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Gelatin (GEL), pectin (PEC), carboxymethyl cellulose (CMC), and whey protein isolate (WPI) were employed to formulate hydrogels for stabilizing N-Acetylneuraminic Acid (NeuAc). GEL/WPI-NeuAc hydrogels, irrespective of the ratio, exhibited a flexible and smooth surface with a continuous three-dimensional network structure internally. Porosity of the three types of hydrogels increased from 3.69% to 86.92% (GEL/WPI), 41.67% (PEC/WPI), and 87.62% (CMC/WPI), rendering them suitable as carriers for NeuAc encapsulation. The dynamic swelling behavior of all hydrogels followed Schott's second-order kinetics model. The degradation performance of GEL, PEC, and CMC/WPI-NeuAc hydrogels was optimal at a 5: 5 ratio, with degradation rates of 80.39 ± 1.26%, 82.38 ± 1.96%, and 81.39 ± 1.57%, respectively. GEL, PEC, CMC/WPI-NeuAc hydrogels demonstrated decreased release rates of 44.56%, 31.04%, and 41.26%, respectively, compared to free NeuAc, post gastric digestion. The present investigation suggests the potential of GEL/WPI hydrogels as effective carriers for delivering NeuAc encapsulation., 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 Ltd. All rights reserved.)

To enhance the bioavailability of bioactives with varying efficacy in the gastrointestinal tract (GIT), a co-delivery system of solid-in-oil-in-water (S/O/W) emulsion was designed for the co-encapsulation of two bioactives in this paper. S/O/W emulsions were fabricated utilizing fucoxanthin (FUC)-loaded nanoparticles (NPs) as the solid phase, coconut oil containing curcumin (Cur) as the oil phase, and carboxymethyl starch (CMS)/propylene glycol alginate (PGA) complex as the aqueous phase. The high entrapment efficiency of Cur (82.3-91.3%) and FUC (96.0-96.1%) was found in the CMS/PGA complex-stabilized S/O/W emulsions. Encapsulation of Cur and FUC within S/O/W emulsions enhanced their UV and thermal stabilities. In addition, S/O/W emulsions prepared with CMS/PGA complexes displayed good stability. More importantly, the formed S/O/W emulsion possessed programmed sequential release characteristics, delivering Cur and FUC to the small intestine and colon, respectively. These results contributed to designing co-delivery systems for the programmed sequential release of two hydrophobic nutrients in the GIT., 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 Ltd. All rights reserved.)

A novel curcumin (CUR) delivery system was developed using soybean whey protein (SWP)-based emulsions, enhanced by pH-adjustment and gum arabic (GA) modification. Modulating electrostatic interactions between SWP and GA at oil/water interface, pH provides favorable charging conditions for stable distribution between droplets. GA facilitated the SWP form a stable interfacial layer that significantly enhanced the emulsifying properties and CUR encapsulation efficiency of the system at pH 6.0, which were 90.15 ± 0.67%, 870.53 ± 3.22 m 2 /g and 2157.62 ± 115.31%, respectively. Duncan's test revealed significant improvements in thermal, UV, oxidative, and storage stabilities of CUR (P < 0.05). At pH 6.0, GA effectively protected CUR by inhibiting SWP degradation during gastric digestion and promoting the release of CUR by decreasing steric hindrance with oil droplets during intestinal digestion, achieving the highest CUR bioaccessibility (69.12% ± 0.28%) based on Duncan's test. The SWP-GA-CUR emulsion delivery system would be a novel carrier for nutrients., 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 Ltd. All rights reserved.)

Guavinoside B (GUB) is a characteristic constituent from guava with strong antioxidant activity; however, its low water solubility limits its utilization. Herein, we investigated the interaction between GUB and zein, a prolamin with self-assembling property, using multiple spectroscopic methods and fabricated GUB-zein-NaCas nanoparticles (GUB-Z-N NPs) via the antisolvent coprecipitation approach. GUB caused fluorescence quenching to zein via the static quenching mechanism. Fourier-transform infrared spectroscopy and computational analysis revealed that GUB bound to zein via van der Waals interaction, hydrogen bond, and hydrophobic forces. The GUB-Z-N NPs were in the nanometric size range (< 200 nm) and exhibited promising encapsulation efficiency and redispersibility after freeze-drying. These particles remained stable for up to 31 days at 4 °C and great resistance to salt and pH variation, and displayed superior antioxidant activity to native GUB. The current study highlights the potential of zein-based nanoparticles as delivery vehicles for GUB in the food industry., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Intracellular protein delivery has the potential to revolutionize cell-biological research and medicinal therapy, with broad applications in bioimaging, disease treatment, and genome editing. Herein, we demonstrate successful delivery of a functional protein, cytochrome c (CYC), by using a boron cluster anion as molecular carrier of the superchaotropic anion type (B 12 Br 11 OPr 2- ). CYC was delivered into lipid bilayer vesicles as well as living cells, with a cellular uptake ratio approaching 90%. Mechanistic studies showed that CYC was internalized into cells through a permeation pathway directly into the cytoplasm, bypassing endosomal entrapment. Upon carrier-assisted internalization, CYC retained its bioactivity, as reflected by an induced cell apoptosis rate of 25% at low dose (1 µM). This study furbishes a direct protein delivery method by a molecular carrier with high efficiency, confirming the potential of inorganic cluster ions as protein transport vehicles with an extensive range of future cell-biological or biomedical applications., Competing Interests: Competing interests statement:A.B.-B. and W.M.N. are co-inventors on a related patent (WO 2021/259668 A1).

Hollow hydrogels, characterized by their three-dimensional networks akin to biological tissues, are extensively utilized in artificial blood vessels, drug delivery, and nerve conduits due to their superior biocompatibility and fluid-transportation capacity. Nonetheless, the fabrication of hollow hydrogels presents significant challenges, including intricate steps, costly equipment, and structural instability. Consequently, refining the preparation techniques for hollow hydrogels remains paramount to surmounting the limitations of conventional methods. This research introduces an innovative approach that markedly diverges from traditional techniques, offering notable convenience and efficiency in the creation of hollow hydrogel structures. The central novelty of this method lies in employing laser light to induce an in situ photothermal effect, leading to the formation of hollow configurations. This laser-driven transformation of solid hydrogels into hollow structures addresses numerous shortcomings associated with traditional methods. For instance, conventional chemical approaches often necessitate several days to yield hollow hydrogels, and the resultant structures tend to be fragile and susceptible to damage under external pressure. In contrast, the laser-assisted technique facilitates the formation of hollow structures within 240 s, significantly outpacing traditional methods. To achieve controlled drug release, silk fibroin was integrated into the wall of the hollow hydrogels, enabling modulation of wall permeability and directing the drug release process.

Chemotherapy (CT) can significantly inhibit tumor growth, metastasis, and recurrence during cancer therapy. People have widely used platinum drugs in cancer treatment. However, as most chemotherapeutic drugs, platinum drugs still have shortcomings such as poor solubility, low cell uptake, nonspecific distribution, multidrug resistance, and adverse side effects. Therefore, we synthesized hollow copper sulfide (CuS) nanocubes with photothermal and photodynamic properties as carriers for Pt(IV) drugs. Hollow CuS nanocubes have attracted considerable interest in the field of cancer photothermal therapy (PTT) using multiple biological windows. Under near-infrared (NIR) laser irradiation, Cu 2+ can be reduced into Cu + in the presence of hydrogen peroxide in the tumor microenvironment. The resulting Cu + can be used for photodynamic therapy (PDT), which can perform a Fenton-like reaction under acidic conditions (pH 5.5-6.5) and catalyze hydrogen peroxide to produce ·OH in the tumor microenvironment. In addition, compared with Pt(II) drugs, Pt(IV) drugs not only have lower systemic toxicity but also consume glutathione (GSH), thereby increasing reactive oxygen species (ROS) levels in tumor cells and effectively promoting PDT. In this study, we oxidized ethylenediamine platinum chloride to its tetravalent state, loaded the Pt(IV) complexes using hollow CuS nanocubes, and modified the surfaces of the nanoparticles with PEG to improve the EPR effect. The Pt(IV)-loaded hollow CuS nanocubes modified with PEG (Pt(IV)-CuS@PEG) are expected to be used for tumor chemo/photothermal/photodynamic therapy.

