation of low tissue penetration depth of light. The effectiveness and feasibility of SDT are regarded to rely on not only the development of stable and flexible SDT apparatus, but also the screening of sonosensitizers with good specificity and safety. To give an outlook of the development of SDT equipment, the key technologies are discussed according to five aspects including ultrasonic dose settings, sonosensitizer screening, tumor positioning, temperature monitoring, and reactive oxygen species (ROS) detection. In addition, some state-of-the-art SDT multifunctional equipment integrating diagnosis and treatment for accurate SDT are introduced. Further, an overview of the development of sonosensitizers is provided from small molecular sensitizers to nano/microenhanced sensitizers. Several types of nanomaterial-augmented SDT are in discussion, including porphyrin-based nanomaterials, porphyrin-like nanomaterials, inorganic nanomaterials, and organic-inorganic hybrid nanomaterials with different strategies to improve SDT therapeutic efficacy. There is no doubt that the rapid development and clinical translation of sonodynamic therapy will be promoted by advanced equipment, smart nanomaterial-based sonosensitizer, and multidisciplinary collaboration., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Purpose: Immunologically quiescent of breast cancer cells has been recognized as the key impediment for the breast cancer immunotherapy. In this study, we aimed to investigate the role of nanoparticle-mediated sonodynamic therapy (SDT) in promoting anti-tumor immune of breast cancer cells and its potential immune mechanisms., Materials and Methods: The phase-transformation nanoparticles (LIP-PFH nanoparticles) were in-house prepared and its physiochemical characters were detected. The CCK-8 assay, apoptosis analysis and Balb/c tumor model establishment were used to explore the anti-tumor effect of LIP-PFH nanoparticles triggered by low-intensity focused ultrasound (LIFU) both in vitro and in vivo. Flow cytometry and immunohistochemistry of CD4 + T, CD8 + T, CD8 + PD-1 + T in blood, spleen and tumor tissue were performed to represent the change of immune response. Detection of immunogenic cell death (ICD) markers was examined to study the potential mechanisms., Results: LIP-PFH nanoparticles triggered by LIFU could inhibit the proliferation and promote the apoptosis of 4T1 cells both in vitro and in vivo. CD4 + T and CD8 + T cell subsets were significantly increased in blood, spleen and tumor tissue, meanwhile CD8 + PD-1 + T cells were reduced, indicating enhancement of anti-tumor immune response of breast cancer cells in the nanoparticle-mediated SDT group. Detection of ICD markers (ATP, high-mobility group box B1, and calreticulin) and flow cytometric analysis of dendritic cell (DC) maturity further showed that the nanoparticle-mediated SDT can promote DC maturation to increase the proportion of cytotoxic T cells by inducing ICD of breast cancer cells., Conclusion: The therapy of nanoparticles-mediated SDT can effectively enhance anti-tumor immune response of breast cancer., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Si et al.)

