Delivery Vehicles Research Articles

Development and Evaluation of the Biological Activities of a Plain Mucoadhesive Hydrogel as a Potential Vehicle for Oral Mucosal Drug Delivery.

This study aimed to develop HGs based on cationic guar gum (CGG), polyethylene glycol (PEG), propylene glycol (PG), and citric acid (CA) using a 2k factorial experimental design to optimize their properties. HGs were characterized through FTIR and Raman spectroscopy, scanning electron microscopy (SEM), and thermogravimetric analysis (TGA). The biological activities of HGs were determined by evaluating their mucoadhesive capacity and antibacterial activity in vitro, whereas their toxicity was analyzed using Artemia salina nauplii as an in vivo model. Results revealed that HGs were successfully optimized for their viscosity, pH, and sensory properties, and it was observed that varying concentrations of PEG-75 did not influence them. Through SEM analyses, it was noted that increased levels of PEG-75 resulted in HGs with distinct porosity and textures, whereas FTIR and Raman spectroscopy exhibited representative peaks of the raw materials used during the synthesis process. TGA studies indicated the thermal stability of HGs, as they presented degradation patterns at 100 and 300 °C. The synthesized HGs exhibited similar mucoadhesion kinetic profiles, demonstrating a displacement factor at an equilibrium of 0.57 mm/mg at 5 min. The antibacterial activity of HGs was appraised as poor against Gram-positive and Gram-negative bacteria due to their MIC90 values (>500 μg/mL). Regarding A. salina, treatment with HGs neither decreased their viability nor induced morphological changes. The obtained results suggest the suitability of CGG/PEG HGs for oral mucosa drug delivery and expand the knowledge about their mucoadhesive capacity, antibacterial potential, and in vivo biocompatibility.

Cell-penetrating peptides TAT and 8R functionalize P22 virus-like particles to enhance tissue distribution and retention in vivo.

Virus-like particles (VLPs) are used as nanocontainers for targeted drug, protein, and vaccine delivery. The phage P22 VLP is an ideal macromolecule delivery vehicle, as it has a large exterior surface area, which facilitates multivalent genetic and chemical modifications for cell recognition and penetration. Arginine-rich cell-penetrating peptides (CPPs) can increase cargo transport efficiency in vivo. However, studies on the tissue distribution and retention of P22 VLPs mediated by TAT and 8R are lacking. This study aimed to analyze the TAT and 8R effects on the P22 VLPs transport efficiency and tissue distribution both in vitro and in vivo. We used a prokaryotic system to prepare P22 VLP self-assembled particles and expressed TAT-or 8R-conjugated mCherry on the VLP capsid protein as model cargoes and revealed that the level of P22 VLP-mCherry penetrating the cell membrane was low. However, both TAT and 8R significantly promoted the cellular uptake efficiency of P22 VLPs in vitro, as well as enhanced the tissue accumulation and retention of P22 VLPs in vivo. At 24 h postinjection, TAT enhanced the tissue distribution and retention in the lung, whereas 8R could be better accumulation in brain. Thus, TAT was superior in terms of cellular uptake and tissue accumulation in the P22 VLPs delivery system. Understanding CPP biocompatibility and tissue retention will expand their potential applications in macromolecular cargo delivery.

Micelles of poly[oligo(ethylene glycol) methacrylate] as delivery vehicles for zinc phthalocyanine photosensitizers