The porous materials known as metal-organic frameworks (MOFs) stand out for their enormous surface area, adaptable pore size and shape, and structural variety. These characteristics make them well-suited for various applications, especially in healthcare. This review thoroughly summarizes recent studies on the use of MOFs in drug delivery, biosensing, and therapeutics. MOFs may encapsulate medications, target certain cells or tissues, and regulate their release over time. Additionally, MOFs have the potential to be used in biosensing applications, allowing for the selective detection of chemical and biological substances. MOFs' optical or electrical characteristics may be modified to make biosensors that track physiological data. MOFs show potential for targeted drug delivery and the regulated release of therapeutic substances in cancer treatment. In addition, they may work as potent antibacterial agents, providing a less dangerous option than traditional antibiotics that increase antibiotic resistance. For practical applications, further research is required as well as more consideration for the problems with toxicity and biocompatibility. In addition to addressing the difficulties and promising possibilities in this area, this study intends to provide insights into the potential of MOFs in healthcare for drug delivery, biosensing, and treatment. Despite several essential reviews in this area, it was necessary to look into the most recent research on drug delivery, biosensing, and therapy as a combined concept.

Colorectal cancer (CRC) is one of the most common and challenging malignancy that needs some effective and safer chemotherapeutic agents for the treatment. In this study, anticancer agent epirubicin (Epi) was loaded in polymeric polyethylene glycol-polylactic acid-nanoparticles (mPEG-PLA-NPs) coated with a marine anti-cancer non-toxic polysaccharide fucoidan (FC), to achieve a synergistic activity against CRC. The characterization of the NPs revealed that they were spherical, monodispersed, stable, with a negative zeta potential, and exhibited good biocompatibility and controlled release. In vitro anti-cancer activity of the NPs on HCT116 cell line was found to be promising, and corroborated well with in vivo studies involving BALB/C mice injected with C26 murine cancer cells. The outcome of MTT assay demonstrated that IC 50 value of free Epi was 3.72 µM, and that of non-coated and coated Epi nano-formulations was 33.67 and 10.19 µM, respectively. Higher tumor regression, better survival and reduced off-side cardiotoxicity were observed when this novel NPs formulation was used to treat tumor-bearing mice. Free FC and Epi treated mice showed 37.73 % and 61.49 % regression in tumor size, whereas there was 79.76 % and 90.34 % tumor regression in mice treated with non-coated Epi NPs and coated Epi NPs, respectively. Therefore, mPEG-PLA-FC-Epi-NPs hold a potential to be used as an effective chemotherapeutic formulation against CRC, since it exhibited better efficacy and lower 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.)

Epilepsy is a highly prevalent neurological disease and valproic acid (VPA) is used as a first-line chronic treatment. However, this drug has poor oral bioavailability, which requires the administration of high doses, resulting in adverse effects. Alternative routes of VPA administration have therefore been investigated, such as the nose-to-brain route, which allows the drug to be transported directly from the nasal cavity to the brain. Here, the use of nanostructured lipid carriers (NLC) to encapsulate drugs administered in the nasal cavity has proved advantageous. The aim of this work was to optimise a mucoadhesive formulation of VPA-loaded NLC for intranasal administration to improve the treatment of epilepsy. The Design of Experiment (DoE) was used to optimise the formulation, starting with component optimisation using Mixture Design (MD), followed by optimisation of the manufacturing process parameters using Central Composite Design (CCD). The optimised VPA-loaded NLC had a particle size of 76.1 ± 2.8 nm, a polydispersity index of 0.190 ± 0.027, a zeta potential of 28.1 ± 2.0 mV and an encapsulation efficiency of 85.4 ± 0.8%. The in vitro release study showed VPA release from the NLC of 50 % after 6 h and 100 % after 24 h. The in vitro biocompatibility experiments in various cell lines have shown that the optimised VPA-loaded NLC formulation is safe up to 75 µg/mL, in neuronal (SH-SY5Y), nasal (RPMI 2650) and hepatic (HepG2) cells. Finally, the interaction of the optimised VPA-loaded NLC formulation with nasal mucus was investigated and mucoadhesive properties were observed. The results of this study suggest that the use of intranasal VPA-loaded NLC may be a promising alternative to promote VPA targeting to the brain, thereby improving bioavailability and minimising adverse effects., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Globally, colorectal cancer is a major health problem that ranks in third place in terms of occurrence and second in terms of mortality worldwide. New cases increase annually, with the absence of effective therapies, especially for metastatic colorectal cancer, emphasizing the need for novel therapeutic approaches. Although conventional treatments are commonly used in oncotherapy, their success rate is low, which leads to the exploration of novel technologies. Recent efforts have focused on developing safe and efficient cancer nanocarriers. With their nanoscale properties, nanocarriers have the potential to utilize internal metabolic modifications amid cancer and healthy cells. Drug repurposing is an emerging strategy in cancer management as it is a faster, cheaper, and safer method than conventional drug development. However, most repurposed drugs are characterized by low-key pharmacokinetic characteristics, such as poor aqueous solubility, permeability, retention, and bioavailability. Nanoparticles formulations and delivery have expanded over the past few decades, creating opportunities for drug repurposing and promises as an advanced cancer modality. This review provides a concise and updated overview of colorectal cancer treatment regimens and their therapeutic limitations. Furthermore, the chemotherapeutic effect of various FDA-approved medications, including statins, non-steroidal anti-inflammatory drugs, antidiabetic and anthelmintic agents, and their significance in colorectal cancer management. Along with the role of various nanocarrier systems in achieving the desired therapeutic outcomes of employing these redefined drugs., 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.)

The fabrications of hollow microcapsules (MCs) with new architecture and ability to incorporate different nanomaterials have received great interest for targeted cancer therapy. Recently, CuS based nanomaterials have been demonstrated to possess the ability to mimic Fenton-like activity in tumor environment and inducing cancer cell apoptosis by generating highly reactive oxygen species (ROS). In this study, we have developed poly(allylamine) hydrochloride (PAH)/dextran sulfate (DS) polyelectrolyte MCs capable of carrying doxorubicin (DOX) for targeted cancer therapy and ultrasound imaging. The electron microscopy investigations showed the formation of polymeric MCs of 3 µm in size with incorporated CuS NRs in their interior structure. The surface modification of MCs with folic acid (FA), and encapsulation of model hydrophilic molecules in MCs was studied by UV-Visible (UV-Vis) spectroscopy, Fourier transform infra-red (FTIR) spectroscopy and confocal laser scanning microscopy. The encapsulation efficiency of DOX was found to be 56 % and the release was found to be linear at pH 5.5 and 7.4 in the absence of ultrasound exposure. The ultrasound exposure resulted in sudden rupture of MCs at 1 MHz and 1 W/cm 2 and caused burst release of DOX at both pH conditions. The FA decorated PAH/DS/CuS NR MCs exhibited improved anti-cancer activity against MDA-MB-231 cancer cells due to the synergistic effects of ultrasound mediated burst release of chemotherapeutic drug (DOX), glutathione-stimulated ROS and targeted cancer therapy. Further, the capsules showed better echogenicity than that of control PAH/DS MCs when imaged under medical ultrasound-scanning system. Hence, the MCs demonstrated in this study have huge potential for targeted cancer theranostics by offering an option to image the cancer cells during the treatment period., 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.)

