Osteoinductivity enhancement by tailoring the surface chemical bond status: A strategy to mobilize host bone growth factors for in situ bone regeneration.

The incorporation of growth factors and biomaterials is a promising strategy for improving osseointegration. However, current strategies to develop biomaterials with exogenous growth factors present disadvantages like inefficiency, difficult deployment, and potential off-target activation, making their translation into clinical practice challenging. This study reveals a bioactive N-doped tantalum carbide (TaC) solid solution film that can be used to construct a TaCN film via bionic interface engineering to recruit host bone growth factors to the wounded site and improve bone regeneration. X-ray photoelectron spectroscopy (XPS) and protein absorption analysis reveal that the performance of TaCN is related to the surface chemical bonds of films. The introduction of N to TaC causes a cascade effect wherein negative charges enrich on the TaCN surface, and the recruitment of positively charged bone growth factors around the TaCN film is facilitated. Under these circumstances, the endogenous bone growth factors enhance bone healing. The TaCN film shows an outstanding performance for in vivo osteogenic differentiation along with a superior in vitro cytocompatibility. Incorporation of N atoms into TaC provides a new clinically translatable strategy to mobilize host bone growth factors for in situ bone regeneration without the need for incorporation of exogenous growth factors.

Effect of pH on the surface charges of permanently/variably charged soils and clay minerals.

Traditionally, the surface charge number (SCN) of permanently charged soils/clay minerals is believed to be unaffected by environmental pH. However, recent studies have revealed the occurrence of polarization-induced covalent bonding between H+ and the surface O atoms of permanently charged clay minerals. This discovery challenges the traditional notions of "permanently charged soil" and "permanently charged clay mineral". The purpose of this study is to confirm that there are no true "permanently charged clay" or "permanently charged soil". In this study, the SCNs of two permanently charged clay minerals, two variably charged clay minerals, five permanently charged soils (temperate soils), and four variably charged soils (tropical or subtropical soils) were measured at different pH values using the universal determination method of SCN. The results showed that: (1) The SCNs of the permanently/variably charged soils and clay minerals decreased significantly with decreasing pH; (2) the SCN of montmorillonite decreased less with decreasing pH than the SCNs of variably charged minerals, whereas the SCN of illite decreased to nearly the same extent, indicating strong polarization-induced covalent bonding between H+ and the surface O atoms of illite; (3) the SCNs of permanently charged soils decreased to a similar extent as those of variably charged soils with decreasing pH. This study demonstrated that the concepts, "permanently charged clay mineral" or "permanently charged soil", are questionable because of the polarization-induced covalent bonding between H+ and the surface O atoms of clay minerals.

Stick, Slide, or Bounce: Charge Density Controls Nanoparticle Diffusion.

The diffusion and interaction dynamics of charged nanoparticles (NPs) within charged polymer networks are crucial for understanding various biological and biomedical applications. Using a combination of coarse-grained molecular dynamics simulations and experimental diffusion studies, we investigate the effects of the NP size, relative surface charge density (ζ), and concentration on the NP permeation length and time. We propose a scaling law for the relative diffusion of NPs with respect to concentration and ζ, highlighting how these factors influence the NP movement within the network. The analyses reveal that concentration and ζ significantly affect NP permeation length and time, with ζ being critical, as critical as concentration. This finding is corroborated by controlled release experiments. Further, we categorize NP dynamics into sticking, sliding, and bouncing regimes, demonstrating how variations in ζ, concentration, and NP size control these behaviors. Through normalized attachment time (NAT) analyses, we elucidate the roles of electrostatic interactions, steric hindrance, and hydrodynamic forces in governing NP dynamics. These insights provide guidance for optimizing NP design in targeted drug delivery and advanced material applications, enhancing our understanding of NP behavior in complex environments.

Role of size, surface charge, and PEGylated lipids of lipid nanoparticles (LNPs) on intramuscular delivery of mRNA.

