Efficient Delivery Research Articles

Estimation of stops of last-mile delivery vehicles: An application in the food industry in the city of Santiago de Chile

The study of vehicle stops in last-mile delivery has gained ground in the specialized logistics literature. An efficient last-mile delivery reduces distribution costs and mitigates negative externalities such as pollution and congestion. This paper estimates the stops of last-mile trucks that deliver food products in Santiago, Chile. The aim is to study last-mile delivery operations using a non-intrusive, low-cost method. Particularly, we devise a novel methodology that employs multiple data sources to detect the primary stops of cargo vehicles. The proposed methodology involves the following two steps. First, we use GPS data to identify all the candidates for stops, that is, clusters of points close to each other in terms of distance and time, and then, these stops are classified as primary according to the proximity to planned visits or check-out markings. Finally, we conduct a case study involving food distribution, deriving managerial and public policy insights. We find that the most adequate time threshold to detect stops in our context is 4 min, which is considerably lower than previous studies. This last may be explained by the last-mile nature of our study. Our results show that primary (i.e., delivery) stops are concentrated mainly in the center of Santiago, with a duration that decreases as the hours go by. This last means that some of the externalities caused by truck stops (e.g., road capacity reduction) are exacerbated during the morning rush hour. We also find that the average duration of the primary stops is 12.5 min, while the mean distance traveled between two consecutive stops is 4.68 km.

Voice Recognition Based Vital Parameter Monitoring Patient BED

In healthcare protocols continuous monitoring of vital parameters plays a crucial role in patient care. Integrating advanced technologies for both monitoring and patient comfort enhances the efficiency of healthcare delivery. This paper presents the design and development of a novel patient bed system equipped with vital parameter monitoring capabilities and adjustable head position controlled through voice commands. The proposed system leverages state-of-the-art sensors to monitor vital parameters such as heart rate, blood pressure, oxygen saturation, and temperature. These sensors are seamlessly integrated into the bed, providing non-intrusive and continuous monitoring of the patient's health status. Real-time data acquisition and processing algorithms ensure accurate and timely assessment of the patient's condition. Furthermore, the patient bed is designed with an adjustable head position feature, allowing for optimal comfort and support. Unlike conventional manual or automated adjustment mechanisms, our system employs voice control technology for intuitive and hands-free operation. Patients can simply issue verbal commands to adjust the head position according to their preferences, enhancing overall comfort and facilitating better rest.

Inhalable FN-binding liposomes or liposome-exosome hybrid bionic vesicles encapsulated microparticles for enhanced pulmonary fibrosis therapy

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.

Medical Drone a Life Saver in Emergency Situations (Organ Delivery Drone)

This paper explores the emerging field of medical drones for organ delivery, addressing the critical need for timely transportation of organs to enhance transplantation procedures and save lives. Medical drones offer a novel solution to overcome geographical barriers, particularly in remote or inaccessible regions, by providing rapid and efficient delivery of organs and blood samples. By significantly reducing transportation times compared to conventional methods, medical drones have the potential to revolutionize healthcare logistics and improve access to critical care services. This abstract highlights the key benefits and challenges associated with the integration of medical drones in organ delivery, emphasizing their role in expediting transplant procedures and ensuring timely interventions for patients in need.

Smart osteoclasts targeted nanomedicine based on amorphous CaCO3 for effective osteoporosis reversal

BackgroundOsteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis.ResultsOsteoclasts’ microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model.ConclusionThe work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.

An IoT Intelligent Approach for Safety and Efficiency of Robotic Medicine Delivery in Hospitals

In this paper, we introduce an IoT-based robotic medicine delivery system designed to boost safety and efficiency in hospital settings. This IoT-embedded robotic system integrates advanced sensors such as proximity, temperature, pressure, pulse rate, etc., sensors for ensuring real-time health and environmental monitoring behind this system. The robot is connected to a centralised controller, enabling healthcare workers to monitor patients using a cloud-based system. . Our robotic system moves about with the support of both line follower and LiDAR scanning technology for environmental safety and proximity detection. Experimental results show that the robotic system was able to navigate static obstacles and dynamically move away from the mobile entities within its reach without touching them. Besides, the proposed robotic system was able to reach the bed at the right time under normal operating conditions, which shows the efficiency of this approach in real-time settings. Patient feedback suggests that patients are very happy about the system, in terms of its usefulness, trustworthiness, and to their suprise to be taken care of by a robot. Overall, our study shows the potential of the proposed robotic system in streamlining the existing medicine delivery process in hospitals. It can potentially improve various aspects including safety, efficiency, patient compliance, and quality of care delivery. The promising results suggest further studies for incorporating advanced features and for ensuring compliance with regulatory requirements. Additional studies are to be conducted to further improve the proposed sensor-based robotic medicine delivery system, to facilitate its adoption in hospitals.