This study investigates the biodistribution of a nano lipid carrier system (NLCs) containing the hydrophobic drug erlotinib (ERL-NLCs). The system was labelled with the fluorescent dye IR-780 for real-time dynamic imaging. ERL-NLCs were initially developed using the ultrasonication method with oleic acid and stearic acid. In vitro and ex vivo studies were performed to confirm the formation and penetration of NLCs within the intestine. Subsequently, the biological distribution of ERL-NLCs was monitored using a fluorescent dye through the IVIS® fluorescent optical imaging technique in whole live animals. Mice were orally administered blank IR 780 dye solution, ERL suspension, and IR 780 labelled NLCs. Fluorescence images were acquired at different time intervals up to 24 h and then total radiant efficiency was calculated through the region of interest (ROI) of the whole animal at each interval of time for all three groups. To validate the results obtained from in vivo imaging, various organs including lungs, heart, liver, both kidneys, stomach, and intestine were subsequently extracted and examined after 24 h. The ROI was found to be higher in the blank IR 780 dye solution, followed by the drug suspension and IR 780 labelled NLCs. These results confirm that the plain ERL suspension distributes across the body, and its encapsulation in NLCs facilitates passage through the lymphatic intestinal pathway, effectively avoiding first-pass metabolism. The remarkable results indicated that the NLCs formulation effectively circumvents first-pass metabolism by adopting the intestinal lymphatic pathway, thereby enhancing the oral bioavailability of the drug. This observed behaviour underscores the potential of NLCs in optimizing drug delivery and minimizing adverse effects associated with gastrointestinal and metabolic processes., 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.)

Pulmonary drug delivery via aerosolization is a non-intrusive method for achieving localized and systemic effects. The aim of this study was to establish the impact of viscosity as a novel aspect (i.e., low, medium and high) using various lipid-based formulations (including liposomes (F1-F3), transfersomes (F4-F6), micelles (F7-F9) and nanostructured lipid carriers (NLCs; F10-F12)) as well as to investigate their impact on in-vitro nebulization performance using Trans-resveratrol (TRES) as a model anticancer drug. Based on the physicochemical properties, micelles (F7-F9) elicited the smallest particle size (12-174 nm); additionally, all formulations tested exhibited high entrapment efficiency (>89 %). Through measurement using capillary viscometers, NLC formulations exhibited the highest viscosity (3.35-10.04 m 2 /sec). Upon using a rotational rheometer, formulations exhibited shear-thinning (non-Newtonian) behaviour. Air jet and vibrating mesh nebulizers were subsequently employed to assess nebulization performance using an in-vitro model. Higher viscosity formulations elicited a prolonged nebulization time. The vibrating mesh nebulizer exhibited significantly higher emitted dose (ED), fine particle fraction (FPF) and fine particle dose (FPD) (up to 97 %, 90 % and 64 µg). Moreover, the in-vitro release of TRES was higher at pH 5, demonstrating an alignment of the release profile with the Korsmeyer-Peppas model. Thus, formulations with higher viscosity paired with a vibrating mesh nebulizer were an ideal combination for delivering and targeting peripheral lungs., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Bacteria can evade antimicrobial therapy by hiding inside host cells such as macrophages. Here we examine the ability of PLGA nanoparticles to deliver antibiotics to intracellular bacteria, specifically focusing upon the impact of nanoparticle size. Different sized Rhodamine-B conjugated PLGA nanoparticles were synthesized and uptake examined in two macrophage cell lines, as well as different epithelial cells, to determine the optimal properties for macrophage uptake. These studies demonstrate macrophages display a consistent increase in uptake with increased PLGA nanoparticle diameter. In a bacteria-macrophage co-culture model, we then examined the efficacy of different sized antibiotic-loaded PLGA nanoparticles against intracellular infections with K. pneumoniae and S. aureus. Increasing the size of antibiotic-loaded PLGA nanoparticles significantly increased their potency against intracellular K. pneumoniae. However, this was not observed for S. aureus, potentially due to the observation these nanoparticles failed to access the compartment in which S. aureus reside. This work demonstrates for the first time that increasing the size of antibiotic-loaded PLGA nanoparticles can significantly enhance antimicrobial efficacy against K. pneumoniae intracellular macrophage infections. However, our S. aureus studies indicate this is not a 'one size fits all' approach for all intracellular infections., 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 The Authors. Published by Elsevier B.V. All rights reserved.)

Docetaxel (DTX) is a recommended treatment in patients with metastasic prostate cancer (PCa), despite its therapeutic efficacy is limited by strong systemic toxicity. However, in localized PCa, intratumoral (IT) administration of DTX could be an alternative to consider that may help to overcome the disadvantages of conventional intravenous (IV) therapy. In this context, we here present the first in vivo preclinical study of PCa therapy with nanomedicines of mesoporous silica nanoparticles (MSN) and DTX by IT injection over a xenograft mouse model bearing human prostate adenocarcinoma tumors. The efficacy and tolerability, the biodistribution and the histopathology after therapy have been investigated for the DTX nanomedicine and the free drug, and compared with the IV administration of DTX. The obtained results demonstrate that IT injection of DTX and DTX nanomedicines allows precise and selective therapy of non-metastatic PCa and minimize systemic diffusion of the drug, showing superior activity than IV route. This allows reducing the therapeutic dose by one order and widens substantially the therapeutic window for this drug. Furthermore, the use of DTX nanomedicines as IT injection promotes strong antitumor efficacy and drug accumulation at the tumor site, improving the results obtained with the free drug by the same route., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Pablo Botella Asuncion reports financial support was provided by State Agency of Research. Pablo Botella Asuncion reports financial support was provided by Government of Valencia. Pablo Botella Asuncion has patent #WO2021/099662 issued to Universitat Politècnica de Valencia-Consejo Superior de Investigaciones Cientificas. If there are other authors, they 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Acute lung injury (ALI) arises from an excessive inflammatory response, usually progressing to acute respiratory distress syndrome (ARDS) if not promptly addressed. There is currently a limited array of effective treatments available for ALI. In this study, we developed disulfide bond-bridged prodrug self-assembled nanoparticles (referred to as DSSS NPs). These nanoparticles were consisted of Dexamethasone (Dex) and stearic acid (SA), and were designed to target and treat ALI. DSSS NPs demonstrated a substantial drug loading capacity with 37.75 % of Dex, which is much higher than conventional nanomedicines (usually < 10 %). Moreover, they exhibited the potential to specifically target injured lung tissue and inflammatory microenvironment-responsive release drugs. Consequently, DSSS NPs reduced significantly the levels of pro-inflammatory cytokines and tissue damage in mice with ALI induced by lipopolysaccharide (LPS). Overall, DSSS NPs offer a promising strategy for treatment of acute lung injury., 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.)

The goal of this work is to investigate if the synergistic antifungal activity between cyclosporine A, CsA, and voriconazole, VRZ, increases when both drugs are encapsulated in a nanocarrier as compared when they are free. The preparation and characterization of blank and VRZ and CsA loaded polymeric based PLGA nanoparticles (PLGA, PLGA-PEG, and PLGA+PEG) was a necessary previous step. Using the more suitable NPs, those of PLGA, the antifungal susceptibility tests performed with VRZ-loaded PLGA NPs, show no significant increase of the antifungal activity in comparison to that of free VRZ. However, the synergistic behavior found for the (VRZ+CsA)-loaded PLGA NPs was fourfold stronger than that observed for the two free drugs together. On the other hand, the investigation into the suppression of C. albicans biofilm formation showed that blank PLGA NPs inhibit the biofilm formation at high NPs concentrations. However, a minor effect or even a slight biofilm increase formation was observed at low and moderate NPs concentrations. Therefore, the enhancement of the biofilm inhibition found for the three tested treatments (CsA alone, VRZ alone, and VRZ+CsA) when comparing free and encapsulated drugs, within the therapeutic window, can be attributed to the drug encapsulation approach. Indeed, polymeric PLGA NPs loaded with CsA, VRZ, or VRZ+CsA are more effective at inhibiting the C. albicans biofilm growth than their free counterparts., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Controlled drug release systems are pivotal in optimizing therapeutic outcomes and mitigating side effects in treatment protocols. While traditional delivery vectors such as liposomes, micro/nanoparticles, and microspheres are effective, they often struggle with consistency in drug release rates. This study addresses these issues by integrating stimuli-responsive elements specifically magnetic, thermal, and pH-responsive components into drug delivery systems for precise control. Central to our approach is the use of silk fibroin (SF), chosen for its superior biocompatibility and tunable degradation kinetics. We developed uniform carrier microspheres (CMs) by embedding polydopamine nanoparticles (PDA NPs) into SF microspheres using a custom-designed microfluidic platform. The development process and the application of this platform are detailed, highlighting the precision in control achievable. These CMs showcased enhanced photothermal effects, with the thermal response finely adjustable by altering the PDA NPs concentration, achieving a notable temperature increase of 24.5 ° C at 7.4 wt% concentration. High drug loading capacity (7.5%) and encapsulation efficiency (91.6%) were achieved, along with a pH-responsive release profile under near-infrared irradiation, paving the way for targeted anticancer drug delivery systems using the model drug doxorubicin hydrochloride. These findings underscore the potential of the developed CMs for external topical application, offering promising prospects for targeted cancer therapy utilizing drug-loaded microspheres., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Multifunctional colloidal microgels that exhibit stimuli-responsive behaviour and excellent biocompatibility have attracted particular attention for developing functional compartmentalized networks. Herein, a series of stimuli-responsive microgels (M0, M1, and M2) were designed through the copolymerization of di(ethylene glycol) methyl ether methacrylate (DEGMA) and methacrylic acid (MAA) monomers using hydroxy ethyl methacrylate-coupled azobenzene (HEMA-Az) and ethylene glycol dimetharylate (EGDMA) as crosslinkers. The behaviour of the microgels in response to temperature, pH, and light was thoroughly investigated using spectroscopic, microscopic, and light-scattering techniques. Interestingly, the microgels deswelled with an increase in temperature, decrease in pH, and under the irradiation of UV light. Such a reversible swelling/deswelling behaviour was exploited for microgel M2, which showed better photoactuation at pH 5 with a higher fluid pumping velocity. The actuating microgel M2 was optimized for loading the drug ciprofloxacin (Cf) to study its release at different temperature, pH, and light conditions. Microgel M2 exhibited photoresponsive Cf release at pH 5 and 37 °C, demonstrating its potential for application in on-demand drug release.