Lipid nanoparticles (LNPs) are currently the most commonly used non-viral gene delivery system. Their physiochemical attributes, encompassing size, charge and surface modifications, significantly affect their behaviors both in vivo and in vitro. Nevertheless, the effects of these properties on the transfection and distribution of LNPs after intramuscular injection remain elusive. In this study, LNPs with varying sizes, lipid-based charges and PEGylated lipids were formulated to study their transfection and in vivo distribution. Luciferase mRNA (mLuc) was entraped in LNPs as a model nucleic acid molecule. Results indicated that smaller-sized LNPs and those with neutral potential presented superior transfection efficiency after intramuscular injection. Surprisingly, the sizes and charges did not exert a notable influence on the in vivo distribution of the LNPs. Furthermore, PEGylated lipids with shorter acyl chains contributed to enhanced transfection efficiency due to their superior cellular uptake and lysosomal escape capabilities. Notably, the mechanisms underlying cellular uptake differed among LNPs containing various types of PEGylated lipids, which was primarily attributed to the length of their acyl chain. Together, these insights underscore the pivotal role of nanoparticle characteristics and PEGylated lipids in the intramuscular route. This study not only fills crucial knowledge gaps but also provides significant directions for the effective delivery of mRNA via LNPs.

Combined Liposome-Gold Nanoparticles from Honey: The Catalytic Effect of Cassyopea® Gold on the Thermal Isomerization of a Resonance-Activated Azobenzene.

Gold nanoparticles (AuNPs) have been synthesized directly inside liposomes using honey as a reducing agent. The obtained aggregates, named Cassyopea® Gold due to the method used for their preparation, show remarkable properties as reactors and carriers of the investigated AuNPs. A mean size of about 150 nm and negative surface charge of -46 mV were measured for Cassyopea® Gold through dynamic light scattering and zeta potential measurements, respectively. The formation of the investigated gold nanoparticles into Cassyopea® liposomes was spectroscopically confirmed by the presence of their typical absorption band at 516 nm. The catalytic activity of the combined liposome-AuNP nanocomposites was tested via the thermal cis-trans isomerization of resonance-activated 4-methoxyazobenzene (MeO-AB). The kinetic rate constants (kobs) determined at 25 °C in the AuNP aqueous solution and in the Cassyopea® Gold samples were one thousand times higher than the values obtained when performing MeO-AB cis-trans conversion in the presence of pure Cassyopea®. The results reported herein are unprecedented and point to the high versatility of Cassyopea® as a reactor and carrier of metal nanoparticles in chemical, biological, and technological applications.

Towards Efficient White-light Emission in Sulfur Dots through Surface Charge Engineering.

Sulfur dots (SDs) have emerged as promising photoluminescence (PL) materials owing to their intrinsic merits such as abundant electronic effects, outstanding biocompatibility and available photocatalytic activity. Typically based on quantum confinement effects, SDs are reported usually confined emission in blue-to-green region. However, it is challenging to achieve their broad emission tunability in the visible region, restricted by inherent band gap of bulk sulfur (ca. 2.79 eV). Herein, we present white-light-emitting SDs achieved by surface charge engineering that hybridizes the surface of SDs with oleylamine. The resulting SDs exhibit broadband emissions (full width at half maximum of 187 nm) with PL quantum yields of up to 12.1% and Commission International de I'Eclairage color coordinates of (0.27, 0.32). Detailed experimental and calculation results reveal that the strong orbital coupling between oleylamine and sulfur on the hybrid surfaces of the SDs causes electron delocalization, leading to the generation of low-energy charge transfer (CT) states. These CT states are highly sensitive to sulfur-oleylamine hybrid structures, which complicate the transition dynamics and promote multi-energy emission, accounting for efficient white-light emission. The demonstration of white-light SDs based on surface charge engineering is an important step towards the development of sulfur-based PL materials.

Phase Dependence of Surface Charge Measurement on Epoxy Insulator in C4F7N/CO2 under AC Voltage.