Assessment of the cytotoxic effect of carboxymethyl chitosan-loaded amygdalin nanoparticles against human normal and cancer cell lines

In recent years, the development of antitumor drugs has been dedicated to natural products. Amygdalin is a natural herbal cyanoglycoside that has anticarcinogenic effect on many types of cancers once hydrogen cyanide (HCN) is released. The main objective of the present study is to synthesize and investigate the potential of carboxymethyl chitosan nanoparticles (CMC NPs) as drug delivery agents for amygdalin encapsulation and its delivery to cancer and normal cell lines. In this study, carboxymethyl chitosan nanoparticles encapsulated with amygdalin (CMC-Am NPs) were prepared and characterized through their particle size, surface charge, chemical structure and dielectric properties. Also, the invitro drug release of amygdalin from CMC NPs was studied. Additionally, the cytotoxcity of the amygdalin and CMC-loaded amygdalin NPs were evaluated through MTT assay. The results showed that the prepared CMC-loaded amygdalin NPs exhibited a small particle size of 129 nm, high zeta potential value of − 43 mV and confirmed the amygdalin stability and compatibility with CMC NPs. Furthermore, the CMC NPs demonstrated sustained release of amygdalin during 24 h. Moreover, compared to free amygdalin, amygdalin-loaded CMC NPs have significant anti-cancerous effect on human colon HCT-116 and breast MCF-7 cancer cell lines while being safe on normal cells BJ1. In conclusion, CMC NPs can be employed as an efficient drug delivery vehicle for controlled and sustained amygdalin release with enhanced cytotoxicity on malignant cells without harming normal cells.

Home blood pressure telemonitoring in the Netherlands: a pilot study in GP practices

BackgroundHome Blood Pressure Telemonitoring  (HBPT) has been proposed to improve drug adherence, blood pressure control, and efficient care delivery in patients with hypertension. Its adoption in GP practices however remains low. In this pilot study we evaluated barriers and facilitators for successful implementation, patient satisfaction, clinical effectiveness, and efficiency for a HBPT project in Dutch GP practices by means of the Quadruple Aim Model.MethodsGP practices included patients with hypertension that were part of their regular cardiovascular disease program. We conducted semi-structured interviews at 3- and 6-months to identify barriers and facilitators for successful implementation. Patient satisfaction was measured with Telehealth Usability (TUQ)—and Mhealth App Usability (MAUQ) Questionnaires. A SPRINT-protocol blood pressure measurement was performed after the pilot project to assess clinical effectiveness. Efficiency data were collected on the number of registered consultations and practice measurements performed during the 6-month project.ResultsThree GP practices included 19 patients. Barriers for implementation were a lack of a reimbursement structure, lack of information technology (IT) system integration and increased experienced workload when using HBPT. Facilitators included the positive effects on blood pressure control, increased sense of safety for patient and care provider, and increased disease-insight. Median satisfaction scores for TUQ and MAUQ questionnaires (scale 1–7) were 6 (IQR 5–6) and 6 (IQR 5–7). At baseline, 16% of the patients had a blood pressure < 140/90 mmHg. Based on the performed SPRINT measurements, 68% had a well-controlled blood pressure (< 140/90 mmHg) after 6 months. Average blood pressure improved from 151/89 mmHg to 132/81 mmHg (p =  < 0.05). On average, one monthly contact moment related to hypertension between patient and GP practice was registered.ConclusionsWe found positive results following the introduction of HBPT in GP practices on clinical outcomes and patients’ satisfaction, however for large-scale implementation improvements with regards to organizational efficiency and a clear reimbursement structure are needed.