Nicotinamide mononucleotide (NMN), a precursor of the coenzyme nicotinamide adenine dinucleotide (NAD+), has gained wide attention as an anti-aging agent, which plays a significant role in intracellular redox reactions. However, its effectiveness is limited by easy metabolism in the liver and subsequent excretion as nicotinamide, resulting in low bioavailability, particularly in the brain. Additionally, the blood-brain barrier (BBB) further hinders NMN supply to the brain, compromising its potential anti-aging effects. Herein, we developed a biocompatible polydopamine (PDA) platform to deliver NMN for boosting NAD+ levels in the brain for the first time. The lactoferrin (Lf) ligand was covalently attached to the PDA spheres to improve BBB transport efficiency. The resultant PDA-based system, referred to as PDA-Lf-NMN, not only exhibited superior BBB penetration ability but also improved the utilization rate of brain NMN in elevating NAD+ levels compared to NMN alone for both young (3 months) and old (21 months) mice. Moreover, after the old mice were treated with low-dose PDA-Lf-NMN (8 mg kg -1 day -1 ), they exhibited improved spatial cognition. Importantly, these nanomedicines did not induce any cellular necrosis or apoptosis. It provides a promising avenue for delivering NMN specifically to the brain, boosting NAD+ levels for promoting longevity and treating brain aging-related diseases.

Exosomes are nanosized, lipid membrane vesicles secreted by cells, facilitating intercellular communication by transferring cargo from parent to recipient cells. This capability enables biological crosstalk across multiple tissues and cells. Extensive research has been conducted on their role in the pathogenesis of degenerative musculoskeletal diseases such as osteoarthritis (OA), a chronic and painful joint disease that particularly affects cartilage. Currently, no effective treatment exists for OA. Given that exosomes naturally modulate synovial joint inflammation and facilitate cartilage matrix synthesis, they are promising candidates as next generation nanocarriers for OA therapy. Recent advancements have focused on engineering exosomes through endogenous and exogenous approaches to enhance their joint retention, cartilage and chondrocyte targeting properties, and therapeutic content enrichment, further increasing their potential for OA drug delivery. Notably, charge-reversed exosomes that utilize electrostatic binding interactions with cartilage anionic aggrecan glycosaminoglycans have demonstrated the ability to penetrate the full thickness of early-stage arthritic cartilage tissue following intra-articular administration, maximizing their therapeutic potential. These exosomes offer a non-viral, naturally derived, cell-free carrier for OA drug and gene delivery applications. Efforts to standardize exosome harvest, engineering, and property characterization methods, along with scaling up production, will facilitate more efficient and rapid clinical translation. This article reviews the current state-of-the-art, explores opportunities for exosomes as OA therapeutics, and identifies potential challenges in their clinical translation.

Introduction: Exosomes (Exos) are promising drug delivery systems due to their low immunogenicity, minimal toxicity, high biocompatibility, and effective delivery capabilities. However, addressing the cardiotoxicity and other toxic side effects associated with anthracyclines has proven challenging., Methods: In this study, we loaded doxorubicin (Dox) into Exos derived from human placental mesenchymal stem cells (MSCs) and modified them with carboxylated Fe 3 O 4 nanoparticles (NPs) to create an Exo-Dox-NP delivery system. Using an external magnetic force (MF), we regulated the distribution of Exos for targeted Dox delivery in breast cancer treatment. We characterized and determined the drug-loading efficiency of Exo-Dox-NPs, their uptake by tumor cells, and the modulation of drug release. The therapeutic efficacy of Exo-Dox-NPs was evaluated through both in vitro and in vivo anti-tumor experiments., Results: Our results indicated that Exo-Dox-NPs remain stable in the bloodstream while releasing the drug in the acidic environment of tumor cells and their lysosomes. As a drug delivery system, Exo-Dox-NPs enhanced Dox absorption by tumor cells, demonstrating high targeting specificity. Moreover, Exo-Dox-NPs inhibited the migration of breast cancer cells, as confirmed by scratch migration and Transwell Matrigel invasion assays. In vivo experiments confirmed the effective targeting and delivery of Dox to malignant tumors using Exo-Dox-NPs/MFs, with the Exo-Dox-NP/MF formulation exhibiting the most potent anti-tumor activity., Conclusion: The utilization of Exos as carriers for Dox showed promising efficacy in breast cancer management. Carboxylated Fe 3 O 4 NPs demonstrated to be suitable targeting agents, potentially advancing the development of natural nanocarriers for combination cancer therapy., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Xu et al.)

Acute myeloid leukemia (AML) is an aggressive blood cancer with frequently poor clinical outcomes. This heterogeneous malignancy encompasses genetically, molecularly, and even clinically different subgroups. This makes it difficult to develop therapeutic agents that are effective for all subtypes of the disease. Therefore, a selective, universal, and adaptable delivery platform capable of carrying various types of anti-neoplastic agents is an unmet requirement in this area. Two multifunctional fusion proteins were designed for the delivery of biotinylated cargoes to human myeloid leukemia cells by fusing an anti-IL-1RAP single-chain antibody with streptavidin (tetramer or monomer), a cell-penetrating peptide (CPP), and an endosomolytic peptide in a single biomacromolecule. The designed fusions were analyzed primarily in silico, and the biofunctionality of the selected fusion was fully characterized via several binding assays, hemolysis assay, confocal microscopy and cell cytotoxicity assay after production via the Escherichia coli (E. coli) system. The refolded protein exhibited desirable binding activity to leukemic cells, pure antigen and biotinylated BSA. Further analyses revealed efficient cellular uptake, endosomolytic activity, and nuclear penetration without any detectable cytotoxicity toward normal epithelial cells. The described platform seems to have great potential for targeted delivery of different therapeutics to malignant myeloid cells., (© 2024. The Author(s).)

