Extracellular vesicles (EVs) are nano-sized bilayer vesicles that are shed or secreted by virtually every cell type. A variety of biomolecules, including proteins, lipids, coding and non-coding RNAs, and mitochondrial DNA, can be selectively encapsulated into EVs and delivered to nearby and distant recipient cells, leading to alterations in the recipient cells, suggesting that EVs play an important role in intercellular communication. EVs play effective roles in physiology and pathology and could be used as diagnostic and therapeutic tools. At present, although the mechanisms of exosome biogenesis and secretion in donor cells are well understood, the molecular mechanism of EV recognition and uptake by recipient cells is still unclear. This review summarizes the current understanding of the molecular mechanisms of EVs\' biological journey in recipient cells, from recognition to uptake and cargo release. Furthermore, we highlight how EVs escape endolysosomal degradation after uptake and thus release cargo, which is crucial for studies applying EVs as drug-targeted delivery vehicles. Knowledge of the cellular processes that govern EV uptake is important to shed light on the functions of EVs as well as on related clinical applications.
胞外囊泡（EVs）是几乎所有细胞均能分泌的纳米级脂质双层囊泡，可通过将其内含的多种包括蛋白质、脂质、编码和非编码RNA、线粒体DNA等在内的生物活性分子递送到邻近和远处的受体细胞中，以改变受体细胞功能，从而实现细胞间的信息交流。EVs在生理和病理过程中均发挥着重要作用，可用于疾病诊疗。尽管EVs在供体细胞中的生物发生和分泌机制已基本清晰，但受体细胞对EVs的识别和摄取的分子机制尚不清楚。本文对EVs进入受体细胞的生物过程包括受体细胞对EVs的识别、摄取以及EVs的货物释放进行综述，并重点关注了EVs在摄取后如何通过“溶酶体逃逸”，从而释放货物，将有助于推进EVs作为药物递送载体的研究。此外，了解和控制EVs在受体细胞中的有效摄取，对阐明EVs的功能及其临床应用同样至关重要。.

The quality of pistachio, one of the export products of Iran, will be decreased during storage as a result of mold spoilage, toxins production, and oil oxidation. This study aimed to investigate the capability of pistachio hull extract (PHE) loaded in fenugreek seed gum (FSG):whey protein isolate (WPI) nanoemulsion to control oil oxidation, and fungi growth in fresh pistachio nut during storage at 4°C. The total anthocyanin and total phenolic content of the PHE were 125.44 μg/g and 675.18 mg/g, respectively. The DPPH radical scavenging activity of PHE at 100 ppm was higher than that of tert-butylhydroquinon (TBHQ). In comparison with other concentrations, 50 ppm showed the strongest antifungal activity against Aspergillus flavus, Aspergillus parasiticus, and Aspergillus nomius. All nanoemulsions have a mean size lower than 265 nm. The polydispersity index (PDI) of different nanoemulsions was lower than 0.3, and a negative zeta potential was observed. The encapsulation efficiency was higher than 67.0% and all nanoemulsions had spherical morphology. The pistachio nuts were coated with different coating solutions containing 0 and 100 ppm of PHE and stored at 4°C for 8 weeks. The results showed that the pistachio sample coated with a composite coating of WPI and FSG containing 100 ppm of PHE has a higher moisture content and lower changes in L*, a*, and b* indexes, oil oxidation, fungi development, and total mold and yeast count. This treatment exhibited higher overall acceptance than other samples at the end of storage time. The results of this study suggest the use of biodegradable coatings enriched with natural extracts that have high antioxidant and antifungal activities.

Injections are one way of delivering drugs directly to the joint capsule. Employing this possibility, local anesthetic, such as bupivacaine (Bu), in the form of the suspension can be administered. The aim of this work was to propose a methylcellulose-based hydrogel-incorporated bupivacaine for intra-articular injections and to study the release kinetics of the drug from the hydrogel to different acceptor media, reflecting the synovial fluid of a healthy joint and the synovial fluid of an inflamed joint. The drug release studies were performed employing the flow apparatus. The drug was released to four different acceptor fluids: phosphate buffer pH = 7.4 (PBS7.4), phosphate buffer pH = 6.8 (PBS6.8), phosphate buffer pH = 7.4 with the high-molecular-weight sodium hyaluronate (PBS7.4H), and phosphate buffer pH = 6.8 with the low-molecular-weight sodium hyaluronate (PBS6.8L). The investigation was carried out at the temperature of 37 °C. The absorbance of the Bu released was measured at the wavelength of 262 nm every 2 min for 24 h. The release profiles of Bu to the acceptor media PBS7.4, PBS6.8, PBS7.4H, and PBS6.8L were described best by the first-order kinetics and the second-order equation. According to these models, the release rate constants were the highest when Bu was released to the fluid PBS7.4 and were k1 = (7.20 ± 0.01) × 10-5 min-1 and k2 = (3.00 ± 0.04) × 10-6 mg-1 × min-1, respectively. The relative viscosity of the acceptor medium, its pH, and the addition of high-molecular-weight or low-molecular-weight sodium hyaluronate (HAH or HAL) to the acceptor fluid influenced the drug dissolution. The release of Bu into the medium reflecting healthy synovial fluid takes a different pattern from its release into the fluid of an inflamed joint.