The application of binary gas mixtures consisting of heptafluorobutyronitrile (C4F7N) and carbon dioxide (CO2) in AC GIS is currently attracting much attention. Therefore, the evaluation of the gas-solid interface charge distribution characteristics of epoxy resin is indispensable. Additionally, the phase-dependency of the charging behavior remains not fully understood. We simulated coaxial electrode structure in GIS and investigated the surface charge distribution on a down-scaled epoxy insulator. The influence of the truncated phase angle and duration of AC voltage on charge behavior were analyzed, and the charge transport mechanism under AC voltage was theoretically analyzed. The results showed that there was a noticeable negative charge speckle with the presence of the metal particle and the accumulated negative charge on the insulator surface far exceeded that of the positive charge. The maximum surface charge density and the amount of surface charge accumulated first increased and then decreased over time. It was found that the phase angle has a negligible influence on the surface charge distribution at the cut-off moment.

Regulating the surface charge and reactivity of cellulose through quaternized modification to achieve salt-free reactive dyeing process.

Limited research exists on how the structure of quaternary ammonium salt (QAS) affects the electrostatic attraction and hydroxyl reactivity of cationic cotton, which strongly affects reactive dye adsorption, diffusion, and fixation. Thus, in our work, the effects of QAS structure on the electrostatic attraction, hydroxyl reactivity, and dyeing properties were investigated. The intensity at 402.5 eV (-N+(CH3)3) in the XPS rose from 34 % to 70 % as the QAS alkyl chain length increased from 4 to 18 carbon atoms, signifying an enhancement of the positive charge and electrostatic attraction between reactive dye and QAS modified cotton. However, molecular dynamic (MD) simulations of the QAS-modified cotton with octadecyl chains revealed that the reactive dye demonstrated slower molecular mobility compared to the untreated cotton. This is not conducive to the diffusion and fixation of reactive dyes. The QAS-modified cotton with hexyl chains not only alters the activity of hydroxyl at the 6th but also generates additional hydroxyl at the ß-position that contributes to enhancing the improvement of fixation through Gaussian simulations. Therefore, cationic cotton treated with 60 g/L of (3-chloro-2-hydroxypropyl)-dimethyl-octadecylazanium chloride (CT-8) exhibits superior dye uptake levels (91.84 %), K/S values (13.10), and dye fixation percent (88.38 %).

Improving Downstream Process Related Manufacturability Based on Protein Engineering-A Feasibility Study.

While bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Manufacturability in the scientific literature is mostly related to stability of formulated drug substances, with limited focus on downstream process-related manufacturability, that is, how easily can a protein be purified. Process-related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure patient safety. Therefore, during molecule design, the surface charge of the target molecule should preferably differ sufficiently from the surface charge of the impurities to enable an efficient purification strategy. In this feasibility study, we evaluated the possibility of improving manufacturability by adapting the surface charge of the target protein. We generated several variants of a GLP1-receptor-agonist-Fc-domain-FGF21-fusion protein and demonstrated proof of concept exemplarily for an anion exchange chromatography step which then can be operated at high pH values with maximal product recovery allowing removal of HCP and viruses. Altering the surface charge distribution of biotherapeutic proteins can thus be useful allowing for an efficient manufacturing process for removing HCP and viruses, thereby reducing manufacturing costs.

Impact of nanosilver surface electronic distributions on serum protein interactions and hemocompatibility.

The translation of silver-based nanotechnology 'from bench to bedside' requires a deep understanding of the molecular aspects of its biological action, which remains controversial at low concentrations and non-spherical morphologies. Here, we present a hemocompatibility approach based on the effect of the distinctive electronic charge distribution in silver nanoparticles (nanosilver) on blood components. According to spectroscopic, volumetric, microscopic, dynamic light scattering measurements, pro-coagulant activity tests, and cellular inspection, we determine that at extremely low nanosilver concentrations (0.125-2.5µg ml-1), there is a relevant interaction effect on the serum albumin and red blood cells (RBCs). This explanation has its origin in the surface charge distribution of nanosilver particles and their electron-mediated energy transfer mechanism. Prism-shaped nanoparticles, with anisotropic charge distributions, act at the surface level, generating a compaction of the native protein molecule. In contrast, the spherical nanosilver particle, by exhibiting isotropic surface charge, generates a polar environment comparable to the solvent. Both morphologies induce aggregation at NPs/bovine serum albumin ≈ 0.044 molar ratio values without altering the coagulation cascade tests; however, the spherical-shaped nanosilver exerts a negative impact on RBCs. Overall, our results suggest that the electron distributions of nanosilver particles, even at extremely low concentrations, are a critical factor influencing the molecular structure of blood proteins' and RBCs' membranes. Isotropic forms of nanosilver should be considered with caution, as they are not always the least harmful.