Bacterial keratitis (BK) is a serious ocular infection that can lead to vision impairment or blindness if not treated promptly. Herein, we report the development of a versatile composite hydrogel consisting of silk fibroin and sodium alginate, reinforced by antibiotic-loaded mesoporous silica nanoparticles (MSNs) for the treatment of BK. The drug delivery system is constructed by incorporating vancomycin- and ceftazidime-loaded MSNs into the hydrogel network. The synthesized MSNs were found to be spherical in shape with an average size of about 95 nm. The loading capacities of both drugs were approximately 45% and 43%, for vancomycin and ceftazidime respectively. Moreover, the formulation exhibited a sustained release profile, with 92% of vancomycin and 90% of ceftazidime released over a 24 h period. The cytocompatibility of the drug carrier was also confirmed by MTT assay results. In addition, we performed molecular dynamics (MD) simulations to better reflect the drug-drug and drug-MSN interactions. The results obtained from RMSD, number of contacts, and MSD analyses perfectly corroborated the experimental findings. In brief, the designed drug-MSN@hydrogel could mark an intriguing new chapter in the treatment of BK., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Ferroptosis is an iron-dependent cell death pathway triggered by the toxic accumulation of lipid peroxides on cellular membranes. However, an imbalance in iron metabolism in tumor cells leads to the insufficient accumulation of iron ions in the iron pool, which inhibits ferroptosis. Nonspecific delivery of iron species may increase the risk of promoting tumor proliferation as well as trigger undesirable detrimental effects such as anaphylactic reactions in normal tissues. This study found that a constructed self-enhancing targeted nanocarrier can accurately regulate the iron pool levels in tumor cells. We constructed a programmatic targeted enhanced nanotherapy strategy by loading the ferroptosis inducer erastin into a self-enhancing targeted nanocarrier. This nanosystem was more effective at inducing tumor ferroptosis after upregulating the iron pool levels in tumor cells with self-enhancing targeted nanocarriers. Both in vitro and in vivo outcomes demonstrated notable anticancer ferroptosis efficacy, indicating that self-enhancing targeted nanocarriers can effectively regulate the level of the iron pool in tumor cells and promote ferroptosis. The combination of this nanotherapy strategy with self-enhancing targeted chemotherapy nanomedicines can achieve complete tumor clearance. Moreover, this self-enhancing targeted ferroptosis nanotherapy strategy is expected to be beneficial for future progress in the field of cancer self-enhancing targeted therapy.

Nanoformulation of chemotherapies represents a promising strategy to enhance outcomes in cancer therapy. Gemcitabine is a chemotherapeutic agent approved by the Food and Drug Administration for the treatment of various solid tumors. Nevertheless, its therapeutic effectiveness is constrained by its poor metabolic stability and pharmacokinetic profile. Nanoformulations of gemcitabine in lipid and polymer nanocarriers usually lead to poor loading capability and an inability to effectively control its release profile due to the physicochemical characteristics of the drug and matrices. Here, we propose metal-gemcitabine complexation with biorelevant metal cations as a strategy to alter the properties of gemcitabine in a noncovalent manner, paving the way for the development of novel nanoformulations. A speciation study on gemcitabine and Mn 2+ , Zn 2+ , and Ca 2+ was performed with the aim of investigating the extent of the interaction between the drug and the proposed metal cations, and selecting the best conditions of temperature, pH, and drug-to-metal molar ratio that optimize such interactions. Also, a series of density functional theory calculations and spin-polarized ab initio molecular dynamics simulations were carried out to achieve insights on the atomistic modalities of these interactions. Mn 2+ -gemcitabine species demonstrated the ability to maintain gemcitabine's biological activity in vitro . The scientific relevance of this study lies in its potential to propose metal-gemcitabine as a valuable strategy for developing nanoformulations with optimized quality target product profiles. The work is also clinically relevant because it will lead to improved treatment outcomes, including enhanced efficacy and pharmacokinetics, decreased toxicity, and new clinical possibilities for this potent therapeutic molecule.

Lung cancer has emerged as the second most common type of malignant tumor worldwide, and it has the highest mortality rate. The overall 5-year survival rate stands at less than 20%, which is primarily related to the limited therapeutic options and the complexity of the tumor immune microenvironment. In the tumor microenvironment, M1 macrophages are known for their tumor-killing capabilities. Although they are less numerous, they play an important role in tumor immunity. Therefore, increasing M1 macrophages' presence is considered a strategy to enhance targeted phagocytosis and antitumor efficacy in nonsmall cell lung cancer (NSCLC). This study introduces the development of folic acid (FA)-conjugated liposomal nanobubbles for precise delivery of PFH, STAT3 siRNA, and Fe 3 O 4 to the tumor microenvironment. These encapsulated PFH liposomal nanobubbles exhibit significant visualization potential and underwent phase transition when exposed to low-intensity focused ultrasound (LIFU). The release of Fe 3 O 4 activates the IRF5 signaling pathway, converting M2-like macrophages to M1. In addition, STAT3 siRNA effectively interrupts the JAK-STAT3 pathway, inhibiting the polarization of M2-like macrophages in tumor-associated macrophages (TAMs). This dual-action therapy facilitates T-cell activation and proliferation, thereby enhancing the immune response against NSCLC.

The loading capacity of dsRNA by nanocarriers is a key parameter in the process of RNAi commercialisation. In this research, a sustainable, simple, and cheap method was developed to determine the dsRNA loading capacity by popular cationic nanocarriers. In this method, the fluorescence emission of the cationic nanocarrier + (dsRNA-DAPI) shows blue shift in comparison to that of dsRNA-DAPI. When dsRNA-DAPI is completely loaded by cationic nanocarriers, the fluorescence peak coincides with the emission wavelength of DNA-DAPI. The samples of nanocarrier + (dsRNA-DAPI) are simply tested in a fluorometer with no damage to the samples. The reported method is simpler, cheaper, and more sustainable than gel electrophoresis and HPLC, and will fulfill the industry need for reliable and quick quality administration/control in the production process.

Osteoporosis is a disease that plagues the world, the complications of which, spinal fractures and hip fractures, seriously endanger the health of the elderly. At present, the main treatment for osteoporosis is anti-osteoporosis drugs, some of which, however, have poor efficacy and side effects. Thus, the development of new drugs for the treatment of osteoporosis is of clinical significance. Berberine (BBR) has a good therapeutic effect on osteoporosis, but its poor solubility and instability limit its effect. Tetrahedral framework nucleic acids (tFNAs) are a novel nano-drug delivery tool, and their good cell entry ability and stability make them an excellent carrier. Therefore, a new nanocomplex T-BBR was synthesized by carrying BBR with tFNAs. Compared with BBR, T-BBR showed better osteogenic and anti-osteoporosis abilities in both in vivo and in vitro experiments, the mechanism of which was realized through the Wnt signaling pathway.

This study presents the use of nanoscale covalent organic frameworks (nCOFs) conjugated with tumor-targeting peptides for the targeted therapy of triple-negative breast cancer (TNBC). While peptides have previously been used for targeted delivery, their conjugation with COFs represents an innovative approach in this field. In particular, we have developed alkyne-functionalized nCOFs chemically modified with cyclic RGD peptides (Alkyn-nCOF-cRGD). This configuration is designed to specifically target α v β 3 integrins that are overexpressed in TNBC cells. These nCOFs exhibit excellent biocompatibility and are engineered to selectively disintegrate under acidic conditions, allowing for precise and localized drug release in tumor environment. Doxorubicin, a chemotherapeutic agent, has been encapsulated in these nCOFs with high loading efficiency. The therapeutic potential of Alkyn-nCOF-cRGD has been demonstrated in vitro and in vivo models. It shows significantly improved drug uptake and targeted cell death in TNBC, highlighting the efficacy of receptor-mediated endocytosis and pH-controlled drug release. This strategy leverages the unique properties of nCOFs with targeted drug delivery to achieve significant advances in personalized cancer therapy and set a new standard for precision chemotherapeutic delivery.

Self-assembly of hydrogels for mechanical support and drug delivery has been extensively researched in traumatic brain injury (TBI), where treatment options are limited. The chief challenge is that most self-assembled hydrogels rely on high molecular carriers or the incorporation of exogenous inactive substances as mediators. It is difficult for these drug delivery systems to achieve clinical translation due to concerns regarding biological safety. Here we report a small molecule hydrogel (GBR-gel) loading small molecule drugs (glycyrrhizic acid, berberine, and rhein) that originated from popular Chinese medicines without additional drug loading or inactive components under physiological conditions. In the long run, GBR-gel possesses several advantages, including ease of preparation, cost-effectiveness, and high biocompatibility. As a proof-of-concept, GBR-gel allows for prompt administration at the site of brain injury to exert potent pharmacodynamic effects. Further single-cell RNA sequencing and experimental validation indicated that GBR-gel can effectively rescue the suppressed glutamatergic synapse pathway after TBI, thereby attenuating inflammatory responses and neural impairments. Our work provides an alternative strategy for timely intervention of TBI.