Emulsion-based delivery systems are extensively employed for encapsulating functional active ingredients, protecting them from degradation, and enhancing bioavailability and release efficiency. Here, a CO2-responsive surfactant synthesized from rosin displays rapid responsiveness to CO2 at room temperature, transitioning reversibly switches between active and inactive states multiple times. The dual tertiary amines on the rosin rigid structure contributes to its CO2 sensitivity. When in its active cationic form, in conjunction with silica nanoparticles, it exhibits desired Pickering emulsification performance across various oil phases. In the Pickering emulsion loaded with quercetin, the encapsulation efficiency and loading efficiency reached 80.50% and 0.69%, respectively, with stability lasting at least 30 days. The system provides robust protection for quercetin against external factors, such as UV and heat, revealing sustained release effects. This study investigated the potential of using rosin-based CO2-responsive surfactants alongside nanoparticles to design stable Pickering emulsion systems for active substance encapsulation and sustained release.

Nose-to-brain delivery (NTBD) offering potential benefits for treating Alzheimer\'s disease. In previous research, insulin dry powder (IDP) formulation for NTBD was developed, exhibiting favorable stability. This study aims to conduct in vitro and ex vivo assessment of release, permeation, mucoadhesion and histopathology, as well as an in vivo biodistribution study to produce IDP for NTBD and evaluate brain biodistribution. Spray-freeze-dried IDP formulations with varying weight ratios of trehalose-to-inulin were produced and analyzed. The release study was carried out in PBS with a pH of 5.8 stirred at 50 rpm and maintained at 37 °C ± 0.5 °C. Goat nasal mucosa was used for ex vivo permeation and mucoadhesion testing under similar conditions. An ex vivo histopathological examination and an in vivo study using enzyme-linked immunosorbent assay, were also performed. The IDP dissolution study demonstrated complete release of all IDPs within 120 min. The permeation study indicated that steady-state conditions were observed between 30 and 240 min. The mucoadhesion study unveiled that IDP F5 exhibited the fastest mucoadhesion time and the least force required within the fastest time of 43.60 ± 2.57 s. The histopathological study confirmed that none of the tested IDPs induced irritation in the nasal mucosa. Furthermore, the biodistribution study demonstrated the absence of detectable insulin in the plasma, while IDP F3 exhibited the highest deposited concentration of insulin within both the olfactory bulb and the whole brain. The extensive evaluation of the IDP formulations through in vitro, ex vivo, and in vivo studies implies their strength non-invasive NTBD. IDP F3, with a 1:1 wt ratio of trehalose to inulin, exhibited favorable brain biodistribution outcomes and was recommended for further investigation and development in the context of NTBD.

L-asparaginase (L-ASNase) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia and is used to treat acute lymphoblastic leukemia. It is also toxic to the cells of some solid tumors, including melanoma cells. Immobilization of this enzyme can improve its activity against melanoma tumor cells. In this work, the properties of bacterial cellulose (BC) and feasibility of BC films as a new carrier for immobilized L-ASNase were investigated. Different values of growth time were used to obtain BC films with different thicknesses and porosities, which determine the water content and the ability to adsorb and release L-ASNase. Fourier transform infrared spectroscopy confirmed the adsorption of the enzyme on the BC films. The total activity of adsorbed L-ASNase and its release were investigated for films grown for 48, 72 or 96 h. BC films grown for 96 h showed the most pronounced release as described by zero-order and Korsmayer-Peppas models. The release was characterized by controlled diffusion where the drug was released at a constant rate. BC films with immobilized L-ASNase could induce cytotoxicity in A875 human melanoma cells. With further development, immobilization of L-ASNase on BC may become a potent strategy for anticancer drug delivery to superficial tumors.

