Nanoparticle Platform Research Articles

Metal-organic-framework-based sitagliptin-release platform for multieffective radiation-induced intestinal injury targeting therapy and intestinal flora protective capabilities

In patients with abdominal or pelvic tumors, radiotherapy can result in radiation-induced intestinal injury (RIII), a potentially severe complication for which there are few effective therapeutic options. Sitagliptin (SI) is an oral hypoglycemic drug that exhibits antiapoptotic, antioxidant, and anti-inflammatory activity, but how it influences RIII-associated outcomes has yet to be established. In this study, a pH-responsive metal-organic framework-based nanoparticle platform was developed for the delivery of SI (SI@ZIF-8@MS NP). These NPs incorporated mPEG-b-PLLA (MS) as an agent capable of resisting the effects of gastric acid, and are capable of releasing Zn2+ ions. MS was able to effectively shield these SI@ZIF-8 NPs from rapid degradation when exposed to an acidic environment, enabling the subsequent release of SI and Zn2+ within the intestinal fluid. Notably, SI@ZIF-8@MS treatment was able to mitigate radiation-induced intestinal dysbiosis in these mice. restored radiation-induced changes in bacterial composition. In summary, these data demonstrate the ability of SI@ZIF-8@MS to protect against WAI-induced intestinal damage in mice, suggesting that these NPs represent a multimodal targeted therapy that can effectively be used in the prevention or treatment of RIII.

A Facile and Safe Route to Fabricate Boscalid‐Loaded ZIF‐8 Nanoparticles With Efficient Antibacterial Activity and Long‐Sustained Release

ABSTRACTSynthesis of ZIF‐8 mainly uses zinc nitrate hexahydrate (Zn(NO3)2.6H2O) as the zinc source. Zn (NO3)2.6H2O is flammable, explosive, and highly corrosive, posing a threat to human health. It also requires a molar ratio of 2‐methylimidazole to zinc source greater than 20, resulting in increased costs. In this work, a pH‐sensitive controlled‐release nano‐capsule of fungicide, ZIF‐8@Boscalid, was established using green zinc sources (zinc sulfate and zinc acetate) and was prepared based on metal–organic framework (ZIF‐8) for higher antifungal effect and low bio‐toxicity. The loading ratio is as high as 34%. In addition, the release of fungicide Boscalid showed pH‐sensitive response due to the weak acidic group in the ZIF structure, in which the rate of release was more rapid under acid condition (< 5). Cumulative release rates of the ZIF‐8(A)@Boscalid system and ZIF‐8(S)@Boscalid system were 76.15% and 86.22%, respectively. Meanwhile, the antifungal effect of ZIF‐8@Boscalid was 1.5 times more of that commercially available product on CI‐8 at the concentration of 300 mg/L, and the antibacterial activity values of the ZIF‐8(A)@Boscalid system and ZIF‐8(S)@Boscalid system against CJ‐8 were 84.54% and 78.65%, respectively. Furthermore, the obtained ZIF‐8@Boscalid system using the method described in this article exhibited certain UV resistance. Thus, this work not only proves that ZIF‐8@Boscalid could be used as nanoparticles platform for smart control over CJ‐8 but also has great potential effective utilization of Boscalid and achieving sustained release.

PH-sensitive and redox-responsive poly(tetraethylene glycol) nanoparticle-based platform for cancer treatment

Effective drug delivery with precise tumour targeting is crucial for cancer treatment. To address the challenges posed by the specificity and complexity of the tumour microenvironment, we developed a poly(tetraethylene glycol)-based disulfide nanoparticle (NP) platform and explored its potential in cancer treatment, focusing on drug loading and controlled release performance. Poly(tetraethylene glycol) NPs were characterised using nuclear magnetic resonance spectroscopy, mass spectrometry, and ultraviolet-visible spectroscopy. Additionally, we evaluated physicochemical properties, including dynamic light scattering, zeta potential analysis, drug loading capacity (DLC), and drug loading efficiency (DLE). The impact of NPs on the mouse colorectal cancer cell line (CT26) and NIH3T3 cells was assessed using a cytotoxicity assay, live/dead staining assay, flow cytometry, and confocal fluorescence microscopy. The experimental results align with the expected chemical structure and physicochemical properties of poly(tetraethylene glycol) NPs. These NPs exhibit high DLE (78.7%) and DLC (12%), with minimal changes in particle size over time in different media.In vitroexperiments revealed that the NPs can induce significant cytotoxicity and apoptosis in CT26 cells. Cellular uptake notably increases with increasing concentration and exposure time. The confocal microscopic analysis confirmed the effective distribution and accumulation of NPs within cells. In conclusion, poly(tetraethylene glycol) NPs hold promise for improving drug-delivery efficiency, offering potential advancements in cancer treatment.