Size matters: Altering antigen specific immune tolerance by tuning size of particles.

Precisely co-delivering antigens and immunosuppressants via nano/microcarriers to antigen-presenting cells (APCs) to induce antigen-specific immune tolerance represents a highly promising strategy for treating or preventing autoimmune diseases. The physicochemical properties of nano/microcarriers play a pivotal role in regulating immune function, with particle size and surface charge emerging as crucial parameters. In particular, very few studies have investigated micron-scale carriers of antigens. Herein, various nanoparticles and microparticles (NPs/MPs) with diverse particle sizes (ranging from 200 nm to 5 µm) and surface charges were prepared. Antigen peptides (MOG35-55) and immunosuppressants were encapsulated in these particles to induce antigen-specific immune tolerance. Two emulsifiers, PVA and PEMA, were employed to confer different surface charges to the NPs/MPs. The in vitro and in vivo studies demonstrated that NP/MP-PEMA could induce immune tolerance earlier than NP/MP-PVA and that NP/MP-PVA could induce immune tolerance more slowly and sustainably, indicating that highly negatively charged particles can induce immune tolerance more rapidly. Among the different sizes and charged particles tested, 200-nm-NP-PVA and 3-µm-MP-PEMA induced the greatest immune tolerance. In addition, the combination of NPs with MPs can further improve the induction of immune tolerance. In particular, combining 200 nm-NP-PVA with 3 µm-MP-PEMA or combining 500 nm-NP-PEMA with 3 µm-MP-PVA had optimal therapeutic efficacy. This study offers a new perspective for treating diseases by combining NPs with MPs and applying different emulsifiers to prepare NPs and MPs.

Monitoring changes in the zeta potential and the surface charge of human glioblastoma cells and phosphatidylcholine liposomes induced by curcumin as a function of pH.

Curcumin (CUR) has received worldwide attention for its beneficial effects on human health. Research report possible cytotoxic activity against various cancers, including glioblastoma. So far, little attention has been given to the binding properties of CUR to lipid membranes, which influences their electrical characteristics and can provide insight into their membrane-permeation abilities. Biophysical interactions between the polyphenol and in vitro models (liposomes and LN-18 human glioblastoma cells) were investigated by monitoring zeta potential and the membrane's surface charge as a function of pH. We focused on practical measurements and undertook a theoretical analysis of interactions in the natural cell membrane. We used the MTT assay to evaluate the viability of CUR-treated cells. Measurements performed using the Electrophoretic Light Scattering method demonstrated the dose-dependent effect of CUR on both membrane surface charge and zeta potential analyzed in vitro models. We determined theoretical parameters characterizing the cell membrane based on a quantitative description of the adsorption equilibria formed due to the binding of solution ions to the membrane of glioblastoma cells. The interaction of CUR with liposomes and human cancer cells is pH-dependent.

Surface Charge-Modulated Toxicity of Cysteine-Stabilized Silver Nanoparticles.