Microneedle combined with iontophoresis and electroporation for assisted transdermal delivery of goniothalamus macrophyllus for enhancement sonophotodynamic activated cancer therapy

The underlying study was carried out aiming at transdermal drug delivery (TDD) of Goniothalamus macrophyllus as sono-photo-sensitizer (SPS) using microneedle (MN) arrays with iontophoresis (MN-IP), electroporation (MN-EP) in conjunction with applying photodynamic therapy (PDT), sonodynamic therapy (SDT) and sono-photodynamic therapy (SPDT) as an up-to-date activated cancer treatment modality. Study was conducted on 120 male Swiss Albino mice, inoculated with Ehrlich ascites carcinoma (EAC) divided into 9 groups. We employed three different arrays of MN electrodes were used (parallel, triangular, and circular), EP, IP with different volts (6, 9, 12 V), an infrared laser and an ultrasound (pulsed and continuous wave) as our two energy sources. Results revealed that parallel 6 V TDD@MN@IP@EP can be used as effective delivery system for G. macrophyllus from skin directly to target EAC cells. In addition MN@IP@EP@TDD G. macrophyllus is a potential SPS for SPDT treatment of EAC. With respect to normal control mice and as opposed to the EAC untreated control mice, MN@EP@IP TDD G. macrophyllus in the laser, ultrasound, and combination activated groups showed a significant increase in the antioxidant markers TAC level and the GST, GR, Catalase, and SOD activities, while decrease in lipid peroxidation oxidative stress parameter MDA levels. In addition significantly increased apoptotic genes expressions (p53, caspase (3, 9), Bax, and TNF alpha) and on the other hand decreased anti- apoptotic (Bcl-2) and angiogenic (VEGF) genes expressions. Moreover significantly ameliorate liver and kidney function decreasing ALT, AST, urea and creatinine respectively. Furthermore MN@IP@EP@TDD G. macrophyllus combined with SPDT was very effective at reducing the growth of tumors and even causing cell death according to microscopic H&E stain results. This process may be related to a sono- and/or photochemical activation mechanism. According to the findings, MN@IP@EP@TDD G. macrophyllus has a lot of potential as a novel, efficient delivery method that in combination with infrared laser and ultrasound activation SPDT demonstrated promising anticancer impact for treating cancer.

Implementing DevOps Adoption within United States SMEs

DevOps is an integration of "Development" (Dev) and "Operations" (Ops) and has emerged as a transformational way of software development, with the objective of enabling rapid and efficient delivery of software. While accepted at larger scales in enterprises, there has been hardly any literature review based on the implementation of DevOps in Small and Medium Enterprises (SMEs) in the United States. This research, therefore, seeks to analyze in detail the challenges, methodologies, and outcomes of implementing DevOps adoption within SMEs in the United States. This research investigates the strategies, benefits, and barriers of SMEs toward the implementation of DevOps using mixed-methods research, including qualitative data from a case study and both interview and quantitative survey data. The results offer a contribution to an understanding of how SMEs adopt DevOps and present valuable knowledge for both practitioners and researchers.

Implementing DevOps Adoption within United States SMEs

DevOps is an integration of "Development" (Dev) and "Operations" (Ops) and has emerged as a transformational way of software development, with the objective of enabling rapid and efficient delivery of software. While accepted at larger scales in enterprises, there has been hardly any literature review based on the implementation of DevOps in Small and Medium Enterprises (SMEs) in the United States. This research, therefore, seeks to analyze in detail the challenges, methodologies, and outcomes of implementing DevOps adoption within SMEs in the United States. This research investigates the strategies, benefits, and barriers of SMEs toward the implementation of DevOps using mixed-methods research, including qualitative data from a case study and both interview and quantitative survey data. The results offer a contribution to an understanding of how SMEs adopt DevOps and present valuable knowledge for both practitioners and researchers.

Minimizing the ratio of ionizable lipid in lipid nanoparticles for in vivo base editing

Abstract Lipid nanoparticles have gained clinical approval as carriers for both siRNA and mRNA. Among the crucial components of LNPs, ionizable lipids play a pivotal role in determining the efficiency of RNA delivery. In this study, we synthesized a series of ionizable lipids, denoted as HTO, with a higher count of hydroxyl groups compared to SM-102. Remarkably, LNPs based on HTO12 lipid demonstrated comparable mRNA delivery efficiency and biosafety to those based on SM-102. However, the former reduced the ratio of ionizable lipid to mRNA in LNPs by 2.5 times compared to SM-102. The HTO12 LNP efficiently encapsulated adenine base editor mRNA and sgRNA targeting Pcsk9, leading to substantial gene editing within the liver of mice and effective reduction of the target protein. Our study underscores that ionizable lipids with multiple hydroxyl groups may facilitate an improved lipid-to-mRNA ratio to minimize the dosage of ionizable lipids for in vivo delivery.

Transmembrane Protein TMEM230, Regulator of Glial Cell Vascular Mimicry and Endothelial Cell Angiogenesis in High-Grade Heterogeneous Infiltrating Gliomas and Glioblastoma.

High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.