Nanoparticle Delivery of an Oligonucleotide Payload in a Glioblastoma Multiforme Animal Model.

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain malignancy for which there is no cure. The blood-brain barrier is a significant hurdle in the delivery of therapies to GBM. Reported here is an image-guided, iron oxide-based therapeutic delivery nano platform capable of bypassing this physiological barrier by virtue of size and accumulating in the tumor region, delivering its payload. This 25 nm nano platform consists of crosslinked dextran-coated iron oxide nanoparticles labeled with Cy5.5 fluorescent dye and containing antisense oligonucleotide as a payload. The magnetic iron oxide core enables tracking of the nanoparticles through in vivo magnetic resonance imaging, while Cy5.5 dye allows tracking by optical imaging. This report details the monitoring of the accumulation of this nanoparticle platform (termed MN-anti-miR10b) in orthotopically implanted glioblastoma tumors following intravenous injection. In addition, it provides insight into the in vivo delivery of RNA oligonucleotides, a problem that has hampered the translation of RNA therapeutics into the clinic.

Synthesis, characterization, and surface modification of degradable polar hydrophobic ionic polyurethane nanoparticles for the delivery of therapeutics to vascular tissue

Degradable polar hydrophobic ionic polyurethanes (D-PHI) are an emerging class of biomaterials with particular significance for blood-contacting applications due to their immunomodulatory effects and highly customizable block chemistry. In this manuscript, D-PHI polymer was formulated as a nanoparticle excipient for the first time by inverse emulsion polymerization. The nanoparticles were optimized with consideration of diameter, surface charge, size variability, and yield as a delivery vehicle for a custom vascular therapeutic peptide. A layer-by-layer (LBL) surface modification technique using poly-L-lysine was integrated within the nanoparticle design to optimize therapeutic loading efficiency. Solvent pH played a pivotal role in emulsion micelle formation, LBL polymer secondary structure, and the polymer functional group interactions critical for high therapeutic loading. The resulting nanoparticle platform met target size (200 ± 20 nm), polydispersity (<0.07), and storage stability standards, was nontoxic, and did not affect therapeutic peptide bioactivity in vitro. Surface-modified D-PHI nanoparticles can be reproducibly manufactured at low cost, generating a highly customizable excipient platform suitable for delivery of biomolecular therapeutics. These nanoparticles have potential applications in vascular drug delivery via localized infusion, drug eluting stents, and drug-coated angioplasty balloons. Statement of significanceNanoscale excipients have become critical in the delivery of many therapeutics to enhance drug stability and targeted biodistribution through careful design of nanoparticle composition, surface chemistry, and size. This manuscript describes the development of a nanoparticle excipient derived from an immunomodulatory degradable polar hydrophobic ionic polyurethane, in combination with a layer-by-layer surface modification approach utilizing poly-L-lysine, to transport a mimetic peptide targeting smooth muscle cell migration in vascular disease. The nanoparticle platform draws on the effect of pH to maximize drug loading and tailor particle properties. The low cost and easily reproducible system presents a highly customizable platform that can be adapted for therapeutic delivery across a wide range of clinical indications.

PEGylated Pemetrexed and PolyNIPAM Decorated Gold Nanoparticles: A Biocompatible and Highly Stable CT Contrast Agent for Cancer Imaging.

This study describes a multifunctional nanoparticle platform for targeted CT imaging and therapy of cancers. Pemetrexed (conjugated with polyethylene glycol, MW 2000 Da) and polyNIPAM (PEGylated) were designed for targeted delivery to folate receptors and thermally ablated tumors, respectively. These moieties were coated on gold nanoparticles (7 and 30 nm), and the prepared compounds were characterized using 1H NMR, FT-IR, CHNS, DLS, TEM, TGA, and UV-vis. The resulting agents exhibited 2-4 times higher X-ray attenuation compared to Visipaque and demonstrated specific accumulation in tumor tissue (4T1 xenograft model) 90 min after injection in mice. The nanoparticles displayed anticancer activity against 4T1 and MDA-MB-231 breast cancer cells (IC50: 182.87 and 206.18 μg/mL) and good biocompatibility. Importantly, the platform showed excellent stability over a year and at pH 2-12 and temperature range of -78 to 40 °C, and a water-dichloromethane extraction method was optimized for efficient purification, facilitating large-scale production.

