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Metabolic dysfunction-associated steatohepatitis (MASH) poses challenges for targeted delivery and retention of therapeutic proteins due to excess extracellular matrix (ECM). Here we present a new approach to treat MASH, termed "Fibrosis overexpression and retention (FORT)". In this strategy, we design (1) retinoid-derivative lipid nanoparticle (LNP) to enable enhanced mRNA overexpression in fibrotic regions, and (2) mRNA modifications which facilitate anchoring of therapeutic proteins in ECM. LNPs containing carboxyl-retinoids, rather than alcohol- or ester-retinoids, effectively deliver mRNA with over 10-fold enhancement of protein expression in fibrotic livers. The carboxyl-retinoid rearrangement on the LNP surface improves protein binding and membrane fusion. Therapeutic proteins are then engineered with an endogenous collagen-binding domain. These fusion proteins exhibit increased retention in fibrotic lesions and reduced systemic toxicity. In vivo, fibrosis-targeting LNPs encoding fusion proteins demonstrate superior therapeutic efficacy in three clinically relevant male-animal MASH models. This approach holds promise in fibrotic diseases unsuited for protein injection., (© 2024. The Author(s).)

Shingles is caused by the reactivation of varicella zoster virus (VZV) and manifests as painful skin rashes. While the recombinant protein-based vaccine proves highly effective, it encounters supply chain challenges due to a shortage of the necessary adjuvant. Messenger RNA (mRNA)-based vaccines can be rapidly produced on a large scale, but their effectiveness relies on efficient delivery and sequence design. Here, an mRNA-based VZV vaccine using a synergistic lipid nanoparticle (Syn-LNP) containing two different ionizable lipids is developed. Syn-LNP shows superior mRNA expression compared to LNPs formulated with either type of ionizable lipid and to a commercialized LNP. After encapsulating VZV glycoprotein E (gE)-encoding mRNA, mgE@Syn-LNP induces robust humoral and cellular immune responses in two strains of mice. The magnitude of these responses is similar to that induced by adjuvanted recombinant gE proteins and significantly higher than that observed with live-attenuated VZV. mgE@Syn-LNP exhibits durable humoral responses for over 7 months without obvious adverse effects. In addition, mgE@Syn-LNP protects vaccinated guinea pigs against live VZV challenges. Preliminary studies on the mRNA antigen design reveal that the removal of glycosylation sites of gE greatly reduces its immune responses. Collectively, Syn-LNP encapsulating gE-encoded mRNA holds great promise as a shingles vaccine., (© 2023 Wiley‐VCH GmbH.)

The efficacy of messenger RNA (mRNA)-based vaccines or therapies relies on delivery vehicles that can transport them into the cytosol of cells. Lipid nanoparticles (LNPs) are the most clinically advanced carrier for mRNA. The chemical structure of an ionizable lipid is critical for the delivery efficiency of the LNPs. Herein, we synthesize a new ionizable lipid containing fluorinated alkyl chains (F-L319) and evaluate its mRNA delivery efficiency compared to its hydrocarbon counterpart (L319). While LNPs formulated with F-L319 alone showed decreased mRNA encapsulation and delivery efficiencies in comparison to the L319-LNP, we found that combining the appropriate ratios of F-L319 and L319 as hybrid ionizable lipids in LNPs (hybrid-LNPs) greatly enhanced mRNA delivery efficiency both in vitro and in vivo . Upon intravenous injection, the hybrid-LNP showed targeted mRNA expression in the spleen. Mechanistic studies indicate that the enhanced mRNA delivery of the hybrid-LNP is attributed to both improved mRNA encapsulation and cellular uptake. Collectively, fluorination of ionizable lipids represents a promising strategy to improve the delivery efficiency of LNPs.

Lipid-like nanoparticles (LNPs) have potential as non-viral delivery systems for mRNA therapies. However, repeated administrations of LNPs may lead to accumulation of delivery materials and associated toxicity. To address this challenge, we have developed biodegradable lipids which improve LNPs clearance and reduce toxicity. We modify the backbone structure of Dlin-MC3-DMA by introducing alkyne and ester groups into the lipid tails. We evaluate the performance of these lipids when co-formulated with other amine containing lipid-like materials. We demonstrate that these formulations synergistically facilitate robust mRNA delivery with improved tolerability after single and repeated administrations. We further identify albumin-associated macropinocytosis and endocytosis as an ApoE-independent LNP cellular uptake pathway in the liver. Separately, the inclusion of alkyne lipids significantly increases membrane fusion to enhance mRNA release, leading to synergistic improvement of mRNA delivery. We believe that the rational design of LNPs with multiple amine-lipids increases the material space for mRNA delivery.