This study focused on developing a thermosensitive gel with nanostructured lipid carriers (NLCs) loaded with paroxetine (PAR) to enhance the treatment and management of depression via nasal administration. Micro emulsion technique was utilized for the PAR-NLCs preparation. The acetyl alcohol and oleic acid were used in the ratio of 76:24. In the NLCs Tween 40, Span40 and Myrj 52 were used as a surfactant. The NLCs were then added into Poloxamer mixture to get thermosensitive NLCs based gel. Characterization, in vitro and in vivo studies were performed to check the efficiency of formulation in drug delivery. The entrapment efficiency of optimized PAR-NLCs was about 90%. The particle size, zeta potential and PDI were 155 ± 1.4 nm, -25.9 ± 0.5 mV, and 0.12 ± 0.01 respectively. The optimized gel showed a gelling temperature of 31.50 ± 0.50°C and a gelling time of 1 ± 0.12 s with a pH of 6, suitable for nasal administration. The in vitro release assay of PAR-NLC-gel showed a cumulative release of about 59% in the first 6 h after comparison with PAR-NLCs which showed almost 100%release. In vivo studies included forced swim test and tail suspension tests showed significant potential for treating depression when compared to PAR-NLCs. PAR-NLCs and NLCs based gel enhanced the tissue architecture and suppressed the expression of TNF-α in brain cortex from histological and immunohistochemical analysis. PAR- NLCs gel-based delivery system can prove to be an effective delivery system for brain targeting through nose for the better management of depression., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Phytoconstituent based therapies have the potential to reduce the adverse effects and enhance overall patient compliance for different diseased conditions. Embelin (EMB) is a natural compound extracted from Embelia ribes that has demonstrated high therapeutic potential, particularly as anti-inflammatory and anticancer therapeutic applications. However, its poor water solubility and low oral bioavailability limitations make it challenging to use in biomedical applications. Nanostructure-based novel formulations have shown the potential to improve physicochemical and biological characteristics of active pharmaceutical ingredients obtained from plants. Different nanoformulations that have been utilized to encapsulate/entrap EMB for various therapeutic applications are nanoliposomes, nanostructured lipid carriers, niosomes, polymeric nanoparticles, nanosuspensions, phytosomes, self nanoemulsifying drug delivery system, silver nanoparticles, microparticles, solid lipid nanoparticle, gold nanoparticles and nanomicelles. The common methods reported for the preparation of EMB nanoformulations are thin film hydration, nanoprecipitation, ethanol injection, emulsification followed by sonication. The size of nanoformulations ranged in between 50 and 345 nm. In this review, the mentioned EMB loaded nanocarriers are methodically discussed for size, shape, drug entrapment, zeta potential, in vitro release & permeation and in vivo studies. Potential of EMB with other drugs (dual drug approach) incorporated in nanocarriers are also discussed (physicochemical and preclinical characteristics). Patents related to EMB nanoformulations are also presented which showed the clinical translation of this bioactive for future utilization in different indications., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Iloperidone, a second-generation USFDA approved antipsychotic and BCS class II drug shows poor oral bioavailability of 28%. The present research deals with optimization of transnasal nanoemulsions of Iloperidone using Design Expert (Version 11) and further surface functionalization with chitosan for potentiating nose to brain delivery. Chitosan functionalized transnasal Iloperidone nanoemulsions were developed using oleic acid, charge inducer, Tween 80, Transcutol HP and chitosan using ultrasonication technique and evaluated. Droplet size, polydispersity index and zeta potential of Iloperidone nanoemulsions was found to be 173 ± 0.5 nm, 0.413 ± 0.2 and - 22.5 ± 0.1 mV while that of chitosan functionalized Iloperidone nanoemulsions was 146.4 ± 0.5 nm, 0.291 ± 0.02 and + 23.6 ± 0.3 mV respectively. Ninhydrin assay, TEM and FTIR studies confirmed surface functionalization of Iloperidone nanoemulsion droplets with chitosan. In vitro release of Iloperidone from nanoemulsions and chitosan functionalized nanoemulsions was 90.41 ± 2.1% and 72.02 ± 0.21% while ex vivo permeation of Iloperidone across goat nasal mucosa was 1270.58 ± 0.023 μg/cm 2 and 1096.13 ± 0.043 μg/cm 2 respectively at the end of 8 h. Studies in RPMI 2650 nasal and Neuro2A brain cell line lines indicated safety of chitosan functionalized transnasal Iloperidone nanoemulsions. Studies in Wistar rats showed increased cataleptic effects, reduced cognitive impairment and anxiety-related behaviour with greater brain accumulation indicating promising potential of this approach in nose to brain drug delivery., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

In order to achieve a therapeutic effect, many drugs have to reach specific cellular compartments. Nanoscale drug delivery systems extend the circulation time, reduce adverse effects and thus improve tolerability compared to systemic administration. We have developed two types of albumin-coated nanocarriers equipped with built-in dyes to track their cellular uptake and intracellular enzymatic opening. Using the approved antiprotozoal drug and STAT3 inhibitor Atovaquone (Ato) as prototype for a hydrophobic small molecule, we show that Ato-loaded ovalbumin-coated nanocapsules (Ato-nCap) preferentially enter human myeloid cells. In contrast, Ato nanocrystals coated with human serum albumin (Ato-nCry) distribute their cargo in all different immune cell types, including T and B cells. By measuring the effect of Ato nanocarriers on induced STAT3 phosphorylation in IL-10-primed human dendritic cells and constitutive STAT3 phosphorylation in human melanoma cells, we demonstrate that the intracellular Ato release is particularly effective from Ato nanocrystals and less toxic than equal doses of free drug. These new nanocarriers thus represent effective systems for intracellular drug delivery.

A series of hybrid hydrogels of poly(ethylene glycol) (PEG) were synthesized using gelatin as a crosslinker and investigated for controlled delivery of the first-generation cephalosporin antibiotic, Cefazedone sodium (CFD). A commercially available 4-arm-PEG-OH was first modified to obtain four-arm-PEG-succinimidyl glutarate (4-arm-PEG-SG), which formed the gelatin-PEG composite hydrogels (S n N m ) through crosslinking with gelatin. To regulate the drug delivery, S n N m hydrogels with various solid contents and crosslinking degrees were prepared. The effect of solid contents and crosslinking degrees on the thermal, mechanical, swelling, degradation, and drug release properties of the hydrogels were intensively investigated. The results revealed that increasing the crosslinking degree and solid content of S n N m could not only enhance the thermal stability, swelling ratio (SR), and compression resistance capacity of S n N m but also prolong the degradation and drug release times. The release kinetics of the S n N m hydrogels were found to follow the first-order model, suggesting that the transport rate of CFD within the matrix of hydrogels is proportional to the concentration of the drug where it is located. Specifically, S 1 N 1 -III showed 90% mass loss after 60 h of degradation and a sustained release duration of 72 h. The cytotoxicity assay using the MTT method revealed that cell viability rates of S 1 N 1 were higher than 95%, indicating excellent cytocompatibility. This study offers new insights and methodologies for the development of hydrogels as biomedical composite materials.

Covalent drugs can offer significant advantages over non-covalent drugs in terms of pharmacodynamics (i.e., target-binding properties). However, the development of covalent drugs is sometimes hampered by pharmacokinetic limitations (e.g., low bioavailability, rapid metabolism and toxicity due to off-target binding). Polymeric nanoparticles offer a potential solution to these limitations. Delivering covalent drugs via polymeric nanoparticles provides myriad benefits in terms of drug solubility, permeability, lifetime, selectivity, controlled release and the opportunity for synergistic administration alongside other drugs. In this short review, we examine each of these benefits in turn, illustrated through multiple case studies.