Development of Pro-resolving and Pro-efferocytic Nanoparticles for Atherosclerosis Therapy.

Atherosclerosis is a major contributor to cardiovascular diseases with a high global prevalence. It is characterized by the formation of lipid-laden plaques in the arteries, which eventually lead to plaque rupture and thrombosis. While the current lipid-lowering therapies are generally effective in lowering the risk of cardiovascular events, they do not address the underlying causes of disease. Defective resolution of inflammation and impaired efferocytosis are the main driving forces of atherosclerosis. Macrophages recognize cells for clearance by the expression of "eat me" and "do not eat me" signals, including the CD47-SIRPα axis. However, the "do not eat me" signal CD47 is overexpressed in atherosclerotic plaques, leading to compromised efferocytosis and secondary necrosis. In this context, prophagocytic antibodies have been explored to stimulate the clearance of apoptotic cells, but they are nonspecific and impact healthy tissues. In macrophages, downstream of signal regulatory protein α, lie protein tyrosine phosphatases, SHP 1/2, which can serve as effective targets for selectively phagocytosing apoptotic cells. While increasing the efferocytosis targets the end stages of lesion development, the underlying issue of inflammation still persists. Simultaneously increasing efferocytosis and reducing inflammation can be effective therapeutic strategies for managing atherosclerosis. For instance, IL-10 is a key anti-inflammatory mediator that enhances efferocytosis via phosphoSTAT3 (pSTAT3) activation. In this study, we developed a combination nanotherapy by encapsulating an SHP-1 inhibitor (NSC 87877) and IL-10 in a single nanoparticle platform [(S + IL)-NPs] to enhance efferocytosis and inflammation resolution. Our studies suggest that (S + IL)-NPs successfully encapsulated both agents, entered the macrophages, and delivered the agents into intracellular compartments. Additionally, (S + IL)-NPs decreased inflammation by suppressing pro-inflammatory markers and enhancing anti-inflammatory mediators. They also exhibited the potential for improved phagocytic activity via pSTAT3 activation. Our nanomedicine-mediated upregulation of the anti-inflammatory and efferocytic responses in macrophages shows promise for the treatment of atherosclerosis.

Photothermal therapy co-localized with CD137 agonism improves survival in an SM1 melanoma model without hepatotoxicity.

Aim: We investigate combining Prussian Blue nanoparticles (PBNPs), as photothermal therapy (PTT) agents, with agonistic CD137 antibodies (αCD137) on a single nanoparticle platform to deliver non-toxic, anti-tumor efficacy in SM1 murine melanoma.Methods: We electrostatically coated PBNPs with αCD137 (αCD137-PBNPs) and quantified their physicochemical characteristics, photothermal and co-stimulatory capabilities. Next, we tested the efficacy and hepatotoxicity of PTT using αCD137-PBNPs (αCD137-PBNP-PTT) in SM1 tumor-bearing mice.Results: The αCD137-PBNPs retained both the photothermal and agonistic properties of the PBNPs and αCD137, respectively. In vivo, SM1 tumor-bearing mice treated with αCD137-PBNP-PTT exhibited a significantly higher survival rate (50%) without hepatotoxicity, compared with control treatments.Conclusion: These data suggest the potential utility of co-localizing PBNP-PTT with αCD137-based agonism as a novel combination nanomedicine.

Using a Bacterial Protein to Selectively Target Bacterial Biofilms: Treatment of S. epidermidis Biofilms with Targeted Photothermal Gold Nanoparticles.