The toxicity of silver nanoparticles (AgNPs) depends on their physicochemical properties. The ongoing research aims to develop effective methods for modifying AgNPs using molecules that enable control over the processes induced by nanoparticles in both normal and cancerous cells. Application of amino acid-stabilized nanoparticles appears promising, exhibiting tunable electrokinetic properties. Therefore, this study focused on determining the influence of the surface charge of cysteine (CYS)-stabilized AgNPs on their toxicity towards human normal B (COLO-720L) and T (HUT-78) lymphocyte cell lines. CYS-AgNPs were synthesized via the chemical reduction. Transmission electron microcopy (TEM) imaging revealed that they exhibited a quasi-spherical shape with an average size of 18 ± 3 nm. CYS-AgNPs remained stable under mild acidic (pH 4.0) and alkaline (7.4 and 9.0) conditions, with an isoelectric point observed at pH 5.1. Following a 24 h treatment of lymphocytes with CYS-AgNPs, concentration-dependent alterations in cell morphology were observed. Positively charged CYS-AgNPs notably decreased lymphocyte viability. Furthermore, they exhibited grater genotoxicity and more pronounced disruption of biological membranes compared to negatively charged CYZ-AgNPs. Despite both types of AgNPs interacting similarly with fetal bovine serum (FBS) and showing comparable profiles of silver ion release, the biological assays consistently revealed that the positively charged CYS-AgNPs exerted stronger effects at all investigated cellular levels. Although both types of CYS-AgNPs have the same chemical structure in their stabilizing layers, the pH-induced alterations in their surface charge significantly affect their biological activity.

Impact of surface charge density modulation on ion transport in heterogeneous nanochannels.

The PNP nanotransistor, consisting of emitter, base, and collector regions, exhibits distinct behavior based on surface charge densities and various electrolyte concentrations. In this study, we investigated the impact of surface charge density on ion transport behavior within PNP nanotransistors at different electrolyte concentrations and applied voltages. We employed a finite-element method to obtain steady-state solutions for the Poisson-Nernst-Planck and Navier-Stokes equations. The ions form a depletion region, influencing the ionic current, and we analyze the influence of surface charge density on the depth of this depletion region. Our findings demonstrate that an increase in surface charge density results in a deeper depletion zone, leading to a reduction in ionic current. However, at very low electrolyte concentrations, an optimal surface charge density causes the ion current to reach its lowest value, subsequently increasing with further increments in surface charge density. As such, at V app = + 1 V and C 0 = 1 mM , the ionic current increases by 25% when the surface charge density rises from 5 to 20  mC . m - 2 , whereas at C 0 = 10 mM , the ionic current decreases by 65% with the same increase in surface charge density. This study provides valuable insights into the behavior of PNP nanotransistors and their potential applications in nanoelectronic devices.

Counterion Distribution in the Stern Layer on Charged Surfaces.

Counterion adsorption at the solid-liquid interface affects numerous applications. However, the counterion adsorption density in the Stern layer has remained poorly evaluated. Here we report the direct determination of surface charge density at the shear plane between the Stern layer and the diffuse layer. By the Grahame equation extension and streaming current measurements for different solid surfaces in different aqueous electrolytes, we are able to obtain the counterion adsorption density in the Stern layer, which is mainly related to the surface charge density but is less affected by the bulk ion concentration. The charge inversion concentration is further found to be sensitive to the ion type and ion valence rather than to the charged surface, which is attributed to the ionic competitive adsorption and ion-ion correlations. Our findings offer a framework for understanding ion distribution in many physical and chemical processes where the Stern layer is ubiquitous.

Influence of titanium surface roughness on a nanoscale on the zeta potential and platelet adhesion.

Thromboembolic complications still arise on blood contacting surfaces. Surface charge and topography influence the subsequent deposition of proteins and platelets, potentially leading to thrombi. Research showed a correlation of surface charge and nanoscale roughness, and a negative surface charge as well as a smooth surface finish are associated with lower thrombogenicity. The aim of this study was to compare the platelet adhesion on titanium with different nanoscale roughnesses and to examine if those roughness variations caused a change in surface charge. Titanium samples were polished and roughened to four different nanoscale roughness levels. Platelet adhesion (covered surface area (CSA), N = 8) was tested in flow chambers with human whole blood using fluorescence imaging. ζ-potential was measured over a broad range of pH-values and interpolated to obtain the ζ-potential for pHBlood (7.4). Platelet adhesion tests were evaluated in terms of p-values and the Wilcoxon test effect size and the trend of the ζ-potential at pHBlood and the CSA was compared. Ra-values ranged between 35 (polished) and 156 nm. Regarding platelet adhesion, the polished sample showed the lowest mean CSA with a medium or strong effect size compared to the roughened samples. The interpolated ζ-potentials for pHBlood follow a similar trend as the CSA, with the lowest ζ-potential measured for the polished surface. These findings suggest that the decreasing ζ-potential due to lower nanoscale roughness might be an additional explanation for the improved hemocompatibility besides the smoother topography.