Background: The present limitations related to the ocular administration of antifungal drugs for the treatment of fungal keratitis include poor ocular bioavailability, limited retention time, and low ocular tissue penetration., Methods: This study aimed to prepare a novel ophthalmic voriconazole-loaded nanosuspension based on Eudragit RS 100. Pharmasolve® was explored as a corneal permeation enhancer in voriconazole ophthalmic formulation using in vitro and in vivo experiments. Briefly, 1% voriconazole-loaded nanosuspension was prepared using the quasi-emulsion solvent evaporation process., Results: Characterizations of the voriconazole-loaded nanosuspension by Zetasizer Nano ZS and Transmission Electron Microscope (TEM) showed a uniform spherical shape without any agglomeration. The well-discreted nanoparticle with a size of 138 ± 1.3 nm was achieved with high entrapment efficiency (98.6 ± 2.5%) and positive zeta potential in the range of 22.5-31.2mV, indicating excellent physical stability., Discussion: Voriconazole-loaded nanosuspension containing the penetration enhancer displayed good permeability both in vitro and in vivo compared with the commercial voriconazole injection. The voriconazole-loaded nanosuspension exhibited good antifungal activity, significantly inhibiting the growth of Candida albicans at a lower concentration of voriconazole (2.5μg/mL, p < 0.05)., Conclusion: In conclusion, the voriconazole-loaded nanosuspension containing Pharmasolve® can be used as an effective ophthalmic formulation for the topical ocular delivery of voriconazole., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: In the field of antibacterial, nanomaterials are favored by researchers because of their unique advantages. Medicinal plants, especially traditional Chinese medicine, are considered to be an important source of new chemicals with potential therapeutic effects, as well as an important source for the discovery of new antibiotics. MRSA is endangering people's lives as a kind of multidrug-resistant Staphylococcus aureus, which is resistant to tetracycline, amoxicillin, norfloxacin and other first-line antibiotics. It is a hotspot to find good anti-drug-resistant bacteriae, nature-originated nanomaterials with good biocompatibility., Objective: We reported the formation of phytochemical nanoparticles (NPs) by the self-assembly of berberine (BBR) and 3,4,5-methoxycinnamic acid (3,4,5-TCA) from Chinese herb medicine, which had good antibacterial activity against MRSA., Methods and Results: We found that NPs had good antibacterial activity against MRSA; especially, its antibacterial activity was better than first-line amoxicillin, norfloxacin and its self-assembling precursors on MRSA. When the concentration reached 0.1 μmol/mL, the inhibition rate of NPs reached 94.62%, which was higher than that of BBR and the other two antibiotics (p < 0.001). It was observed by Field-Emission Scanning Electron Microscopy (FESEM) that NPs could directly adhere to the bacterial surface, which might be an important aspect of the antibacterial activity of NPs. Meanwhile, we further analyzed that the self-assembly was formed by hydrogen bonds and π-π stacking through Ultraviolet-Visible (UV-vis), Fourier Transform Infrared Spectroscopy (FTIR), hydrogen Nuclear Magnetic Spectrum (1H NMR), and powder X-ray Diffraction (pXRD). NPs' morphology was observed by FESEM and TEM. The particle size and surface charge were characterized by Dynamic Light Scattering (DLS); and the surface charge was -31.6 mv, which proved that the synthesized NPs were stable., Conclusion: We successfully constructed a naturally self-assembled nanoparticle, originating from traditional Chinese medicine, which had a good antibacterial activity for MRSA. It is a promising way to obtain natural nanoparticles from medicinal plants and apply them to antibacterial therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Multimodal imaging-guided synergistic anticancer strategies have attracted increasing attention for efficient diagnosis and therapy of cancer. Herein, a multifunctional nanotheranostic agent FePtMn-Ce6/FA (FPMCF NPs) is constructed by covalently anchoring photosensitizer chlorin e6 (Ce6) and targeting molecule folic acid (FA) on ultrasmall homogeneous ternary FePtMn nanocrystals. Response to tumor microenvironment (TME), FPMCF NPs can release Fe 2+ to catalyze H 2 O 2 into •OH by Fenton reaction and simultaneously catalyze hydrogen peroxide (H 2 O 2 ) into O 2 to overcome the tumor hypoxia barrier. Released O 2 is further catalyzed into 1 O 2 under 660 nm laser irradiation with Ce6. Thus, the FPMCF NPs exhibit superior dual-ROS oxidization capability including ferroptosis chemodynamic oxidization and 1 O 2 -based photodynamic oxidization. Interestingly, FPMCF NPs reveal strong photothermal conversion efficiency exposed to an 808 nm laser, which can assist dual-ROS oxidization to suppress solid tumor remarkably. Additionally, Mn 2+ can be released from FPMCF NPs to enhance longitudinal relaxivity (T 1 -weighted magnetic resonance (MR) imaging) and Fe-synergistic transverse relaxivity (T 2 -weighted MR imaging), which is convenient for diagnosis of solid tumors. Meanwhile, the fluorescent/photothermal (FL/PT) imaging function of FPMCF NPs can also accurately monitor tumor location. Therefore, FPMCF NPs with multimodal MR/FL/PT imaging-guided synergistic chemodynamic/photodynamic/photothermal cancer therapy capability have potential bioapplication in bionanomedicine field., (© 2020 Wiley-VCH GmbH.)

CRISPR-Cas9, the breakthrough genome-editing technology, has emerged as a promising tool to prevent and cure various diseases. The efficient genome editing technology strongly relies on the specific and effective delivery of CRISPR/Cas9 cargos. However, the lack of a safe, specific, and efficient non-viral delivery system for in vivo genome editing remains a major limit for its clinical translation. In this review, we will first briefly introduce the working mechanism of CRISPR/Cas9 and the patterns of CRISPR/Cas9 delivery. Furthermore, the physiological obstacles for the delivery process in vivo are elaborated. Finally, the key considerations will be deeply discussed in designing non-viral nanovectors for therapeutic CRISPR/Cas9 delivery in vivo, including the effective encapsulation of large-size macromolecules, targeting specific tissues and cells, efficient endosomal escape and safety concerns of the vector systems, in the hope of inviting more comprehensive studies on the development of safe, specific, and efficient non-viral nanovectors for delivering a CRISPR/Cas9 system.