The current research attempted to address the suitability of bioactive Sambucus nigra extract entrapped in albumin-decorated nanostructured lipid carriers (NLCs) as a promising "adjuvant" in improving tumour penetration for multiple antitumour therapy. The new hybrid albumin-decorated NLCs were characterised based on, e.g., the particle size, zeta electrokinetic potential, SambucusN entrapment efficiency, and fluorescence spectroscopy and tested for different formulation parameters. The antioxidant activity of NLC- SambucusN was significantly enhanced by a bovine serum albumin (BSA) polymer coating. According to the real-time cell analysis (RTCA) results, NLC-I- SambucusN -BSA behaved similarly to the chemotherapeutic drug, cisplatin, with cell viability for LoVo tumour cells of 21.81 ± 1.18%. The new albumin-NLC- SambucusN arrested cancer cells in G1 and G2 cycles and intensified the apoptosis process in both early and late phases. An advanced induction, over 50% apoptosis in LoVo colon cells, was registered for 50 μg/mL of NLC-II- SambucusN -BSA, a fourfold increase compared to that of untreated cells. RTCA and flow cytometry results showed that concentrations of the hybrid NLC- SambucusN up to 50 μg/mL do not affect the proliferation of normal HUVEC cells. This approach provides insightful information regarding the involvement of phytochemicals in future therapeutic strategies. Albumin-decorated NLCs can be considered a noteworthy strategy to be connected to antitumour therapeutic protocols.

Chemotherapy for hepatoblastoma is limited by organ toxicity and poor outcomes, prompting the search for new, more effective treatments with minimal side effects. Vincristine sulfate, a potent chemotherapeutic, faces challenges due to P-glycoprotein-mediated resistance and its systemic toxicity. Nanoparticles offer a promising solution by improving pharmacokinetics, targeting tumor cells, thus reducing side effects. Moreover, the use of fluorescent nanomaterials is emerging in biomedical applications such as bioimaging, detection and therapies. This study describes a promising delivery system utilizing carbon dots encapsulated with vincristine in biodegradable polycaprolactone nanoparticles via a double emulsion technique. The fine characterization of these nanoparticles showed that they are spherical, uniformly sized with around 200 nm and exhibit excellent colloidal stability. Moreover, the release profile showed prolonged release for both vincristine and carbon dots. In vitro cell viability studies revealed enhanced cancer cell inhibition for the encapsulated drug compared to the vincristine solution. The uptake study indicated clear fluorescence for carbon dots solution and vincristine and carbon dots loaded nanoparticles upon excitation. Additionally, studies on primary mouse hepatocytes demonstrated higher fluorescence intensity in treatment groups. These results suggest that vincristine and carbon dots loaded nanoparticles are effective, target-specific carriers for liver cancer treatment. Furthermore, the carbon dots were not cytotoxic, highlighting their potential in bioimaging and cancer cell studies., (© 2024. The Author(s).)

Natural compound-based treatments provide innovative ways for ulcerative colitis therapy. However, poor targeting and rapid degradation curtail its application, which needs to be addressed. Inspired by biomacromolecule-based materials, we have developed an orally administrated nanoparticle (GBP@HA NPs) using bovine serum albumin as a carrier for polyphenol delivery. The system synergizes galactosylated bovine serum albumin with two polyphenols, epigallocatechin gallate and tannic acid, which is then encased in "nanoarmor" of ε-Polylysine and hyaluronic acid to boost its stability and targeting. Remarkably, the nanoarmor demonstrated profound therapeutic effects in both acute and chronic mouse models of ulcerative colitis, mitigating disease symptoms via multiple mechanisms, regulating inflammation related factors and exerting a modulatory impact on gut microbiota. Further mechanistic investigations indicate that GBP@HA NPs may act through several pathways, including modulation of Keap1-Nrf2 and NF-κB signaling, as well as Caspase-1-dependent pyroptosis. Consequently, this novel armored nanotherapy promotes the way for enhanced polyphenol utilization in ulcerative colitis treatment research., (© 2024. The Author(s).)

Nanoparticle-based antigen carrier systems have become a significant area of research with the advancement of nanotechnology. Biodegradable polymers have emerged as particularly promising carrier vehicles due to their ability to address the limitations of existing vaccine systems. In this study, we successfully encapsulated the G5-24 linear peptide, located between amino acids 253 and 275 in the primary sequence of the rabies virus G protein, into biodegradable and biocompatible PLGA copolymer using the double emulsion solvent evaporation method. The resulting nanoparticles had a size of approximately 230.9 ± 0.9074 nm, with a PDI value of 0.168 ± 0.017 and a zeta potential value of -9.86 ± 0.132 mV. SEM images confirmed that the synthesized nanoparticles were uniform in size and distribution. Additionally, FTIR spectra indicated successful peptide loading into the nanoparticles. The encapsulation efficiency of the peptide-loaded nanoparticles was 73.3%, with a peptide loading capacity of 48.2% and a reaction yield of 30.4%. Peptide release studies demonstrated that 65.55% of the peptide was released in a controlled manner over 28 d, following a 'biphasic burst release' profile consistent with the degradation profile of PLGA. This controlled release is particularly beneficial for vaccine studies. Cytotoxicity tests revealed that the R-NP formulation did not induce cytotoxicity in fibroblast cells and enhanced NO production in macrophages, indicating its potential for vaccine development., (Creative Commons Attribution license.)

Among bacteria used as anticancer vaccines, attenuated Listeria monocytogenes (Lm at ) stands out, because it spreads from one infected cancer cell to the next, induces a strong adaptive immune response, and is suitable for repeated injection cycles. Here, we use click chemistry to functionalize the Lm at cell wall and turn the bacterium into an "intelligent carrier" of the chemotherapeutic drug doxorubicin. Doxorubicin-loaded Lm at retains most of its biological properties and, compared to the control fluorophore-functionalized bacteria, shows enhanced cytotoxicity against melanoma cells both in vitro and in a xenograft model in zebrafish. Our results show that drugs can be covalently loaded on the Lm at cell wall and pave the way to the development of new two-in-one therapeutic approaches combining immunotherapy with chemotherapy.

Purpose: Liver cancer is associated significantly with morbidity and mortality. The combination of low-intensity ultrasound with nanomedicine delivery systems holds promise as an alternative for the treatment for liver cancer. This study focuses on the utilization of folic acid (FA) modified nanoparticles, which are loaded with fluorescent dye DiR and liquid fluorocarbon (PFP). These nanoparticles have the potential to enhance liver cancer targeting under ultrasound stimulation and future applications in vivo., Methods: The pharmacokinetics and tissue distribution of folic acid-modified Crebanine polyethylene glycol-polylactic acid copolymer nanoparticles (FA-Cre@PEG-PLGA NPs) were investigated. The pharmacokinetic parameters, liver targeting, and in vivo distribution were assessed. Additionally, the inhibitory impacts of FA-Cre@PEG-PLGA NPs in combination with ultrasonic irradiation on the proliferation and acute toxicity of H22 cells of mouse hepatoma were investigated in vitro. The tumor targeting and anti-tumor efficacy of FA-Cre@PEG-PLGA NPs were assessed utilizing a small animal in vivo imaging system and an in situ hepatocellular carcinoma transplantation model, respectively., Results: The pharmacokinetic studies and tissue distribution tests demonstrated that FA-Cre@PEG-PLGA NPs conspicuously prolonged the half-life and retention time of the drug in rats, and the liver targeting effect was pronounced. Additionally, the in vivo acute toxicity test indicated that FA-Cre@PEG-PLGA NPs had minimal adverse reactions and could fulfill the aim of attenuating the drug. The outcomes of the animal experiments further substantiated that FA-Cre@PEG-PLGA NPs had a longer retention time at the tumor site, a superior anti-tumor effect, and less damage to liver and kidney tissue., Conclusion: The integration of FA-Cre@PEG-PLGA NPs with ultrasound irradiation demonstrated exceptional safety and potent anti-tumor efficacy in vivo, presenting a promising therapeutic strategy for the treatment of liver cancer through the combination of ultrasound technology with a nanomedicine delivery system., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Cheng et al.)