Drug-loaded polymeric micelles have proven to be highly effective carrier systems for the efficient delivery of hydrophobic photosensitizers (PSs) in photodynamic therapy (PDT). This study introduces the micellization potential of poly(oligoethylene glycol methyl ether methacrylate) (pOEGMA) as a novel approach, utilizing the hydrophobic methacrylate segments of pOEGMA to interact with highly hydrophobic zinc phthalocyanine (ZnPc), thereby forming a potential micellar drug carrier system. The ZnPc molecule was synthesized from phthalonitrile derivatives and its fluorescence, photodegradation, and singlet oxygen quantum yields were determined in various solvents. In solvents such as tetrahydrofuran, dimethyl sulfoxide, and N,N-dimethylformamide, the ZnPc compound exhibited the requisite photophysical and photochemical properties for PDT applications. The pOEGMA homopolymer was synthesized via reversible addition-fragmentation chain-transfer polymerization, while ZnPc-loaded pOEGMA micelles were prepared using the nanoprecipitation method. Characterization of the pOEGMA, ZnPc, and micelles was conducted using FTIR,1H-NMR, dynamic light scattering, matrix-assisted laser desorption/ionization time-of-flight mass spectrometries, gel permeation chromatography, and transmission electron microscopy. The critical micelle concentration was determined to be 0.027 mg ml-1using fluorescence spectrometry. The drug loading and encapsulation efficiencies of the ZnPc-loaded micelles were calculated to be 0.67% and 0.47%, respectively. Additionally, the release performance of ZnPc from pOEGMA micelles was monitored over a period of nearly 10 d, while the lyophilized micelles exhibited stability for 3 months. Lastly, the ZnPc-loaded micelles were more biocompatible than ZnPc on L929 cell line. The results suggest that the pOEGMA homopolymer possesses the capability to micellize through its methacrylate segments when interacting with highly hydrophobic molecules, presenting a promising avenue for enhancing the delivery efficiency of hydrophobic PSs in PDT. Moreover, it was also deciphered that obtained formulations were highly biocompatible according to cytotoxicity results and could be safely employed as drug delivery systems in further applications.

Decorating Delivery Vehicles Using Hyaluronic Acid Oligosaccharides Enables Active Targeting Toward Cancer and Minimizes Adverse Effect of Chemotherapeutics.

The major drawback of conventional chemotherapeutic treatment is the non-specificity or inability to ascertain and target cancerous cells directly. In this study, an active targeting strategy that is poised to carry the anticancer agents to the desired sites for therapeutic action while avoiding toxicity to normal organs is provided. The active targeting of delivery vehicles is achieved by ligand-receptor interactions, in particular the specific binding between hyaluronic acid oligosaccharides (oHAs) and CD44 receptors. This study first prepares oHAs by the size-exclusion chromatography and utilizes them to decorate chitosan (CTS) as basic materials (oHAs-CTS) for drug delivery, then fabricates oHAs-CTS into micro/nanoscale carriers to encapsulate agents for cancer chemotherapy. The oHAs-CTS micro/nanocarriers exhibit high drug encapsulation efficiency (58-87%), and the drug releases present a sustained behavior. Notably, oHAs-CTS delivery vehicles display an enhanced active targeting toward cancers and alleviate the cytotoxic effects on normal cells. Additionally, in vivo results show that drug-laden oHAs-CTS nanocarriers demonstrate a significant inhibitory effect on 4 T1 tumors without any toxicity to the major organs. Taken together, the findings highlight the potential of oHAs-CTS micro/nanospheres as delivery vehicles with enhanced active targeted capability toward cancers and minimized adverse effects of chemotherapeutic agents for cancer treatment.

Enhanced Anticancer Effects of Intratumorally Injected Electrostatic Doxorubicin‐Loaded Click‐Type Crosslinked Hyaluronic Acid Hydrogel

AbstractInjectable depots have received increasing notoriety as local drug delivery vehicles for tumor treatment. Here, an intratumoral formulation of doxorubicin (Dox) is proposed that relies on the electrostatic interaction between the carboxylic group of click‐type crosslinked hyaluronic acid (Cx‐HA) and cationic Dox to achieve effective tumor treatment. The Dox‐loaded click‐type crosslinked HA (Cx‐HA‐Dox) formulation exhibits adequate injectability for intratumoral injection and rapidly forms a depot at the tumor site, remaining inside the tumor for over 18 days. This enhances the bioavailability and therapeutic efficacy of Dox primarily within the tumor, minimizing off‐target side effects. Intratumoral injection of Cx‐HA‐Dox in animal models significantly suppresses tumor growth, as evidenced by a decrease in tumor volume over time. Histological analysis reveals limited angiogenesis in the treated tumors and an increase in the number of large apoptotic cells. Overall, the findings suggest that the electrostatically crosslinked Cx‐HA‐Dox depot can synergistically enhance the anticancer activity of Dox.