Biofilm-related infections are associated with high mortality and morbidity, combined with increased treatment costs. Traditional antibiotics are becoming less effective due to the emergence of drug-resistant bacterial strains. The need to treat biofilms on medical implants is particularly acute, and one persistent challenge is selectively directing nanoparticles to the biofilm site. Here, we present a protein-based functionalization strategy that targets the extracellular matrix of biofilms. The protein, derived from the extracellular Staphylococcus epidermidis autolysin, directs nanoparticles to S. epidermidis cell wall components, which are not expected to be present in mammalian tissues. This functionalization is applied to a gold nanoparticle (AuNP) core, along with elastin-like polypeptides (ELPs), which generate a robust photothermal response. In addition to biofilm targeting, the particles exhibit low protein binding, and the photothermal conversion can be modulated by changing the ELP transition temperature. These functionalized AuNPs strongly interact with biofilms under static and flow conditions but exhibit weak interactions with serum-coated surfaces. Near-infrared laser irradiation resulted in a 10,000-fold improvement in killing efficiency compared to untreated controls (p < 0.0001). The targeting strategy utilized here represents a versatile approach to targeting drug-resistant infections and could be readily expanded to other anti-biofilm nanoparticle platforms.

A strategy to reutilize silver nanoparticles on silicon nanowires via photocathodic activation for enhanced and sustainable hydrogen evolution

The development of electrodes for hydrogen evolution via water splitting in a neutral electrolyte is highly desirable, especially considering that natural water resources such as seawater typically have a neutral pH. In this study, silicon nanowires (SiNWs) arrays with uniform silver (Ag) decoration are prepared as a cathode material, which exhibits excellent and stable electrochemical performance for neutral water electrolysis. Ag ions, utilized in the preparation of SiNWs through metal-assisted chemical etching technique, are retained and decorated within the SiNWs array without undergoing a dissolution process, referred to as Native SiNWs. Remained Ag+ ions on the SiNWs are activated photocathodically and reduced to Ag0, resulting in a significantly enhanced performance as an electrocatalyst for hydrogen evolution reaction (HER). Hence, this photocathodic activation of Native SiNWs (PCA-Native SiNWs) eliminates the need for additional cocatalyst deposition for HER, utilizing the Ag ions employed in the SiNWs preparation process. This enhancement in HER activity is exclusively observed by photocathodic activation, not by cathodic activation without light irradiation, indicating the crucial role of photoelectrons in SiNWs under light irradiation for the activation. Additionally, the nanowire structure serves as an ideal platform for Ag nanoparticles, providing sufficient surface area, resulting in excellent dispersion and an increased number of active sites. Furthermore, PCA-Native SiNWs demonstrates outstanding electrochemical stability for over 60 h, with no significant reduction in current density or structural degradation in a neutral electrolyte. Several characterizations and electrochemical analyses have been conducted to elucidate the in-situ decoration of Ag nanoparticles on SiNWs and investigate the surface chemistry for the activation mechanism. This work introduces a new perspective on using Ag-decorated SiNWs directly as an electrocatalyst for effective hydrogen evolution in a neutral media.

Saponin nanoparticle adjuvants incorporating Toll-like receptor agonists drive distinct immune signatures and potent vaccine responses.

Over the past few decades, the development of potent and safe immune-activating adjuvant technologies has become the heart of intensive research in the constant fight against highly mutative and immune evasive viruses such as influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and human immunodeficiency virus (HIV). Herein, we developed a highly modular saponin-based nanoparticle platform incorporating Toll-like receptor agonists (TLRas) including TLR1/2a, TLR4a, and TLR7/8a adjuvants and their mixtures. These various TLRa-saponin nanoparticle adjuvant constructs induce unique acute cytokine and immune-signaling profiles, leading to specific T helper responses that could be of interest depending on the target disease for prevention. In a murine vaccine study, the adjuvants greatly improved the potency, durability, breadth, and neutralization of both COVID-19 and HIV vaccine candidates, suggesting the potential broad application of these adjuvant constructs to a range of different antigens. Overall, this work demonstrates a modular TLRa-SNP adjuvant platform that could improve the design of vaccines and affect modern vaccine development.

Discovery of a Peptoid-Based Nanoparticle Platform for Therapeutic mRNA Delivery via Diverse Library Clustering and Structural Parametrization.