Photodynamic therapy (PDT) shows great promise for the treatment of colon cancer. However, practically, it is a great challenge to use a nanocarrier for the codelivery of both the photosensitizer and oxygen to improve PDT against PDT-induced hypoxia, which is closely related to tumor metastasis. Hence, an effective strategy was proposed to develop an oxygen self-supplemented PDT nanocarrier based on the ultrasonic dispersion of perfluorooctyl bromide (PFOB) liquid into the preformed porphyrin grafted lipid (PGL) nanoparticles (NPs) with high porphyrin loading content of 38.5%, followed by entrapping oxygen. Interestingly, the orderly arranging mode of porphyrins and alkyl chains in PGL NPs not only guarantees a high efficacy of singlet oxygen generation but also reduces fluorescence loss of porphyrins to enable PGL NPs to be highly fluorescent. More importantly, PFOB liquid was stabilized inside PGL NPs with an ultrahigh loading content of 98.15% due to the strong hydrophobic interaction between PGL and PFOB molecules, facilitating efficient oxygen delivery. Both in vitro and in vivo results demonstrated that the obtained O 2 @PFOB@PGL NPs could act as a prominent oxygen reservoir and effectively replenish oxygen into the hypoxic tumors with no need for external stimulation, conducive to augmented singlet oxygen generation, hypoxia relief, and subsequent downregulation of COX-2 expression. As a result, the use of O 2 @PFOB@PGL NPs for hypoxia relief dramatically inhibits tumor growth and liver metastasis in an HT-29 colon cancer mouse model. In addition, the O 2 @PFOB@PGL NPs could serve as a bimodal contrast agent to enhance fluorescence and CT imaging, visualizing nanoparticle accumulation to guide the subsequent laser irradiation for precise PDT.

Introduction: Sonodynamic Therapy (SDT) has good targeting and non-invasive advantages in solid cancers, but its antitumor effect is not sufficient to replace traditional treatments. Some studies that combined SDT with chemotherapy or nanoparticles have managed to enhance its efficiency and overcome the side effects of chemotherapy., Materials and Methods: In this study, we synthesized and characterized mesoporous silica nanoparticles (MSN-DOX-Ce6) loaded with doxorubicin (DOX) and sonosensitizer, chlorin e6 (Ce6). Then, we conducted in vitro and in vivo experiments to explore the antitumor effect of MSN-DOX-Ce6 under ultrasound (US) treatment., Results: The characterization tests showed that the nanoparticles are uniformly sized spheres with mesoporous structure, resulting in a high drug-loading efficiency. In the in vitro experiments, MSN-DOX-Ce6 could effectively inhibit cell proliferation under US but not more than other treatment groups. However, the in vivo studies showed that MSN-DOX-Ce6+US has better antitumor effect than DOX+Ce6+US or DOX alone on xenograft tumor-bearing mice., Conclusion: In summary, MSNs showed a great potential for DOX and Ce6 delivery. We concluded that under US, MSN-DOX-Ce6 nanocomposites increase the antitumor effect of DOX and SDT and thereby are a potential treatment for solid tumors., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Xu et al.)

Breast cancer with HER2 overexpressing type links to malignant tumor growth and poor clinical outcome. Successful development of sensitive and selective nano-probe for identification of HER2-positive breast cancer cells is of great importance for breast cancer early diagnosis, subtype classification, and treatment planning. Herein, we report a HER2 antibody conjugated near infrared (NIR) emitted MnCuInS/ZnS qumtun dots (QDs) encapsulated bovine serum albumin (BSA) nano-probe for accurately targeted imaging of HER2-positive breast cancer cells. This NIR nano-probe shows good biocompatibility, low nonspecificity and cytotoxicity, high colloidal stability, and allows HER2-positive breast cancer cell identification with good selectivity. The practicality of this targeted NIR fluorescent nano-probe was proved by successful identifying HER2-positive breast cancer cells from HER2-negative breast cancer cells, which indicates that it can be efficiently applied in selective screening of HER2 overexpressing cancer cells, and provide a platform for the strategy design on the distinction of different breast cancer subtypes., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Despite rapid advancements in antitumor drug delivery, insufficient intracellular transport and subcellular drug accumulation are still issues to be addressed. Cancer cell membrane (CCM)-camouflaged nanoparticles (NPs) have shown promising potential in tumor therapy due to their immune escape and homotypic binding capacities. However, their efficacy is still limited due to inefficient tumor penetration and compromised intracellular transportation. Herein, a yolk-shell NP with a mesoporous silica nanoparticle (MSN)-supported PEGylated liposome yolk and CCM coating, CCM@LM, was developed for chemotherapy and exhibited a homologous tumor-targeting effect. The yolk-shell structure endowed CCM@LM with moderate rigidity, which might contribute to the frequent transformation into an ellipsoidal shape during infiltration, leading to facilitated penetration throughout multicellular spheroids in vitro (up to a 23.3-fold increase compared to the penetration of membrane vesicles). CCM@LM also exhibited a cellular invasion profile mimicking an enveloped virus invasion profile. CCM@LM was directly internalized by membrane fusion, and the PEGylated yolk (LM) was subsequently released into the cytosol, indicating the execution of an internalization pathway similar to that of an enveloped virus. The incoming PEGylated LM further underwent efficient trafficking throughout the cytoskeletal filament network, leading to enhanced perinuclear aggregation. Ultimately, CCM@LM, which co-encapsulated low-dose doxorubicin and the poly(ADP-ribose) polymerase inhibitor, mefuparib hydrochloride, exhibited a significantly stronger antitumor effect than the first-line chemotherapeutic drug Doxil. Our findings highlight that NPs that can undergo facilitated tumor penetration and robust intracellular trafficking have a promising future in cancer chemotherapy.