Non-viral gene therapy for neuromuscular diseases including Duchenne muscular dystrophy using nanovesicles derived from human cells

One of the biggest challenges in AAV gene delivery for Duchenne muscular dystrophy (DMD) is that some patients cannot be treated due to pre-existing neutralizing antibodies. As an alternative, nanovesicles derived from diverse human cells have emerged as highly efficient delivery vehicles for genetic materials. This is due to their superior biocompatibility and capability to cross diverse tissue barriers. Notably, the lack of strong host immune response was witnessed in multiple preclinical studies, as well as clinical trials recently completed using human allogeneic nanovesicles. Engineering nanovesicles with tissue-specific ligands on the surface can also enhance tissue selectivity, thus reducing off-target effects. Taken together, these findings raise the possibility that this novel non-viral approach can serve as an attractive alternative to risk-prone viral-mediated gene therapy. This review discusses the recent advances in a non-viral gene therapy approach using cell-derived nanovesicles, and highlights their therapeutic potential in treating neuromuscular diseases, such as DMD, along with current challenges that need to be further addressed.

Revitalizing elixir with orange peel amplification of alginate fish oil beads for enhanced anti-aging efficacy

The research introduces a novel method for creating drug-loaded hydrogel beads that target anti-aging, anti-oxidative, and anti-inflammatory effects, addressing the interconnected processes underlying various pathological conditions. The study focuses on the development of hydrogel beads containing anti-aging compounds, antioxidants, and anti-inflammatory drugs to effectively mitigate various processes. The synthesis, characterization and in vitro evaluations, and potential applications of these multifunctional hydrogel beads are discussed. A polymeric alginate-orange peel extract (1:1) hydrogel was synthesized for encapsulating fish oil. Beads prepared with variable fish oil concentrations (0.1, 0.3, and 0.5 ml) were characterized, showing no significant decrease in size i.e., 0.5 mm and a reduction in pore size from 23 to 12 µm. Encapsulation efficiency reached up to 98% within 2 min, with controlled release achieved upto 45 to 120 min with increasing oil concentration, indicating potential for sustained delivery. Fourier-transform infrared spectroscopy confirmed successful encapsulation by revealing peak shifting, interaction between constituents. In vitro degradation studies showed the hydrogel's biodegradability improved from 30 to 120 min, alongside anti-inflammatory, anti-oxidative, anti-collagenase and anti-elastase activities, cell proliferation rate enhanced after entrapping fish oil. In conclusion, the synthesized hydrogel beads are a promising drug delivery vehicle because they provide stable and effective oil encapsulation with controlled release for notable anti-aging and regenerative potential. Targeted delivery for inflammatory and oxidative stress-related illnesses is one set of potential uses. Further research may optimize this system for broader applications in drug delivery and tissue engineering.

Advancements in Micellar Formulation: Drug Delivery Vehicle for Water-Insoluble Drugs

: Micellar systems, particularly polymeric micelles, have emerged as a promising drug delivery vehicle for water-insoluble compounds. Polymeric micelles, self-assembled nanostructures made from amphiphilic block copolymers, have emerged as a promising drug delivery vehicle for water-insoluble compounds. These micelles offer high drug loading capacity, stability, and the ability to solubilize large amounts of hydrophobic drugs, making them an attractive option for delivering drugs with limited solubility and bioavailability. Their small size allows for efficient delivery and targeting of specific tissues or cells, reducing off-target effects and improving therapeutic outcomes. This review provides a brief overview of drug delivery system challenges, solutions, techniques of micelle formation, factors affecting micelle stability and drug loading, applications, pharmacokinetics and pharmacodynamics of micellar formulations, toxicological considerations, limitations, recent advancements, and clinical trials of micelles in drug delivery. By addressing these key aspects, this review seeks to provide a comprehensive understanding of the current status and prospects of polymeric micelles as a promising drug delivery system.