Effect of glycosylation on soy protein isolate–sodium carboxymethyl cellulose conjugates heat-induced gels and their applications as carriers of riboflavin

The objective of this study was to improve the rheological properties and riboflavin delivery ability of soy protein isolate (SPI) gels by incorporating sodium carboxymethyl cellulose (CMC) through glycosylation. The investigation focused on the structural and gel properties of SPI–CMC conjugates at different Maillard reaction times (30, 60, 90, 120, and 150 min). The results showed that the degree of grafting initially increased and then decreased as the Maillard reaction times increased, reaching its peak at 90 min (25.52%). The changes in the structure and conformation of the SPI–CMC conjugates were verified by Fourier transform infrared spectroscopy and surface hydrophobicity. An appropriate Maillard reaction reduced the content of highly ordered α-helix and β-sheet while increasing the content of disordered random coil and β-turn. This secondary structural change led to protein unfolding, exposure of surface hydrophobic groups, and orderly aggregation, forming a dense cross-linked gel network. When the Maillard reaction times increased, especially for 90 min, the gel strength and water-holding capacity of the SPI–CMC conjugate gels were significantly increased, along with a denser microstructure. Compared with the SPI and SPI–CMC mixture, SPI–CMC conjugate gels with 60 and 90 min reaction times exhibited notably increased viscosity and storage modulus (G′), as well as better structural recovery characteristics. The above physicochemical property improvements markedly enhanced the riboflavin encapsulation efficiency and riboflavin delivery ability of SPI–CMC conjugate gels, improving the ability to protect riboflavin from photodegradation and slowly releasing riboflavin in the simulated intestinal environment. Hence, SPI–CMC conjugate gels have significant potential for the delivery of nutrients.

Efficient Delivery of Lomitapide using Hybrid Membrane-Coated Tetrahedral DNA Nanostructures for Glioblastoma Therapy.

Glioblastoma (GBM) is the most aggressive and prevalent primary malignant tumor of the central nervous system. Traditional chemotherapy has poor therapeutic effects and significant side effects due to drug resistance, the natural blood-brain barrier (BBB), and nonspecific distribution, leading to a lack of clinically effective therapeutic drugs. Here, 1430 small molecule compounds are screened based on a high-throughput drug screening platform and a novel anti-GBM drug, lomitapide (LMP) is obtained. Furthermore, a bionic nanodrug delivery system (RFA NPs) actively targeting GBM is constructed, which mainly consists of tetrahedral DNA nanocages (tFNA NPs) loaded with LMP as the core and a folate-modified erythrocyte-cancer cell-macrophage hybrid membrane (FRUR) as the shell. FRUR camouflage conferred unique features on tFNA NPs, including excellent biocompatibility, improved pharmacokinetic profile, efficient BBB permeability, and tumor targeting ability. The results show that the LMP RFA NPs exhibited superior and specific anti-GBM activities, reduced off-target drug delivery, prolonged lifespan, and has negligible side effects in tumor-bearing mice. This study combines high-throughput drug screening with biomimetic nanodrug delivery system technology to provide a theoretical and practical basis for drug development and the optimization of clinical treatment strategies for GBM treatment.

Nanomaterials-mediated lysosomal regulation: a robust protein-clearance approach for the treatment of Alzheimer’s disease

Abstract Alzheimer's disease is a debilitating, progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins, including amyloid plaques and intracellular tau tangles, primarily within the brain. Lysosomes, crucial intracellular organelles responsible for protein degradation, play a key role in maintaining cellular homeostasis. Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases, including Alzheimer's disease. Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer's disease. Currently, the efficacy of drugs in treating Alzheimer's disease is limited, with major challenges in drug delivery efficiency and targeting. Recently, nanomaterials have gained widespread use in Alzheimer's disease drug research owing to their favorable physical and chemical properties. This review aims to provide a comprehensive overview of recent advances in using nanomaterials (polymeric nanomaterials, nanoemulsions, and carbon-based nanomaterials) to enhance lysosomal function in treating Alzheimer's disease. This review also explores new concepts and potential therapeutic strategies for Alzheimer's disease through the integration of nanomaterials and modulation of lysosomal function. In conclusion, this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer's disease. The application of nanotechnology to the development of Alzheimer's disease drugs brings new ideas and approaches for future treatment of this disease.

Effect of Interrupting Heated Humidification on Nebulized Drug Delivery Efficiency, Temperature, and Absolute Humidity During Mechanical Ventilation: A Multi-Lab In Vitro Study.