Because of the high mortality of coronary atherosclerotic heart diseases, it is necessary to develop novel early detection methods for vulnerable atherosclerotic plaques. Phenotype transformation of vascular smooth muscle cells (VSMCs) plays a vital role in progressed atherosclerotic plaques. Osteopontin (OPN) is one of the biomarkers for phenotypic conversion of VSMCs. Significant higher OPN expression is found in foam cells along with the aggravating capacity of macrophage recruitment due to its arginine-glycine-aspartate sequence and interaction with CD44. Herein, a dual-modality imaging probe, OPN targeted nanoparticles (Cy5.5-anti-OPN-PEG-PLA-PFOB, denoted as COP-NPs), is constructed to identify the molecular characteristics of high-risk atherosclerosis by ultrasound and optical imaging. Characterization, biocompatibility, good binding sensibility, and specificity are evaluated in vitro. For in vivo study, apolipoprotein E deficien (ApoE -/- ) mice fed with high fat diet for 20-24 weeks are used as atherosclerotic model. Ultrasound and optical imaging reveal that the nanoparticles are accumulated in the vulnerable atherosclerotic plaques. OPN targeted nanoparticles are demonstrated to be a good contrast agent in molecular imaging of synthetic VSMCs and foam cells, which can be a promising tool to identify the vulnerable atherosclerotic plaques., (© 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cell membrane-coated nanocarriers have been developed for drug delivery due to their enhanced blood circulation and tissue targeting capacities; however, previous works have generally focused on spherical nanoparticles and extracellular barriers. Many living organisms with different shapes, such as rod-shaped bacilli and rhabdovirus, display different functionalities regarding tissue penetration, cellular uptake, and intracellular distribution. Herein, we developed cancer cell membrane (CCM)-coated nanoparticles with spherical and rod shapes. CCM-coated nanorods (CRs) showed superior endocytosis efficiency compared with their spherical counterparts (CCM-coated nanospheres, CSs) due to the caveolin-mediated pathway. Moreover, CRs can effectively accumulate in the endoplasmic reticulum (ER) region and ship the loaded DOX to the nucleus at a considerable concentration, resulting in ER stress and subsequent apoptosis. After intravenous injection into human pancreatic adenocarcinoma cell (BxPC-3) and pancreatic stellate cell (HPSC) hybrid tumor-bearing nude mice, CRs exhibited improved immune escape ability, rapid extracellular matrix (ECM) penetration (8.2-fold higher than CSs), and enhanced tumor accumulation, further contributing to the enhanced antitumor efficacy. These findings may actually suggest the significance of shape design in improving current cell membrane-based drug delivery systems for effective subcellular targets and tumor therapy.

Sorafenib (SOR) is a multi-kinase inhibitor that was approved as the first-line systematic treatment agent of hepatocellular carcinoma (HCC). However, the anti-cancerous effect of SOR is dramatically impaired by the drug resistance, insufficient accumulation at tumor tissues, and limited tumor inner penetration. To combat the above issues, the PLA-based nanoparticles were first fabricated and co-loaded with SOR and plantamajoside (PMS), natural herbal medicines that possess excellent anti-cancerous effect on many types of drug resistant cancers. Then, the polypeptide CT, which is tumor-homing and cell membrane penetrable, was further decorated on the dual-agents loaded nanoparticles (CTNP-PMS/SOR) to enhance tumor accumulation of drugs. Importantly, the CT peptide is a conjugate derived from the covalent conjugation of CVNHPAFAC peptide, a tumor-homing peptide, on the fourth lysine of TAT, namely cell membrane penetrating peptide, through a pH-sensitive hydrazone bond. By this way, the cell penetrating ability of TAT was dramatically sealed under the normal condition and immediately recovered once the nanoparticles reached tumor sites. Both in vivo and in vitro experiments demonstrated that the anti-cancerous effect of SOR on malignant HCC was significantly enhanced after co-loaded with PMS. Mechanisms studies revealed that the PMS is capable of reprograming the tumor hypoxic microenvironment, which represents the main cause of drug-resistance of tumor cells. Besides, functionalization of the NP-PMS/SOR with CT peptides signally improved the accumulation of drugs at tumor sites and penetration of agents into tumor cells, which in turn resulted in stronger capacity of tumor growth inhibition.