Low-molecular-weight (LMW) gelators are a versatile class of compounds able to self-assemble and to form supramolecular materials, such as gels. The use of LMW peptides to produce these gels shows many advantages, because of their wide structure tunability, the low-cost and effective synthesis, and the in vivo biocompatibility and biodegradability, which makes them optimal candidates for release and delivery applications. In addition, in these materials, the binding of the hosts may occur through a variety of noncovalent interactions, which are also the main factors responsible for the self-assembly of the gelators, and through specific interactions with the fibers or the pores of the gel matrix. This review aims to report LMW gels based on amino acid and peptide derivatives used for the release of many different species (drugs, fragrances, dyes, proteins, and cells) with a focus on the possible strategies to incorporate the cargo in these materials, and to demonstrate how versatile these self-assembled materials are in several applications.

The generation of acid mine drainage (AMD) characterized by high acidity and elevated levels of toxic metals primarily results from the oxidation and dissolution of sulfide minerals facilitated by microbial catalysis. Although there has been significant research on microbial diversity and community composition in AMD, as well as the relationship between microbes and heavy metals, there remains a gap in understanding the microbial community structure in uranium-enriched AMD sites. In this paper, water samples with varying levels of uranium pollution were collected from an abandoned stone coal mine in Jiangxi Province, China during summer and winter, respectively. Geochemical and high-throughput sequencing analyses were conducted to characterize spatiotemporal variations in bacterial diversity and community composition along pollution groups. The results indicated that uranium was predominantly concentrated in the AMD of new pits with strong acid production capacity, reaching a peak concentration of 9,370 μg/L. This was accompanied by elevated acidity and concentrations of iron and total phosphorus, which were identified as significant drivers shaping the composition of bacterial communities, rather than fluctuations in seasonal conditions. In an extremely polluted environment (pH < 3), bacterial diversity was lowest, with a predominant presence of acidophilic iron-oxidizing bacteria (such as Ferrovum), and a portion of acidophilic heterotrophic bacteria synergistically coexisting. As pollution levels decreased, the microbial community gradually evolved to cohabitation of various pH-neutral heterotrophic species, ultimately reverting back to background level. The pH was the dominant factor determining biogeochemical release of uranium in AMD. Acidophilic and uranium-tolerant bacteria, including Ferrovum, Leptospirillum, Acidiphilium, and Metallibacterium, were identified as playing key roles in this process through mechanisms such as enhancing acid production rate and facilitating organic matter biodegradation.

Interactions between phenolic compounds and the allergen Mal d 1 are discussed to be the reason for better tolerance of apple cultivars, which are rich in polyphenols. Because Mal d 1 is susceptible to proteolytic digestion and allergenic symptoms are usually restricted to the mouth and throat area, the release of native Mal d 1 during the oral phase is of particular interest. Therefore, we studied the release of Mal d 1 under different in vitro oral digestion conditions and revealed that only 6-15% of the total Mal d 1 present in apples is released. To investigate proposed polyphenol-Mal d 1 interactions, various analytical methods, e.g., isothermal titration calorimetry, 1H-15N-HSQC NMR, and untargeted mass spectrometry, were applied. For monomeric polyphenols, only limited noncovalent interactions were observed, whereas oligomeric polyphenols and browning products caused aggregation. While covalent modifications were not detectable in apple samples, a Michael addition of epicatechin at cysteine 107 in r-Mal d 1.01 was observed.

This study aims to evaluate and determine the correlation between in vitro release and in vivo pharmacokinetics of two extended-release dosage forms of Cilostazol. In vitro release profiles for two dosage forms, tablet and capsule, were analyzed under physiologically mimicked medium conditions using the paddle and basket USP release apparatus. A single-dose, two-period crossover study design in beagle dogs was applied for the pharmacokinetic study. The fed and fast effects were considered for evaluation. Pseudo gastric release medium transfer setup study from pH 1.2 to pH 6.8 (+0.5% SLS) and pH 1.2 to pH 6.8 (+1.0% SLS) demonstrated that Pletaal® SR 200 mg capsules have higher drug release rates than Cilostan® CR 200 mg tablets. Similarly, in vivo study showed Cilostazol concentration in plasma and AUC was lower under the fast state than the fed state. The ratio of least squared geometric mean values, Cmax, AUC0-t, and AUC0-inf of Cilostazol were 2.53-fold, 2.89-fold, and 2.87-fold higher for Pletaal® SR 200 mg capsules compared with Cilostan® CR 200 mg tablets, respectively. Correlation of in vitro/in vivo data indicated that Pletal® SR 200 mg capsules have better release and pharmacodynamic effect than Cilostan® CR 200 mg tablets.