Gaining precise control over the cellular entry pathway of nanomaterials is key in achieving cytosolic delivery, accessing subcellular environments, and regulating toxicity. However, this precise control requires a fundamental understanding of the behavior of nanomaterials at the bio-nano interface. Herein, we report a computational study investigating the synergistic effect of several key physicochemical properties of nanomaterials on their cellular entry pathways. By examining interactions between monolayer-protected nanoparticles and model cell membranes in a three-dimensional parameter space of size, surface charge/pKa, and ligand chemistry, we observed four different types of nanoparticle translocation for cellular entry which are: outer wrapping, free translocation, inner attach, and embedment. Nanoparticle size, surface charge/pKa, and ligand chemistry each play a unique role in determining the outcome of translocation. Specifically, membrane local curvature induced by nanoparticles upon contact is critical for initiating the translocation process. A generalized paradigm is proposed to describe the fundamental mechanisms underlying the bio-nano interface.

Inspired by the fact that chitosan is a representative constituent of the ectocellular structure of Cryptococcus neoformans and a typical biomaterial for improving drug oral absorption, we designed an elegant and efficient C. neoformans-targeted drug delivery system via oral administration. A chitosan-binding peptide screened by phage display was used as the targeting moiety, followed by conjugation to the surface of poly(lactic- co-glycolic acid) nanoparticles as the drug carrier, which was then incubated with free chitosan. The noncovalently bound chitosan adheres to mucus layers and significantly enhances penetration of nanoparticles through the oral absorption barrier into circulation and then re-exposed the targeting ligand for later recognition of the fungal pathogen at the site of infection. After loading itraconazole as a model drug, our drug delivery system remarkably cleared lung infections of C. neoformans and increased survival of model mice. Currently, targeted drug delivery is mainly performed intravenously; however, the system described in our study may provide a universal means to facilitate drug targeting to specific tissues and disease sites by oral administration and may be especially powerful in the fight against increasingly severe fungal infections.

The Ba Ca Zr Ti (BCZT) nano-particles were modified by polyimide (PI) through a chemical coating method. And the PI@BCZT/polyvinylidene fluoride (PVDF) flexible composite films were fabricated by solution casting method. The transmission electron microscopy and scanning electron microscopy results show that the nano-particles is about 50 nm, PI is uniformly coated on the surface of BCZT nano-particles about 7-10 nm as well as there are uniform and improved dispersion in the matrix after modification. A series of dielectric properties were carried out. The results show the 50 vol% composites own a remarkably enhanced dielectric permittivity (ε = 130) at 100 Hz. After modification, the breakdown strength has increased from 20 to 96 kV mm and the loss tangent is reduced from 1.8 to 0.2 at 100 Hz compare with un-modified composites in 40 vol% dopant. With the increase of dopant, ferroelectricity of composites can be enhanced. The optimal residual polarization is 40 vol% PI@BCZT composites, which possess 1.025 μC/cm under 50 kV/mm external electric field. In addition, after modification, thermo-gravimetric analysis exhibits the degradation temperature Td and Td of PI@BCZT/PVDF composites can be enhanced about 5-10 °C and show better thermal stability than un-modified composites. [ABSTRACT FROM AUTHOR]

Using coupling agent isocyanatopropyltriethoxysilane (ICTOS) to modified nano-TiO2, the polyimide (PI) with different titanium dioxide (TiO2) contents (0, 1, 2, 3, 4, and 5 wt %) doped nano-composites were prepared by sol–gel method (PI/TiO2 ICTOS composites). The effect of ICTOS modification on polarization and time-to-breakdown properties of composites were investigated by thermally stimulated depolarization current (TSDC) method, dielectric, and Corona aging measurements. The TSDC spectra show that ICTOS modification enhanced α-peak intensity and make β-peak disappear in composites. Relevant trap parameters were calculated by an approximate model, and the results indicate that introduction of ICTOS is effective for the charge carrier traps, activation energy distribution in composites. Corona aging measurement show corona resistance was also sufficient improved in PI/TiO2 ICTOS composites. The changes of activation energy and intensity of traps in composites may be responsible for the corona resistance. [ABSTRACT FROM AUTHOR]