Reactive oxygen species (ROS)-based anticancer therapy methods were heavily dependent on specific tumor microenvironments such as acidity and excess hydrogen peroxide (H 2 O 2 ). In this work, an acidity-sensitive nanotheranostic agent (FePt@MnO)@DSPE-PEG5000-FA (FMDF NPs)  was successfully constructed for MR imaging guided ferroptosis chemodynamic therapy (FCDT) of cancer. The FMDF NPs could specifically target folic acid (FA) receptor-positive tumor cells (HeLa etc.) and induce ferroptosis efficiently by rapidly releasing active Fe 2+ to catalyze intracellular H 2 O 2 into ROS based on Fenton reaction. On the other hand, the Mn 2+ could also be released due to acidity  and further coordinate with GSH to enhance the longitudinal-transverse relaxivity (T 1 /T 2 -weighted MR imaging), which could obviously strengthen the contrast distinction between solid tumors and the surrounding tissue to accurately real-time monitor the tumor location. Furthermore, the in vivo anticancer study revealed that the growth of solid tumor models could be suppressed remarkably after treating with FMDF NPs and no obvious damage to other major organs. Therefore, the FMDF NPs were competent simultaneously as an enhanced imaging diagnosis contrast agent and efficient therapy agent for promoting more precise and effective treatment in the bionanomedicine field.

Small unilamellar vesicles (SUVs), ubiquitous in organisms, play key and active roles in various biological processes. Although the physical properties of the constituent lipid molecules ( i.e. , the acyl chain length and saturation) are known to affect the mechanical properties of SUVs and consequently regulate their biological behaviors and functions, the underlying mechanism remains elusive. Here, we combined theoretical modeling and experimental investigation to probe the mechanical behaviors of SUVs with different lipid compositions. The membrane bending rigidity of SUVs increased with increasing chain length and saturation, resulting in differences in the vesicle rigidity and deformable capacity. Furthermore, we tested the tumor delivery capacity of liposomes with low, intermediate, and high rigidity as typical models for SUVs. Interestingly, liposomes with intermediate rigidity exhibited better tumor extracellular matrix diffusion and multicellular spheroid (MCS) penetration and retention than that of their stiffer or softer counterparts, contributing to improved tumor suppression. Stiff SUVs had superior cellular internalization capacity but intermediate tumor delivery efficacy. Stimulated emission depletion microscopy directly showed that the optimal formulation was able to transform to a rod-like shape in MCSs, which stimulated fast transport in tumor tissues. In contrast, stiff liposomes hardly deformed, whereas soft liposomes changed their shape irregularly, which slowed their MCS penetration. Our findings introduce special perspectives from which to map the detailed mechanical properties of SUVs with different compositions, provide clues for understanding the biological functions of SUVs, and suggest that liposome mechanics may be a design parameter for enhancing drug delivery.

Transition-metal nanomaterials are very important to non-enzymatic glucose sensing because of their excellent electrocatalytic ability, good selectivity, the fact that they are not easily interfered with by chloride ion (Cl - ), and low cost. However, the linear detection range needs to be expanded. In this paper, Cu 2 O-bovine serum albumin (BSA) core-shell nanoparticles (NPs) were synthesized for the first time in air at room temperature by a facile and green route. The structure and morphology of Cu 2 O-BSA NPs were characterized. The as-prepared Cu 2 O-BSA NPs were used to modify the glassy carbon electrode (GCE) in a Nafion matrix. By using cyclic voltammetry (CV), the influence from scanning speed, concentration of NaOH, and load of Cu 2 O-BSA NPs for the modified electrodes was probed. Cu 2 O-BSA NPs showed direct electrocatalytic activity for the oxidation of glucose in 50 mM NaOH solution at 0.6 V. The chronoamperometry result showed this constructing sensor in the detection of glucose with a lowest detection limit of 0.4 μM, a linear detection range up to 10 mM, a high sensitivity of 1144.81 μAmM -1 cm -2 and reliable anti-interference property to Cl - , uric acid (UA), ascorbic acid (AA), and acetaminophen (AP). Cu 2 O-BSA NPs are promising nanostructures for the fabrication of non-enzymatic glucose electrochemical sensing devices.