Scalable production of siRNA-encapsulated extracellular vesicles for the inhibition of KRAS-mutant cancer using acoustic shock waves.

Extracellular vesicles (EVs) have emerged as a potential delivery vehicle for nucleic-acid-based therapeutics, but challenges related to their large-scale production and cargo-loading efficiency have limited their therapeutic potential. To address these issues, we developed a novel "shock wave extracellular vesicles engineering technology" (SWEET) as a non-genetic, scalable manufacturing strategy that uses shock waves (SWs) to encapsulate siRNAs in EVs. Here, we describe the use of the SWEET platform to load large quantities of KRASG12C-targeting siRNA into small bovine-milk-derived EVs (sBMEVs), with high efficiency. The siRNA-loaded sBMEVs effectively silenced oncogenic KRASG12C expression in cancer cells; they inhibited tumour growth when administered intravenously in a non-small cell lung cancer xenograft mouse model. Our study demonstrates the potential for the SWEET platform to serve as a novel method that allows large-scale production of cargo-loaded EVs for use in a wide range of therapeutic applications.

PH-Responsive Block Copolymer Micelles of Temsirolimus: Preparation, Characterization and Antitumor Activity Evaluation.

Renal cell carcinoma (RCC) is the most common and lethal type of urogenital cancer, with one-third of new cases presenting as metastatic RCC (mRCC), which, being the seventh most common cancer in men and the ninth in women, poses a significant challenge. For patients with poor prognosis, temsirolimus (TEM) has been approved for first-line therapy, possessing pharmacodynamic activities that block cancer cell growth and inhibit proliferation-associated proteins. However, TEM suffers from poor water solubility, low bioavailability, and systemic side effects. This study aims to develop a novel drug formulation for the treatment of RCC. In this study, amphiphilic block copolymer (poly(ethylene glycol) monomethyl ether-poly(beta-amino ester)) (mPEG-PBAE) was utilized as a drug delivery vehicle and TEM-loaded micelles were prepared by thin-film hydration method by loading TEM inside the nanoparticles. Then, the molecular weight of mPEG-PBAE was controlled to make it realize hydrophobic-hydrophilic transition in the corresponding pH range thereby constructing pH-responsive TEM-loaded micelles. Characterization of pH-responsive TEM-loaded nanomicelles particle size, potential and micromorphology while its determination of drug-loading properties, in vitro release properties. Finally, pharmacodynamics and hepatorenal toxicity were further evaluated. TEM loading in mPEG-PBAE increased the solubility of TEM in water from 2.6μg/mL to more than 5 mg/mL. The pH-responsive TEM-loaded nanomicelles were in the form of spheres or spheroidal shapes with an average particle size of 43.83 nm and a Zeta potential of 1.79 mV. The entrapment efficiency (EE) of pH-responsive TEM nanomicelles with 12.5% drug loading reached 95.27%. Under the environment of pH 6.7, the TEM was released rapidly within 12h, and the release rate could reach 73.12% with significant pH-dependent characteristics. In vitro experiments showed that mPEG-PBAE preparation of TEM-loaded micelles had non-hemolytic properties and had significant inhibitory effects on cancer cells. In vivo experiments demonstrated that pH-responsive TEM-loaded micelles had excellent antitumor effects with significantly reduced liver and kidney toxicity. In conclusion, we successfully prepared pH-responsive TEM-loaded micelles. The results showed that pH-responsive TEM-loaded micelles can achieve passive tumor targeting of TEM, and take advantage of the acidic conditions in tumor tissues to achieve rapid drug release.