Nanoparticle-mediated mRNA delivery has emerged as a promising therapeutic modality, but its growth is still limited by the discovery and optimization of effective and well-tolerated delivery strategies. Lipid nanoparticles containing charged or ionizable lipids are an emerging standard for in vivo mRNA delivery, so creating facile, tunable strategies to synthesize these key lipid-like molecules is essential to advance the field. Here, we generate a library of N-substituted glycine oligomers, peptoids, and undertake a multistage down-selection process to identify lead candidate peptoids as the ionizable component in our Nutshell nanoparticle platform. First, we identify a promising peptoid structural motif by clustering a library of >200 molecules based on predicted physical properties and evaluate members of each cluster for reporter gene expression in vivo. Then, the lead peptoid motif is optimized using design of experiments methodology to explore variations on the charged and lipophilic portions of the peptoid, facilitating the discovery of trends between structural elements and nanoparticle properties. We further demonstrate that peptoid-based Nutshells leads to expression of therapeutically relevant levels of an anti-respiratory syncytial virus antibody in mice with minimal tolerability concerns or induced immune responses compared to benchmark ionizable lipid, DLin-MC3-DMA. Through this work, we present peptoid-based nanoparticles as a tunable delivery platform that can be optimized toward a range of therapeutic programs.

Development of an advanced separation and characterization platform for mRNA and lipid nanoparticles using multi-detector asymmetrical flow field-flow fractionation.

In recent years, the use of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA)-based therapies has gained substantial attention in the field of drug development. In such an application, multiple LNP attributes have to be carefully characterized to ensure product safety and quality, whereas accurate and efficient characterization of these complex mRNA-LNP formulations remains a challenging endeavor. Here, we present the development and application of an online separation and characterization platform designed for the isolation and in-depth analysis of mRNAs and mRNA-loaded LNPs. Our asymmetrical flow field-flow fractionation with a multi-detector (MD-AF4) method has demonstrated exceptional resolution between mRNA-LNPs and mRNAs, delivering excellent recoveries (over 70%) for both analytes and exceptional repeatability. Notably, this platform allows for comprehensive and multi-attribute LNP characterization, including online particle sizing, morphology characterization, and determination of encapsulation efficiency, all within a single injection. Furthermore, real-time online sizing by synchronizing multi-angle light scattering (MALS) and dynamic light scattering (DLS) presented higher resolution over traditional batch-mode DLS, particularly in differentiating heterogeneous samples with a low abundance of large-sized particles. Additionally, our method proves to be a valuable tool for monitoring LNP stability under varying stress conditions. Our work introduces a robust and versatile analytical platform using MD-AF4 that not only efficiently provides multi-attribute characterizations of mRNA-LNPs but also holds promise in advancing studies related to formulation screening, quality control, and stability assessment in the evolving field of nanoparticle delivery systems for mRNAs.

Flow cytometric analysis of the murine placenta to evaluate nanoparticle platforms during pregnancy

Clinically approved therapeutics for obstetric conditions are extremely limited, with over 80% of drugs lacking appropriate labeling information for pregnant individuals. The pathology for many of these obstetric conditions can be linked to the placenta, necessitating the development of therapeutic platforms for selective drug delivery to the placenta. When evaluating therapeutics for placental delivery, literature has focused on ex vivo delivery to human placental cells and tissue, which can be difficult to source for non-clinical researchers. Evaluating in vivo drug delivery to the placenta using small animal models can be more accessible than using human tissue, but robust, quantitative methods to characterize delivery remain poorly established. Here, we report a flow cytometric method to evaluate in vivo drug delivery to the murine placenta. Specifically, we describe techniques to identify key cell types in the murine placenta — trophoblasts, endothelial cells, and immune cells — via flow cytometric analysis. While we have employed this method to detect lipid nanoparticle-mediated nucleic acid delivery, this approach can extend to a variety of drug carriers (e.g., liposomes, exosomes, polymeric and metallic nanoparticles) and payloads (e.g., small molecules, proteins, other nucleic acids). Similarly, we describe the application of this method toward immunophenotypic analysis to assess changes in the placental immune environment during disease or in response to a therapeutic. Together, the techniques reported herein aim to broaden the accessibility of placental research in an effort to encourage collaboration between physician-scientists, engineers, placental biologists, and clinicians for developing novel therapeutics to treat placental conditions during pregnancy.

Nanoparticles (NPs)-mediated lncMALAT1 silencing to reverse cisplatin resistance for effective hepatocellular carcinoma therapy.