Iron fertilizers are worthy to be studied due to alleviate the Fe deficiency. Different forms of iron oxide nanoparticles are selected to better understand possible particle applications as an Fe source for crop plants. In this study, we assessed the different effects of γ-Fe 2 O 3 and Fe 3 O 4 NPs on the physiology and fruit quality of muskmelon plants in a pot experiment for five weeks. Results showed that no increased iron content was found under NPs treatment in root, stem, leaf and fruit, except 400 mg/L Fe 3 O 4 NPs had a higher iron content in muskmelon root. With the extension of NPs exposure, both γ-Fe 2 O 3 and Fe 3 O 4 NPs began to promote plant growth. In addition, γ-Fe 2 O 3 and Fe 3 O 4 NPs could increase chlorophyll content at a certain stage of exposure. Happily, 200 mg/L γ-Fe 2 O 3 NPs and 100, 200 mg/L Fe 3 O 4 NPs significantly increased fruit weight of muskmelon by 9.1%, 9.4% and 11.5%. It is noteworthy that both γ-Fe 2 O 3 and Fe 3 O 4 NPs caused positive effects on VC content, particularly 100 mg/L Fe 3 O 4 NPs increased the VC content by 46.95%. To the best of our knowledge, little research has been done on the effect of nanoparticles on the whole physiological cycle and fruit quality of melon. The assessment of physiology and fruit quality of muskmelon plants in vitro upon γ-Fe 2 O 3 and Fe 3 O 4 NPs exposure could lay a foundation for NPs potential impact at every growth period of muskmelon plants., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Inflammation is an immunological response involved in various inflammatory disorders ranging from neurodegenerative diseases to cancers. Luminol has been reported to detect myeloperoxidase (MPO) activity in an inflamed area through a light-emitting reaction. However, this method is limited by low tissue penetration and poor spatial resolution. Here, we fabricated a nanobubble (NB) doped with two tandem lipophilic dyes, red-shifting luminol-emitted blue light to near-infrared region through a process integrating bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET). This BRET-FRET process caused a 24-fold increase in detectable luminescence emission over luminol alone in an inflammation model induced by lipopolysaccharide. In addition, the echogenicity of the BRET-FRET NBs also enables perfused tissue microvasculature to be delineated by contrast-enhanced ultrasound imaging with high spatial resolution. Compared with commercially available ultrasound contrast agent, the BRET-FRET NBs exhibited comparable contrast-enhancing capability but much smaller size and higher concentration. This bioluminescence/ultrasound dual-modal contrast agent was then successfully applied for imaging of an animal model of breast cancer. Furthermore, biosafety experiments revealed that multi-injection of luminol and NBs did not induce any observable abnormality. By integrating the advantages of bioluminescence imaging and ultrasound imaging, this BRET-FRET system may have the potential to address a critical need of inflammation imaging.

The nonradiative conversion of light energy into heat (photothermal therapy, PTT) or sound energy (photoacoustic imaging, PAI) has been intensively investigated for the treatment and diagnosis of cancer, respectively. By taking advantage of nanocarriers, both imaging and therapeutic functions together with enhanced tumour accumulation have been thoroughly studied to improve the pre-clinical efficiency of PAI and PTT. In this review, we first summarize the development of inorganic and organic nano photothermal transduction agents (PTAs) and strategies for improving the PTT outcomes, including applying appropriate laser dosage, guiding the treatment via imaging techniques, developing PTAs with absorption in the second NIR window, increasing photothermal conversion efficiency (PCE), and also increasing the accumulation of PTAs in tumours. Second, we introduce the advantages of combining PTT with other therapies in cancer treatment. Third, the emerging applications of PAI in cancer-related research are exemplified. Finally, the perspectives and challenges of PTT and PAI for combating cancer, especially regarding their clinical translation, are discussed. We believe that PTT and PAI having noteworthy features would become promising next-generation non-invasive cancer theranostic techniques and improve our ability to combat cancers.

Lipid nanovesicles are widely present as transport vehicles in living organisms and can serve as efficient drug delivery vectors. It is known that the size and surface charge of nanovesicles can affect their diffusion behaviors in biological hydrogels such as mucus. However, how temperature effects, including those of both ambient temperature and phase transition temperature ( T m ), influence vehicle transport across various biological barriers outside and inside the cell remains unclear. Here, we utilize a series of liposomes with different T m as typical models of nanovesicles to examine their diffusion behavior in vitro in biological hydrogels. We observe that the liposomes gain optimal diffusivity when their T m is around the ambient temperature, which signals a drastic change in the nanovesicle rigidity, and that liposomes with T m around body temperature (i.e., ∼37 °C) exhibit enhanced cellular uptake in mucus-secreting epithelium and show significant improvement in oral insulin delivery efficacy in diabetic rats compared with those with higher or lower T m Molecular-dynamics (MD) simulations and superresolution microscopy reveal a temperature- and rigidity-mediated rapid transport mechanism in which the liposomes frequently deform into an ellipsoidal shape near the phase transition temperature during diffusion in biological hydrogels. These findings enhance our understanding of the effect of temperature and rigidity on extracellular and intracellular functions of nanovesicles such as endosomes, exosomes, and argosomes, and suggest that matching T m to ambient temperature could be a feasible way to design highly efficient nanovesicle-based drug delivery vectors., Competing Interests: The authors declare no conflict of interest.