In silico Design of a Quadruplex RNA Aptamer Against Carcinoembryonic Antigen, and Evaluating its Potential as a Drug Delivery Vehicle

Background: Colorectal cancer is the third most common cancer worldwide, with carcinoembryonic antigen (CEA) being a key biomarker for tumor prognostic assessment. This study focused on the in silico development of an RNA aptamer capable of efficiently targeting the CEA biomarker, and evaluating its potential to act as a drug delivery vehicle of chemotherapeutic anticancer drugs. Methods: In this study, five G-quadruplex RNA aptamers were manually designed and docked with the CEA protein. The aptamer sequence with the best docking score was optimized through various mutations, and these mutant sequences underwent drug-aptamer docking using AutoDock vina, followed by further docking experiments with CEA, with and without the drug, using the Hdock server. The best aptamer-drug configuration and the entire (aptamers-drug)-CEA complex were then analyzed using molecular dynamics (MD) simulation. Results: Irinotecan exhibited the highest binding affinity with three mutant sequences compared to 5-FU and Raltitrexed, with the seq 3-5/Irinotecan complex showing the best configuration (score: -11.6). This complex also demonstrated a good binding affinity with the target CEA (HDOCK score: -393.07). Throughout 31.6 ns simulation, the RMSD plot of the (aptamer-drug)-CEA complex showed an average of 8.7 A°. The residues of interacting amino acids had lower RMSF than 1.4 Å, except for the ALA A0 (RMSF:1.74 Å). Rg plot showed minimal fluctuation, which were maintained between 19.2 Å and 20.2 Å. The mean SASA was in the range of 112.8–125.8 nm2. H-bonds were observed with an average of 7.3 hydrogen bonds. MD simulation results indicated that the (aptamers-drug)-CEA complex maintained a stable, low-flexibility, and relatively compact structure throughout the simulation. Conclusion: The study concludes that the designed quadruplex RNA aptamer can potentially target the CEA biomarker with good binding affinity and serves as an effective carrier for Irinotecan. However, in vitro and in vivo experiments are necessary for further validation.

Applicability of Quantum Dots in Breast Cancer Diagnostic and Therapeutic Modalities-A State-of-the-Art Review.

The increasing incidence of breast cancers (BCs) in the world population and their complexity and high metastatic ability are serious concerns for healthcare systems. Despite the significant progress in medicine made in recent decades, the efficient treatment of invasive cancers still remains challenging. Chemotherapy, a fundamental systemic treatment method, is burdened with severe adverse effects, with efficacy limited by resistance development and risk of disease recurrence. Also, current diagnostic methods have certain drawbacks, attracting attention to the idea of developing novel, more sensitive detection and therapeutic modalities. It seems the solution for these issues can be provided by nanotechnology. Particularly, quantum dots (QDs) have been extensively evaluated as potential targeted drug delivery vehicles and, simultaneously, sensing and bioimaging probes. These fluorescent nanoparticles offer unlimited possibilities of surface modifications, allowing for the attachment of biomolecules, such as antibodies or proteins, and drug molecules, among others. In this work, we discuss the potential applicability of QDs in breast cancer diagnostics and treatment in light of the current knowledge. We begin with introducing the molecular and histopathological features of BCs, standard therapeutic regimens, and current diagnostic methods. Further, the features of QDs, along with their uptake, biodistribution patterns, and cytotoxicity, are described. Based on the reports published in recent years, we present the progress in research on possible QD use in improving BC diagnostics and treatment efficacy as chemotherapeutic delivery vehicles and photosensitizing agents, along with the stages of their development. We also address limitations and open questions regarding this topic.

Molecular simulation on solubilization of fullerene C60 by C12E6 nonionic surfactants