The surface charge of electroactive materials governs cell behaviour through its effect on protein deposition.

The precise mechanisms underlying the cellular response to static electric cues remain unclear, limiting the design and development of biomaterials that utilize this parameter to enhance specific biological behaviours. To gather information on this matter we have explored the interaction of collagen type-I, the most abundant mammalian extracellular protein, with poly(vinylidene fluoride) (PVDF), an electroactive polymer with great potential for tissue engineering applications. Our results reveal significant differences in collagen affinity, conformation, and interaction strength depending on the electric charge of the PVDF surface, which subsequently affects the behaviour of mesenchymal stem cells seeded on them. These findings highlight the importance of surface charge in the establishment of the material-protein interface and ultimately in the biological response to the material. STATEMENT OF SIGNIFICANCE: The development of new tissue engineering strategies relies heavily on the understanding of how biomaterials interact with biological tissues. Although several factors drive this process and their driving principles have been identified, the relevance and mechanism by which the surface potential influences cell behaviour is still unknown. In our study, we investigate the interaction between collagen, the most abundant component of the extracellular matrix, and poly(vinylidene fluoride) with varying surface charges. Our findings reveal substantial variations in the binding forces, structure and adhesion of collagen on the different surfaces, which collectively explain the differential cellular responses. By exposing these differences, our research fills a critical knowledge gap and paves the way for innovations in material design for advanced tissue regeneration strategies.

Chitosan Coating as a Strategy to Increase Postemergent Herbicidal Efficiency and Alter the Interaction of Nanoatrazine with Bidens pilosa Plants.

The atrazine nanodelivery system, composed of poly(ε-caprolactone) (PCL+ATZ) nanocapsules (NCs), has demonstrated efficient delivery of the active ingredient to target plants in previous studies, leading to greater herbicide effectiveness than conventional formulations. Established nanosystems can be enhanced or modified to generate new biological activity patterns. Therefore, this study aimed to evaluate the effect of chitosan coating of PCL+ATZ NCs on herbicidal activity and interaction mechanisms with Bidens pilosa plants. Chitosan-coated NCs (PCL/CS+ATZ) were synthesized and characterized for size, zeta potential, polydispersity, and encapsulation efficiency. Herbicidal efficiency was assessed in postemergence greenhouse trials, comparing the effects of PCL/CS+ATZ NCs (coated), PCL+ATZ NCs (uncoated), and conventional atrazine (ATZ) on photosystem II (PSII) activity and weed control. Using a hydroponic system, we evaluated the root absorption and shoot translocation of fluorescently labeled NCs. PCL/CS+ATZ presented a positive zeta potential (25 mV), a size of 200 nm, and an efficiency of atrazine encapsulation higher than 90%. The postemergent herbicidal activity assay showed an efficiency gain of PSII activity inhibition of up to 58% compared to ATZ and PCL+ATZ at 96 h postapplication. The evaluation of weed control 14 days after application ratified the positive effect of chitosan coating on herbicidal activity, as the application of PCL/CS+ATZ at 1000 g of a.i. ha-1 resulted in better control than ATZ at 2000 g of a.i. ha-1 and PCL+ATZ at 1000 g of a.i. ha-1. In the hydroponic experiment, chitosan-coated NCs labeled with a fluorescent probe accumulated in the root cortex, with a small quantity reaching the vascular cylinder and leaves up to 72 h after exposure. This behavior resulted in lower leaf atrazine levels and PSII inhibition than ATZ. In summary, chitosan coating of nanoatrazine improved the herbicidal activity against B. pilosa plants when applied to the leaves but negatively affected the root-to-shoot translocation of the herbicide. This study opens avenues for further investigations to improve and modify established nanosystems, paving the way for developing novel biological activity patterns.