A novel all-organic composite comprising polyvinylidene fluoride (PVDF) and diisopropylammonium bromide (DIPAB) crystal particles (0-20 mass%) with significant dielectric properties has been synthesized via coating method. The DIPAB crystal nano-particles were prepared in the PVDF matrix by in situ growth method, which were found effective in transforming structure and enhancing the dielectric properties of the composites. X-ray diffraction pattern and Fourier transform infrared spectroscopy confirmed that the DIPAB in situ particles can improve the content of the electroactive β phase nucleation in PVDF matrix, whereas the PVDF matrix could induce the (00 l) preferred orientation of the DIPAB nano-crystal. And the dielectric performance of the DIPAB/PVDF composite was significant influenced by the enhanced electroactive β phase and (00l) textured DIPAB. Relative dielectric constants as high as 94 was obtained at 40 Hz with 5 mass% DIPAB filler, which is 11-fold higher than that of the pure PVDF matrix (~8.5). The breakdown strength decreased as the mass fraction of DIPAB increased but still stayed more than 38.9 kV/mm. [ABSTRACT FROM AUTHOR]

KTaNbO (KTN) nanoparticles with a perovskite structure were synthesized in orthogonal experiments under different hydrothermal conditions. Controlled sizes were generated by analyzing four variables using an orthogonal array experimental design (OA matrix): reaction temperature, KOH concentration, reaction time and solution volume. The effects of the four factors on the KTN nanoparticle size were systematically examined using range analysis and analysis of variance. The KOH concentration had the largest effect on the average size of the KTN nanoparticles. The KTN particles with a designed grain size can be obtained by controlling the four effect factors. [ABSTRACT FROM AUTHOR]

The hybrid films of well dispersed SiO nanoparticle in polyimide (PI/SiO) were prepared through the sol-gel processing. The pure PI was synthesized from 4, 4′,-oxydianaline (ODA) and pyromellitic dianhydride (PMDA). The residual amino groups which were controlled by the reactant stoichiometric ratio reacted with the coupling agent isocyanatopropyltriethoxysilane (ICTOS) to provide an organic-inorganic bonding. A series amount of tetraethoxysilane (TEOS) was then added, thus producing chemically bonded composite films. The films with different silica contents (0 wt %, 5 wt %, 8 wt %, 10 wt %, 13 wt %, and 15 wt %) were characterized by a variety of techniques including FT-IR, SEM, TGA, and tensile analysis. The results indicated that the chemical interaction between the two phases resulted in the formation of well-dispersed nanoparticles (20-30 nm) in the PI matrix, and superior thermal stability of hybrid films. The tensile measurement showed that the mechanical properties were markedly improved with incorporating various amount of silica, and the maximum of tensile strength was 105.4 MPa with10 wt % of silica concentration. [ABSTRACT FROM AUTHOR]

[Display omitted] Developing near-infrared responsive (NIR) photocatalysts is very important for the development of solar-driven photocatalytic systems. Metal sulfide semiconductors have been extensively used as visible-light responsive photocatalysts for photocatalytic applications owing to their high chemical variety, narrow bandgap and suitable redox potentials, particularly the benchmark ZnIn 2 S 4. However, their potential as NIR-responsive photocatalysts is yet to be reported. Herein, for the first time demonstrated that upconversion nanoparticles can be delicately coupled with hierarchical ZnIn 2 S 4 nanorods (UCNPs/ZIS) to assemble a NIR-responsive composite photocatalyst, and as such composite is verified by ultraviolet–visible diffuse reflectance spectra and upconversion luminescence spectra. As a result, remarkable photocatalytic CO and CH 4 production rates of 1500 and 220 nmol g−1h−1, respectively, were detected for the UCNPs/ZIS composite under NIR-light irradiation (λ ≥ 800 nm), which is rarely reported in the literature. The remarkable photocatalytic activity of the UCNPs/ZIS composite can be understood not only because the heterojunction between UCNPs and ZIS can promote the charge separation efficiency, but also the intimate interaction of UCNPs with hierarchical ZIS nanorods can enhance the energy transfer. This finding may open a new avenue to develop more NIR-responsive photocatalysts for various solar energy conversion applications. [ABSTRACT FROM AUTHOR]