ABSTRACT Coarse grained simulations were adopted to describe the encapsulation and dispersion of fullerene C 60 by hexaoxyethylene dodecyl ether (C 12 E 6 ) surfactants. The self-organised structures of C 12 E 6 molecules in water were captured and the characteristics of micelles composed of different number of C 12 E 6 molecules were analysed. We found that C 60 molecules alone or in clusters can spontaneously translate into the hydrophobic core of micelles. One monomeric C 60 can explore the hydrocarbon-chain region of the micelles with different sizes, and two different preferential locations of C 60 are observed. The small C 60 clusters can disaggregate after entering the micelle. Larger C 60 clusters can penetrate into the micelle as solid-like nanoparticles, although they are partially disaggregated. When investigating the self-assembly of C 12 E 6 surfactants and C 60 molecules, we found that it is very difficult to disperse C 60 in the micelle monomolecularly. At high molar ratio of C 12 E 6 /C 60 , colloidal nanoC 60 aggregates form with C 12 E 6 surfactants adsorbed on the surface. Our simulations provide an explanation for the different observations in fullerene solubilization in micellar solutions and give a guideline for further solubilization of pristine fullerene or small hydrophobic molecules with surfacant micelles, which is helpful for the design of new micelle-based delivery vehicles.

Cellular Uptake of Phase-Separating Peptide Coacervates.

Peptide coacervates self-assembling via liquid-liquid phase separation are appealing intracellular delivery vehicles of macromolecular therapeutics (proteins, DNA, mRNA) owing to their non-cytotoxicity, high encapsulation capacity, and efficient cellular uptake. However, the mechanisms by which these viscoelastic droplets cross the cellular membranes remain unknown. Here, using multimodal imaging, data analytics, and biochemical inhibition assays, identify the key steps by which droplets enter the cell. find that the uptake follows a non-canonical pathway and instead integrates essential features of macropinocytosis and phagocytosis, namely active remodeling of the actin cytoskeleton and appearance of filopodia-like protrusions. Experiments using giant unilamellar vesicles show that the coacervates attach to the bounding membrane in a charge- and cholesterol-dependent manner but do not breach the lipid bilayer barrier. Cell uptake in the presence of small molecule inhibitors - interfering with actin and tubulin polymerization - confirm the active role of cytoskeleton remodeling, most prominently evident in electron microscopy imaging. These findings suggest a peculiar internalization mechanism for viscoelastic, glassy coacervate droplets combining features of non-specific uptake of fluids by macropinocytosis and particulate uptake of phagocytosis. The broad implications of this study will enable to enhance the efficacy and utility of coacervate-based strategies for intracellular delivery of macromolecular therapeutics.

GUANIDINE DELIVERY BY Si-DOPED C60 AND SWCNT: A DFT APPROACH

The interactions between guanidine and silicon decorated fullerene or single walled carbon nanotube were examined for insight into the drug delivery approach. The calculations show that the chemical reactivity and interaction energies are strongly dependent on the interaction site of the guanidine molecule. Depending on the purpose, by determining the interaction sites, it is possible to use Si decorated fullerenes and single walled carbon nanotubes as selective drug delivery vehicles. The results will contribute to further searches on improving drug delivery platforms.

Synthesis and Analysis of Novel Polyamide COF-TH as a Potent Anticancer Delivery Vehicle Under Variable pH Conditions

Synthesis and Analysis of Novel Polyamide COF-TH as a Potent Anticancer Delivery Vehicle Under Variable pH Conditions

Emerging Cancer Immunotherapies: Cutting-Edge Advances and Innovations in Development.

The rise in biological therapies has revolutionized oncology, with immunotherapy leading the charge through breakthroughs such as CAR-T cell therapy for melanoma and B-ALL. Modified bispecific antibodies and CAR-T cells are being developed to enhance their effectiveness further. However, CAR-T cell therapy currently relies on a costly ex vivo manufacturing process, necessitating alternative strategies to overcome this bottleneck. Targeted in vivo viral transduction offers a promising avenue but remains under-optimized. Additionally, novel approaches are emerging, such as in vivo vaccine boosting of CAR-T cells to strengthen the immune response against tumors, and dendritic cell-based vaccines are under investigation. Beyond CAR-T cells, mRNA therapeutics represent another promising avenue. Targeted delivery of DNA/RNA using lipid nanoparticles (LNPs) shows potential, as LNPs can be directed to T cells. Moreover, CRISPR editing has demonstrated the ability to precisely edit the genome, enhancing the effector function and persistence of synthetic T cells. Enveloped delivery vehicles packaging Cas9 directed to modified T cells offer a virus-free method for safe and effective molecule release. While this platform still relies on ex vivo transduction, using cells from healthy donors or induced pluripotent stem cells can reduce costs, simplify manufacturing, and expand treatment to patients with low-quality T cells. The use of allogeneic CAR-T cells in cancer has gained attraction for its potential to lower costs and broaden accessibility. This review emphasizes critical strategies for improving the selectivity and efficacy of immunotherapies, paving the way for a more targeted and successful fight against cancer.