Platinum-based chemotherapy has been widely used for clinical cancer treatment, but drug resistance is the main barrier to induce the poor prognosis of cancer patients. Long non-coding RNAs (lncRNAs) have been recognized as a type of new cancer therapeutic targets due to their important role in regulating cancer progression such as drug resistance. However, it is still challenged to effectively intervene the expression of lncRNAs as they are usually located at various subcellular organelles (e.g., nucleus, mitochondrion, and endoplasmic reticulum). We herein developed an endosomal pH-responsive nanoparticle (NP) platform for small interfering RNA (siRNA) and cisplatin prodrug co-delivery and effective cisplatin-resistant hepatocellular carcinoma (HCC) therapy. This co-delivery nanoplatform is comprised of a hydrophilic polyethylene glycol (PEG) shell and a hydrophobic poly (2-(diisopropylamino)ethyl methacrylate) (PDPA) core, in which cisplatin prodrug and electrostatic complexes of nucleus-targeting amphiphilic peptide (NTPA) and siRNA are encapsulated. After intravenous injection and then uptake by tumor cells, the endosomal pH could trigger the dissociation of nanoplatform and enhance the endosomal escape of loaded cisplatin prodrug and NTPA/siRNA complexes via the "proton sponge" effect. Subsequently, the NTPA/siRNA complexes could specifically transport siRNA into the nucleus and efficiently reverse cisplatin resistance via silencing the expression of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (lncMALAT1) mainly localized in the nucleus, ultimately inhibiting the growth of cisplatin-resistant HCC tumor.

In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells

Monogenic blood diseases are among the most common genetic disorders worldwide. These diseases result in significant pediatric and adult morbidity, and some can result in death prior to birth. Novel ex vivo hematopoietic stem cell (HSC) gene editing therapies hold tremendous promise to alter the therapeutic landscape but are not without potential limitations. In vivo gene editing therapies offer a potentially safer and more accessible treatment for these diseases but are hindered by a lack of delivery vectors targeting HSCs, which reside in the difficult-to-access bone marrow niche. Here, we propose that this biological barrier can be overcome by taking advantage of HSC residence in the easily accessible liver during fetal development. To facilitate the delivery of gene editing cargo to fetal HSCs, we developed an ionizable lipid nanoparticle (LNP) platform targeting the CD45 receptor on the surface of HSCs. After validating that targeted LNPs improved messenger ribonucleic acid (mRNA) delivery to hematopoietic lineage cells via a CD45-specific mechanism in vitro, we demonstrated that this platform mediated safe, potent, and long-term gene modulation of HSCs in vivo in multiple mouse models. We further optimized this LNP platform in vitro to encapsulate and deliver CRISPR-based nucleic acid cargos. Finally, we showed that optimized and targeted LNPs enhanced gene editing at a proof-of-concept locus in fetal HSCs after a single in utero intravenous injection. By targeting HSCs in vivo during fetal development, our Systematically optimized Targeted Editing Machinery (STEM) LNPs may provide a translatable strategy to treat monogenic blood diseases before birth.

Magnetothermal-activated gene editing strategy for enhanced tumor cell apoptosis

Precise and effective initiation of the apoptotic mechanism in tumor cells is one of the most promising approaches for the treatment of solid tumors. However, current techniques such as high-temperature ablation or gene editing suffer from the risk of damage to adjacent normal tissues. This study proposes a magnetothermal-induced CRISPR-Cas9 gene editing system for the targeted knockout of HSP70 and BCL2 genes, thereby enhancing tumor cell apoptosis. The magnetothermal nanoparticulate platform is composed of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles and the modified polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface, on which plasmid DNA can be effectively loaded. Under the induction of a controllable alternating magnetic field, the mild magnetothermal effect (42℃) not only triggers dual-genome editing to disrupt the apoptosis resistance mechanism of tumor cells but also sensitizes tumor cells to apoptosis through the heat effect itself, achieving a synergistic therapeutic effect. This strategy can precisely regulate the activation of the CRISPR-Cas9 system for tumor cell apoptosis without inducing significant damage to healthy tissues, thus providing a new avenue for cancer treatment.