Microplastic polystyrene foam has been found widely in the environment and is readily transported by wind or water. Beached and virgin foams of size 0.45-1 mm were prepared as sorbents to study oxytetracycline sorption. Enhanced adsorption were found in the beached foams compared to the virgin foams, corresponding to the higher specific surface area, micropore area and the degree of oxidation of the former. The Freundlich K f value was 894 ± 84 ((mg kg -1 ) (mg L -1 ) 1/n ) for oxytetracycline adsorption on the beached foams, approximately twice as high as on the virgin foams. Effects of solution pH on adsorption to the beached foams were more pronounced to the virgin foams. Maximum adsorption occurred at pH 5 at which electrostatic repulsion between the microplastic surface and the oxytetracycline zwitterion was minimal, indicating that electrostatic interaction may have regulated adsorption. Moreover, H-bonding and multivalent cationic bridging mechanisms may also have affected the adsorption of oxytetracycline to the beached foams as reflected by the ionic effects. Adsorption was promoted more in the presence of humic acid than of fulvic acid, perhaps owing to π-π conjugation between the humic acid and the microplastic surface which led to enhanced electrostatic attraction for oxytetracycline. This study suggests that weathered polystyrene foams may act as carriers of antibiotics in the environment and their potential risks to ecosystem and human health merit further investigation., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The application of nanotechnology in the treatment of tumors has boomed owing to the vigorous development in cancer nanomedicine. Despite the great success achieved in this field, nanomedicine has not realized its full potential owing to a delivery barrier, the mononuclear phagocytic system (MPS), which cuts off more than 95 % of the administrated nanoparticles. This results in an extremely low drug-delivery efficacy to the tumor and leads to poor therapeutic outcomes. Moreover, the injection of excess nanoparticles also raises toxicity concerns induced by the accumulation of nanomaterials in organs, such as the liver and spleen. Therefore, a reduction in the uptake of nanomedicines by the MPS is vital to enhance the cancer therapeutic effect and decrease side effects. In this critical review, we will summarize the new strategies to reduce nanoparticle uptake by the MPS based on current knowledge of the bio-nano interaction. Further directions will also be highlighted for the development of cancer nanomedicine with a lower off-target rate and better therapeutic outcomes., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Raman scattering provides key information of the biological environment through light-molecule interaction; yet, it is generally very weak to detect. Surface-enhanced Raman scattering (SERS) can boost the Raman signal by several orders-of-magnitude, and thus is highly attractive for biochemical sensing. However, conventional super-resolution imaging of SERS is challenging as the Raman signal is generated from the virtual state which cannot be easily modulated as fluorescence. Here, we demonstrate super-resolution microscopy with a surface-enhanced Raman scattering (SERS) signal, with a resolution of approximately 50 nm. By modulating the polarization angle of the excitation laser, the SERS nanorods display a dramatic anisotropy effect, allowing nanoscale orientation determination of multiple dipoles with dense concentration. Furthermore, a well-established defocused analysis was performed to reconfirm the orientation accuracy of super-resolved SERS nanorods. Sub-diffraction resolution was achieved in the imaging of SERS nanorod labeled vesicles in fixed macrophages. Finally, we demonstrate dynamic SERS nanorod tracking in living macrophages, which provides not only the particle trajectory with high spatial resolution but also the rotational changes at the nanometer scale. This pioneering study paves a new way for subcellular super-resolution imaging with the SERS effect, shedding light on wider biological applications.