Introduction: During mechanical ventilation (MV), inspired gases require heat and humidification. However, such conditions may be associated with reduced aerosol delivery efficiency. The practice of turning off heated humidification before nebulization and the impact of nebulization on humidity in a dry ventilator circuit remain topics of debate. This study aimed to assess the effect of turning off heated humidification on inhaled dose and humidity with nebulizer use during adult MV. Methods: A bronchodilator (albuterol) and two antibiotics (Colistimethate sodium and Amikacin sulfate) were nebulized with a vibrating mesh nebulizer placed at the humidifier inlet and in the inspiratory limb at the Y-piece. Additionally, albuterol was nebulized using a jet nebulizer in both placements. Aerosol particle size distribution was determined through a cascade impactor. Absolute humidity (AH) and temperature of inspired gases were determined with anemometer/hygrometers before, during, and after nebulization, before, during, and up to 60 minutes after interrupting active humidification. Aerosol collected on a filter distal to the endotracheal tube and on impactor stages were eluted and assayed by spectrophotometry. Results: The inhaled dose was greater when both nebulizers were placed at the humidifier inlet than the inspiratory limb at the Y-piece. Irrespective of the nebulizer types and placements, the inhaled dose either decreased or showed no significant change after the humidifier was turned off. The aerosol particle size ranged from 1.1 to 2.7 μm. With interruption of active humidification, humidity of inspired gas quickly dropped below recommended levels, and nebulization in dry ventilator circuit produced an AH between 10 and 20 mgH2O/L, lower than the recommended minimum of 30 mgH2O/L. Conclusion: Interrupting active humidification during MV before nebulization did not improve aerosol delivery efficiency for bronchodilator or antibiotics, but did reduce humidity below recommended levels.

Qualitative analysis of healthcare information technology using a novel short-form questionnaire in a UK district hospital

Background/Aims Healthcare technology is a rapidly expanding field, with the potential to substantially increase the quality and efficiency of care delivery. Despite this, there is no standardised method of assessing the quality of hardware and software information technology (IT) used by frontline healthcare workers. The study aimed to evaluate doctors' perspectives of the IT systems in place at their hospital, with a view to informing wider improvements to healthcare IT. Methods A six-item questionnaire was designed to collect quantitative and qualitative data on the perspectives of clinicians working in a UK hospital regarding the IT at their workplace; this study focused on the qualitative results only. The survey was distributed via the institution's intranet to all contracted doctors at the hospital. Respondents were asked to make up to three comments about the IT systems. Results were classified as positive, negative, neutral suggestion or unusable, and thematic analysis was used to identify themes. Descriptive statistics were used to explore differences between respondents of different levels of seniority (consultant vs junior doctor) and area of specialty. Results A total of 196 doctors completed the questionnaires, of whom 104 were consultants and 92 were junior doctors. A total of 535 comments were made, of which 340 (63.6%) were negative and only 47 (8.8%) were positive. The three most common themes were: speed and ease of use; software and hardware; and integration of systems. Junior doctors gave a higher proportion of negative comments than consultants, while those working in the emergency department, intensive care or anaesthetics gave a lower proportion of negative comments than those working in other specialties. Conclusions Respondents had a largely negative view of the IT systems in place in their hospital. Further evaluation is needed to assess the quality of NHS IT systems on a wider scale, using insights from clinicians to identify and address issues.

Extracellular Microvesicles Modified with Arginine-Rich Peptides for Active Macropinocytosis Induction and Delivery of Therapeutic Molecules.

Extracellular vesicles (EVs), including exosomes and microvesicles (MVs), transfer bioactive molecules from donor to recipient cells in various pathophysiological settings, thereby mediating intercellular communication. Despite their significant roles in extracellular signaling, the cellular uptake mechanisms of different EV subpopulations remain unknown. In particular, plasma membrane-derived MVs are larger vesicles (100 nm to 1 μm in diameter) and may serve as efficient molecular delivery systems due to their large capacity; however, because of size limitations, receptor-mediated endocytosis is considered an inefficient means for cellular MV uptake. This study demonstrated that macropinocytosis (lamellipodia formation and plasma membrane ruffling, causing the engulfment of large fluid volumes outside cells) can enhance cellular MV uptake. We developed experimental techniques to induce macropinocytosis-mediated MV uptake by modifying MV membranes with arginine-rich cell-penetrating peptides for the intracellular delivery of therapeutic molecules.

Exploring Mechanisms of Lipid Nanoparticle-Mucus Interactions in Healthy and Cystic Fibrosis Conditions.

Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerged as versatile non-viral gene delivery systems that could help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery. This article is protected by copyright. All rights reserved.