Development and antioxidant evaluation of mango leaf (Mangifera indica L.) extract loaded silk fibroin nanoparticles

The main antioxidant polyphenol compounds in the mango (Mangifera indica L.) leaf extract are susceptible to environmental degradations. Thus, in biomedical applications, the mango leaf extract is commonly encapsulated in a carrier. However, most studies employed the synthetic carrier materials that could affect the human health, and the complicated formulation procedure that could hinder the scalability. Therefore, this work, for the first time, explored the use of silk fibroin (an FDA-approved biomaterial), in nanoparticles platform, to encapsulate and deliver the mango leaf extract, utilizing the simple coacervation preparation method. Initially, the mango leaf ethanolic extract was obtained through maceration, resulting in a total phenolic content of 76.39 ± 0.14 mg GAE/g DPW and a notably high antioxidant activity (IC50 = 6.872 ± 0.512 μg/mL). Subsequently, silk fibroin nanoparticles loaded with the extract were developed by the coacervation technique. Depending on the fibroin content, these nanoparticles exhibited an appropriate size range of 500–800 nm with narrow size distributions, a spherical shape with smooth surfaces, a dominant silk-II crystalline structure, a drug entrapment efficiency exceeding 70%, and retained the main biomarker mangiferin. Moreover, the phenolic-compounds release profiles from the particles followed the three-step process, the first burst-release step, the second sustained-release step, and the third degradation step. The particles were also non-toxic to the erythrocytes and the human embryonic kidney HEK-293 cell line. Lastly, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay demonstrated that the antioxidant activity of the mango leaf extract was preserved within the extract-loaded nanoparticles. The results suggested that the silk fibroin nanoparticles could be a potential platform to effectively encapsulate and deliver the mango leaf extract for biomedical purposes.

A nanoparticle vaccine displaying varicella-zoster virus gE antigen induces a superior cellular immune response than a licensed vaccine in mice and non-human primates.

Herpes zoster (HZ), also known as shingles, remains a significant global health issue and most commonly seen in elderly individuals with an early exposure history to varicella-zoster virus (VZV). Currently, the licensed vaccine Shingrix, which comprises a recombinant VZV glycoprotein E (gE) formulated with a potent adjuvant AS01B, is the most effective shingles vaccine on the market. However, undesired reactogenicity and increasing global demand causing vaccine shortage, prompting the development of novel shingles vaccines. Here, we developed novel vaccine candidates utilising multiple nanoparticle (NP) platforms to display the recombinant gE antigen, formulated in an MF59-biosimilar adjuvant. In naïve mice, all tested NP vaccines induced higher humoral and cellular immune responses than Shingrix, among which, the gEM candidate induced the highest cellular response. In live attenuated VZV (VZV LAV)-primed mouse and rhesus macaque models, the gEM candidate elicited superior cell-mediated immunity (CMI) over Shingrix. Collectively, we demonstrated that NP technology remains a suitable tool for developing shingles vaccine, and the reported gEM construct is a highly promising candidate in the next-generation shingles vaccine development.

PSMA-targeted combination brusatol and docetaxel nanotherapeutics for the treatment of prostate cancer

Active targeting to cancer involves exploiting specific interactions between receptors on the surface of cancer cells and targeting moieties conjugated to the surface of vectors such that site-specific delivery is achieved. Prostate specific membrane antigen (PSMA) has proved to be an excellent target for active targeting to prostate cancer. We report the synthesis and use of a PSMA-specific ligand (Glu-NH-CO-NH-Lys) for the site-specific delivery of brusatol- and docetaxel-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles to prostate cancer. The PSMA targeting ligand covalently linked to PLGA-PEG3400 was blended with methoxyPEG-PLGA to prepare brusatol- and docetaxel-loaded nanoparticles with different surface densities of the targeting ligand. Flow cytometry was used to evaluate the impact of different surface densities of the PSMA targeting ligand in LNCaP prostate cancer cells at 15 min and 2 h. Cytotoxicity evaluations of the targeted nanoparticles reveal differences based on PSMA expression in PC-3 and LNCaP cells. In addition, levels of reactive oxygen species (ROS) were measured using the fluorescent indicator, H2DCFDA, by flow cytometry. PSMA-targeted nanoparticles loaded with docetaxel and brusatol showed increased ROS generation in LNCaP cells compared to PC-3 at different time points. Furthermore, the targeted nanoparticles were evaluated in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors. Evaluation of the percent relative tumor volume show that brusatol-containing nanoparticles show great promise in inhibiting tumor growth. Our data also suggest that the dual drug-loaded targeted nanoparticle platform improves the efficacy of docetaxel in male athymic BALB/c mice implanted with PSMA-producing LNCaP cell tumors.