Supramolecular assemblies of stimuli-responsive amphiphilic molecules have been of utmost interest in targeted drug delivery applications, owing to their capability of sequestering drug molecules in one set of conditions and releasing them in another. To minimize undesired disassembly and stabilize noncovalently encapsulated drug molecules, the strategy of core or shell cross-linking has become a fascinating approach to constructing cross-linked polymeric or small molecule-based nanoassemblies. In this article, we discuss the design and synthetic strategies for cross-linked nanoassemblies from small molecule-based amphiphiles, with robust stability and enhanced drug encapsulation capability. We highlight their potential biomedical applications, particularly in drug or gene delivery, and cell imaging. This feature article offers a comprehensive overview of the recent developments in the application of small molecule-based covalently cross-linked nanocarriers for materials and biomedical applications, which may inspire the use of these materials as a potential drug delivery system for future chemotherapeutic applications.

Introduction: Cisplatin is one of the most effective chemotherapeutic drugs used in oral cancer treatment, but systemic administration has side effects. The purpose of this study was to evaluate the effect of iontophoresis on the enhancement of cisplatin release from cisplatin-encapsulated chitosan nanoparticles., Methods: The effect of different mass ratios of chitosan to tripolyphosphate (TPP) (5:1, 10:1, 15:1, 20:1) on the encapsulation efficiency of cisplatin was investigated. Uptake of cisplatin-encapsulated chitosan by cells was observed using a confocal laser scanning microscope. The cell viability at different cisplatin concentrations was examined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Three iontophoresis methods, namely constant-current chronopotentiometry (CCCP), cyclic chronopotentiometry (CCP), and differential pulse voltammetry (DPV), were used to enhance cisplatin release from cisplatin-encapsulated chitosan nanoparticles. In addition, mouse oral squamous cell carcinoma cell lines were implanted into the mouse oral mucosa to induce oral cancer. The effects of enhanced cisplatin release by CCCP, CCP, and DPV on tumor suppression in mice were evaluated. Tumors and lymph nodes were isolated for hematoxylin-eosin staining and immunohistochemistry staining including Ki-67 and pan CK after sacrifice. Inductively coupled plasma mass spectrometry was conducted to quantify the platinum content within the tumors., Results: The results showed that nanoparticles with a mass ratio of 15:1 exhibited the highest cisplatin encapsulation efficiency (approximately 15.6%) and longest continued release (up to 35 days) in phosphate buffered saline with a release rate of 100%. Cellular uptake results suggested that chitosan nanoparticles were delivered to the cytoplasm via endocytosis. The results of the MTT assay revealed that the survival rate of cells decreased as the cisplatin concentration increased. The CCP (1 mA, on:off = 1 s: 1 s) and DPV (0-0.06 V) groups were the most effective in inhibiting tumor growth, and both groups exhibited the lowest percentage of Ki-67 positive and pan CK positive., Conclusion: This study is the first to investigate and determine the efficacy of DPV in enhancing in vivo drug release from nanoparticles for the treatment of cancer in animals. The results suggest that the CCP and DPV methods have the potential to be combined with surgery for oral cancer treatment., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 Chen et al.)

Venous thromboembolism (VTE) is a serious health condition and represents an important cause of morbidity and, in some cases, mortality due to the lack of effective treatment options. According to the Centers for Disease Control and Prevention, 3 out of 10 people with VTE will have recurrence of a clotting event within ten years, presenting a significant unmet medical need. For some VTE patients, symptoms can last longer and have a higher than average risk of serious complications; in contrast, others may experience complications arising from insufficient therapies. People with VTE are initially treated with anticoagulants to prevent conditions such as stroke and to reduce the recurrence of VTE. However, thrombolytic therapy is used for people with pulmonary embolism (PE) experiencing low blood pressure or in severe cases of DVT. New drugs are under development, with the aim to ensure they are safe and effective, and may provide an additional option for the treatment of VTE. In this review, we summarize all ongoing trials evaluating anticoagulant interventions in VTE listed in clinicaltrials.gov, clarifying their underlying mechanisms and evaluating whether they prevent the progression of DVT to PE and recurrence of thrombosis. Moreover, this review summarizes the available evidence that supports the use of antiplatelet therapy for VTE. Since thrombolytic agents would cause off-target effects, targeted drug delivery platforms are used to develop various therapeutics for thrombotic diseases. We discuss the recent advances achieved with thrombus-targeting nanocarriers as well as the major challenges associated with the use of nanoparticle-based therapeutics.

Mineralization is a key biological process that is required for the development and repair of tissues such as teeth, bone and cartilage. Exosomes (Exo) are a subset of extracellular vesicles (~50-150 nm) that are secreted by cells and contain genetic material, proteins, lipids, nucleic acids, and other biological substances that have been extensively researched for bone and oral tissue regeneration. However, Exo-free biomaterials or exosome treatments exhibit poor bioavailability and lack controlled release mechanisms at the target site during tissue regeneration. By encapsulating the Exos into biomaterials like hydrogels, these disadvantages can be mitigated. Several tissue engineering approaches, such as those for wound healing processes in diabetes mellitus, treatment of osteoarthritis (OA) and cartilage degeneration, repair of intervertebral disc degeneration, and cardiovascular diseases, etc., have been exploited to deliver exosomes containing a variety of therapeutic and diagnostic cargos to target tissues. Despite the significant efficacy of Exo-laden hydrogels, their use in mineralized tissues, such as oral and bone tissue, is very sparse. This review aims to explore and summarize the literature related to the therapeutic potential of hydrogel-encapsulated exosomes for bone and oral tissue engineering and provides insight and practical procedures for the development of future clinical techniques.

Gliomas are one of the most frequent primary brain tumors and pose a serious threat to people's lives and health. Platelets, a crucial component of blood, have been applied as drug delivery carriers for disease diagnosis and treatment. In this study, we designed engineered nanoplatelets for targeted delivery of therapeutic miR-375 and temozolomide (TMZ, a first-line glioma treatment agent) to enhance glioma therapy. Nanoplatelets were prepared through mild ultrasound, TMZ and miR-375 were co-loaded through ultrasound and electrostatic interactions, respectively, to combine chemotherapy with gene therapy against glioma. To improve the blood brain barrier (BBB) crossing efficiency and glioma targeting ability, the nanoplatelets were modified with central nervous system-specific rabies viral glycoprotein peptide (RVG) through thiol-maleimide click reaction. The RVG modified nanoplatelets co-loaded TMZ and miR-375 (NR/TMZ/miR-375) not only inherited the good stability and remarkable biocompatibility of platelets, but also promoted the cellular uptake and penetration of glioma tissues, and effectively induced cell apoptosis to enhance the therapeutic effect of drugs. In vivo studies showed that NR/TMZ/miR-375 significantly increased the circulation time of TMZ, and exhibited superior combined antitumor effects. In summary, this multifunctional 'natural' nanodrug delivery system provides a potent, scalable, and safety approach for platelet-based combined cancer chemotherapy and gene therapy., (© 2024. The Author(s).)

The low permeability and heterogeneous distribution of drugs (including nanomedicines) have limited their deep penetration into solid tumors. Herein we report the design of gold nanoparticles with virus-like spikes (AuNVs) to mimic viral shapes and facilitate tumor penetration. Mechanistic studies revealed that AuNVs mainly entered cells through macropinocytosis, then transported to the Golgi/endoplasmic reticulum system via Rab11-regulated pathway, and finally exocytosed through recycling endosomes, leading to high cellular uptake, effective transcytosis, and deep tumor penetration compared to gold nanospheres (AuNPs) and gold nanostars (AuNSs). The high tumor accumulation and deep tumor penetration of mitoxantrone (MTO) facilitated by AuNVs endowed effective chemophotothermal therapy when exposed to a near-infrared II laser, significantly reducing tumor sizes in a mouse model of colorectal cancer. This study reveals a potent mechanism of viral-like structures in tissue penetration and highlights their potential as effective drug delivery carriers.