Structure-Activity Relationship of Antibody-Oligonucleotide Conjugates: Evaluating Bioconjugation Strategies for Antibody-Phosphorodiamidate Morpholino Oligomer Conjugates for Drug Development.

Antibody-oligonucleotide conjugates (AOCs) are promising treatments for Duchenne muscular dystrophy (DMD). They work via induction of exon skipping and restoration of dystrophin protein in skeletal and heart muscles. The structure-activity relationships (SARs) of AOCs comprising antibody-phosphorodiamidate morpholino oligomers (PMOs) depend on several aspects of their component parts. We evaluate the SAR of antimouse transferrin receptor 1 antibody (αmTfR1)-PMO conjugates: cleavable and noncleavable linkers, linker location on the PMO, and the impact of drug-to-antibody ratios (DARs) on plasma pharmacokinetics (PK), oligonucleotide delivery to tissues, and exon skipping. AOCs containing a stable linker with a DAR9.7 were the most effective PMO delivery vehicles in preclinical studies. We demonstrate that αmTfR1-PMO conjugates induce dystrophin protein restoration in the skeletal and heart muscles of mdx mice. Our results show that αmTfR1-PMO conjugates are a potentially effective approach for the treatment of DMD.

Gene Editing by Ferrying of CRISPR/Cas Ribonucleoprotein Complexes in Enveloped Virus-Derived Particles.

The invention of next-generation CRISPR/Cas gene editing tools, like base and prime editing, for correction of gene variants causing disease, has created hope for invivo use in patients leading to wider clinical translation. To realize this potential, delivery vehicles that can ferry gene editing tool kits safely and effectively into specific cell populations or tissues are in great demand. In this review, we describe the development of enveloped retrovirus-derived particles as carriers of "ready-to-work" ribonucleoprotein complexes consisting of Cas9-derived editor proteins and single guide RNAs. We present arguments for adapting viruses for cell-targeted protein delivery and describe the status after a decade-long development period, which has already shown effective editing in primary cells, including T cells and hematopoietic stem cells, and in tissues targeted invivo, including mouse retina, liver, and brain. Emerging evidence has demonstrated that engineered virus-derived nanoparticles can accommodate both base and prime editors and seems to fertilize a sprouting hope that such particles can be further developed and produced in large scale for therapeutic applications.

Multi-depot routing problem with van-based driverless vehicles

In order to strengthen the coordination between different delivery participants and means of transport, this work proposes one extension of multi-depot routing problems where vans and driverless vehicles are used in combination during the delivery. The operation process mainly includes two parts. One is that, vans carry several driverless vehicles and goods, and drop off or pick up driverless vehicles at stops. Another is that, driverless vehicles departing directly from depots and dropped off by vans deliver goods to customers in cooperation. During the delivery, vans and driverless vehicles are in close cooperation through the proposed multi-depot joint distribution and the proposed van-van joint distribution. By the two modes, one van can depart from one depot and return to another depot, and one driverless vehicle can be set off by one van at one stop and be picked up by another van at another stop. This multi-depot routing problem with van-based driverless vehicles is formulated as a mixed integer programming model which can be solved by a designed heuristic algorithm. The sensitivity analyses about the maximum number of driverless vehicles in one van and the maximum traveling time of driverless vehicles are also performed. The results reveal that they have limited effects on the delivery cost and the application of the two modes. In addition, the experimental results demonstrate that the application of the two modes is affected by the distribution of depots and stops.