Objective: To evaluate the internal fixation effect of nano-calcium-deficient hydroxyapatite/poly-amino acid (n-CDHA/PAA) composite screws in the intraarticular fracture model., Materials and Methods: A total of 35 New Zealand White rabbits were used in a bilateral femoral intercondylar fracture model and randomly divided into two groups. n-CDHA/PAA screws were used in the experimental group, and medical metal screws were used in the control group. The fracture condition, range of motion, and the screw push-out strength were assessed, and an arthroscopic examination of knee joint was performed at 4, 8, and 12 weeks after surgery. The biodegradation of the n-CDHA/PAA screws in vivo was tested through weighing, and changes in screw structure were assessed by X-ray diffraction at 12 weeks after surgery., Results: The general situation of all animals was good and showed no incision infection and dehiscence after surgery. X-ray scanning showed that significant callus growth was present in both groups at 4 weeks after surgery, and there was no significant difference ( P >0.05) in the Lane-Sandhu score between the experimental and control groups at all time points after surgery. There were no statistically significant differences ( P >0.05) in the range of motion and Oswestry Arthroscopy Score of arthroscopic examination of the knee joints between the two groups. The screw push-out strength of the control group was stronger than that of the experimental group at 4 weeks after surgery ( P <0.05), but after that, there was no significant difference between the groups ( P >0.05). The degradation tests showed that the n-CDHA/PAA screws degraded gradually after implantation, and the weight loss rate was approximately 16% at 12 weeks after surgery. The X-ray diffraction results showed that the crystal structure of the outer surface of the n-CDHA/PAA screw has changed at 12 weeks after surgery., Conclusion: The n-CDHA/PAA screw is an effective and safe implant as a potential internal fixation device for an intercondylar fracture of the femur, and its internal fixation effect was similar to that of medical metal screw., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Ferroptosis as an emerging mechanism has become a research hotspot for killing cancer cells. In this work, a novel ferroptosis agent, FePt-PTTA-Eu3+-FA (FPEF), was rationally designed by harnessing the luminescent lanthanide complexes PTTA-Eu3+ and folic acid (FA) in FePt nanoparticles. FePt-Based nanomaterials have potential applications in magnetic resonance imaging/computed tomography (MRI/CT) in clinical diagnosis and have excellent capacity to induce cancer cell death. Mechanistic studies of FPEP showed that the FePt induced cancer cell death was affirmed as the ferroptosis mechanism. To the best of our knowledge, it will be the first report that proves the existence of the ferroptosis process in FePt NPs. The in vitro tests of FPEF demonstrated that the as-prepared NPs exhibit a satisfactory anticancer effect towards FA-positive tumor cells including 4T1, MCF-7 and HeLa cells. The in vivo studies using tumor-bearing balb/c mice revealed that the FPEF NPs could significantly inhibit tumor progression. Such all-in-one therapeutic strategies have great potential in early diagnosis, prognosis and treatment of cancer.

Multidrug resistance remains one of the main obstacles to efficient chemotherapy of colorectal cancer. Herein, an efficient combination therapeutic strategy is proposed based on porphyrin/camptothecin-floxuridine triad microbubbles (PCF-MBs) with high drug loading contents, which own highly stable co-delivery drug combinations and no premature release. The triad PCF-MBs can act not only as a contrast agent for ultrasound (US)/fluorescence bimodal imaging but also a multimodal therapeutic agent for synergistic chemo-photodynamic combination therapy. Upon local ultrasound exposure under the guidance of ultrasound imaging, in situ conversion of PCF-MBs into porphyrin/camptothecin-floxuridine nanoparticles (PCF-NPs) leads to high accumulation of chemo-drugs and photosensitizer in tumors due to the induced high permeability of the capillary wall and cell membrane temporarily via sonoporation effect, greatly reducing the risk of systemic exposure. Most importantly, it was found that the PCF-MB-mediated photodynamic therapy could significantly reduce the expression of adenosine-triphosphate (ATP)-binding cassette subfamily G member 2 (ABCG 2 ), which is responsible for the drug resistance in chemotherapy, resulting in a prominent intracellular camptothecin increase. In vivo experiments revealed that the PCF-MBs in combination with ultrasound and laser irradiation could achieve a 90% tumor inhibition rate of HT-29 cancer with no recurrence. Therefore, such triad PCF-MB-based combination therapeutic strategy shows great promise for overcoming drug resistance of colorectal cancer and other cancers.

A dual-modal fluorescence-magnetic resonance imaging technique has gained tremendous attention for its potential in the dawning era of early diagnosis of tumors with high accuracy. In this study, a facile approach has been developed to prepare a tumor-targetable nanoprobe, PTTA-Eu3+-CoFeO-FA nanoparticles, for dual-modal time-gated luminescence (TGL)-magnetic resonance (MR) imaging of tumor cells in vitro and in vivo. The multifunctional nanoprobe was constructed by coating a tumor-targeting molecule, folic acid (FA), and a luminescent Eu3+ complex, PTTA-Eu3+, onto the surface of cobalt/iron oxide (CoFeO) nanoparticles. The as-prepared PTTA-Eu3+-CoFeO-FA nanoparticles are well dispersed in water with good biocompatibility, strong long-lived luminescence as well as pronounced transverse relaxivity. The in vitro study reveals that the nanoprobe works well as an effective luminescent probe to achieve the targeted TGL imaging of RAW 264.7 cells without the interference of background fluorescence, and the results of in vivo dual-modal TGL-MR imaging indicate that the fabricated nanoprobe can be preferentially accumulated in the tumor to effectively enhance the signals of T2-weighted MR imaging and TGL imaging. The research achievements will contribute to the development of new dual-modal fluorescence-MR nanoprobes for application in clinical diagnosis and therapy of tumors.