Relationships of the Surface Charge of Low-Density Lipoprotein (LDL) with the Serum LDL-Cholesterol and Atherosclerosis Levels in a Japanese Population: The DOSANCO Health Study.

AIM: This study investigated the associations of the surface charge of low-density lipoprotein (LDL) with the serum LDL-cholesterol and atherosclerosis levels in a community-based Japanese population. METHODS: The study had a cross-sectional design and included 409 community residents aged 35-79 years who did not take medications for dyslipidemia. The potential electric charge of LDL and the zeta potential, which indicate the surface charge of LDL, were measured by laser Doppler microelectrophoresis. The correlations of the zeta potential of LDL (-mV) with the serum LDL-cholesterol levels (mg/dL), cardio-ankle vascular index (CAVI), and serum high-sensitivity C-reactive protein (hsCRP) levels (log-transformed values, mg/L) were examined using Pearson's correlation coefficient (r). Linear regression models were constructed to examine these associations after adjusting for potential confounding factors. RESULTS: A total of 201 subjects with correctly stored samples were included in the primary analysis for zeta potential measurement. An inverse correlation was observed between the LDL zeta potential and the serum LDL-cholesterol levels (r=-0.20; p=0.004). This inverse association was observed after adjusting for sex, age, dietary cholesterol intake, smoking status, alcohol intake, body mass index, and the serum levels of the major classes of free fatty acids (standardized ß=-6.94; p=0.005). However, the zeta potential of LDL showed almost no association with CAVI or the serum hsCRP levels. Similar patterns were observed in the 208 subjects with compromised samples as well as all the original 409 subjects. CONCLUSION: A higher electronegative surface charge of LDL was associated with lower serum LDL-cholesterol levels in the general Japanese population.

Conditional Cell-Penetrating Peptide Exposure as Selective Nanoparticle Uptake Signal.

A major bottleneck diminishing the therapeutic efficacy of various drugs is that only small proportions of the administered dose reach the site of action. One promising approach to increase the drug amount in the target tissue is the delivery via nanoparticles (NPs) modified with ligands of cell surface receptors for the selective identification of target cells. However, since receptor binding can unintentionally trigger intracellular signaling cascades, our objective was to develop a receptor-independent way of NP uptake. Cell-penetrating peptides (CPPs) are an attractive tool since they allow efficient cell membrane crossing. So far, their applicability is severely limited as their uptake-promoting ability is nonspecific. Therefore, we aimed to achieve a conditional CPP-mediated NP internalization exclusively into target cells. We synthesized different CPP candidates and investigated their influence on nanoparticle stability, ζ-potential, and uptake characteristics in a core-shell nanoparticle system consisting of poly(lactid-co-glycolid) (PLGA) and poly(lactic acid)-poly(ethylene glycol) (PLA10kPEG2k) block copolymers with CPPs attached to the PEG part. We identified TAT47-57 (TAT) as the most promising candidate and subsequently combined the TAT-modified PLA10kPEG2k polymer with longer PLA10kPEG5k polymer chains, modified with the potent angiotensin-converting enzyme 2 (ACE2) inhibitor MLN-4760. While MLN-4760 enables selective target cell identification, the additional PEG length hides the CPP during a first unspecific cell contact. Only after the previous selective binding of MLN-4760 to ACE2, the established spatial proximity exposes the CPP, triggering cell uptake. We found an 18-fold uptake improvement in ACE2-positive cells compared to unmodified particles. In summary, our work paves the way for a conditional and thus highly selective receptor-independent nanoparticle uptake, which is beneficial in terms of avoiding side effects.