Nanoparticulate Delivery Systems Research Articles

Lipid-assisted PEG-b-PLA nanoparticles with ultrahigh SN38 loading capability for efficient cancer therapy.

The topoisomerase I inhibitor, 7-ethyl-10-hydroxycamptothecin (SN38), has demonstrated potent anticancer activity. However, its clinical application is hindered by its low solubility and high crystallization propensity, which further complicates its encapsulation into nanoparticles for systemic delivery. Herein, we explore the utilization of lipid-assisted poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) nanoparticles to achieve ultrahigh loading capability for SN38. Through the introduction of cationic, anionic, or neutral lipids, the SN38 loading efficiency and loading capacity is elevated to >90% and >10% respectively. These lipids efficiently attenuate the intermolecular π-π stacking of SN38, thereby disrupting its crystalline structure. Moreover, we assess the therapeutic activity of SN38-loaded formulations in various tumor models and identify an anionic lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) sodium salt (DOPG)-assisted formulation that exhibits the highest anticancer activity and has favorable biosafety. Overall, our findings present a simple and robust strategy to achieve ultrahigh loading efficiency of SN38 using commonly employed PEG-b-PLA nanoparticles, opening up a new avenue for the systemic delivery of SN38.

Enhancing the Dissolution of Oral Dasatinib Tablets Using Zein–Hydroxypropyl Methylcellulose Solid Dispersions

Zein has been used in several pharmaceutical applications because of its unique composition. It is an amphiphilic molecule that is biodegradable, biocompatible, and has adhesive, matrix-forming, and film-coating properties, making it a promising pharmaceutical excipient. Zein-based formulations have been investigated in tablet-coating, nanoparticulate delivery systems, and controlled-release formulations. However, to date, very few studies have been performed on the inclusion of zein in solid dispersion formulations to enhance drug dissolution. This study aimed to improve the dissolution of the weakly basic and poorly soluble oral dasatinib (used as a model) using zein–hydroxypropyl methylcellulose (HPMC) solid dispersion to achieve rapid disintegration and dissolution in the gastric pH. Using the spray-drying technique, four solid dispersions were prepared with different zein, HPMC, and dasatinib ratios. Subsequently, five different tablets were directly compressed using the previously prepared solid dispersions along with basic excipients. Various in vitro characterization analyses were performed to predict their behavior in vivo. Particle size measurement, tablet weight variation and content assay, disintegration, and dissolution studies were also performed. The results indicated that zein solid dispersion improved the disintegration and dissolution of dasatinib in the gastric media by reducing the drug particle size and the formation of the dasatinib amorphous state. Moreover, the tablets exhibited desirable properties in terms of high drug content, friability, and tensile strength. In conclusion, tablets comprising zein–HPMC solid dispersion showed improved properties; however, including a higher ratio of zein in the solid dispersion adversely affected the disintegration and release properties of formulations.

Nanoparticle-based delivery systems as emerging therapy in retinoblastoma: recent advances, challenges and prospects.

Retinoblastoma is the most common intraocular malignancy in children. The treatment of this rare disease is still challenging in developing countries due to delayed diagnosis. The current therapies comprise mainly surgery, radiotherapy and chemotherapy. The adverse effects of radiation and chemotherapeutic drugs have been reported to contribute to the high mortality rate and affect patients' quality of life. The systemic side effects resulting from the distribution of chemotherapeutic drugs to non-cancerous cells are enormous and have been recognized as one of the reasons why most potent anticancer compounds fail in clinical trials. Nanoparticulate delivery systems have the potential to revolutionize cancer treatment by offering targeted delivery, enhanced penetration and retention effects, increased bioavailability, and an improved toxicity profile. Notwithstanding the plethora of evidence on the beneficial effects of nanoparticles in retinoblastoma, the clinical translation of this carrier is yet to be given the needed attention. This paper reviews the current and emerging treatment options for retinoblastoma, with emphasis on recent investigations on the use of various classes of nanoparticles in diagnosing and treating retinoblastoma. It also presents the use of ligand-conjugated and smart nanoparticles in the active targeting of anticancer and imaging agents to the tumour cells. In addition, this review discusses the prospects and challenges in translating this nanocarrier into clinical use for retinoblastoma therapy. This review may provide new insight for formulation scientists to explore in order to facilitate the development of more effective and safer medicines for children suffering from retinoblastoma.

Efficacy of invasive and non-invasive methods for the treatment of Parkinson's disease: Nanodelivery and enriched environment.

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta and the subsequent motor disability. The most frequently used treatments in clinics, such as L-DOPA, restore dopaminergic neurotransmission in the brain. However, these treatments are only symptomatic, have temporary efficacy, and produce side effects. Part of the side effects are related to the route of administration as the consumption of oral tablets leads to unspecific pulsatile activation of dopaminergic receptors. For this reason, it is necessary to not only find alternative treatments, but also to develop new administration systems with better security profiles. Nanoparticle delivery systems are new administration forms designed to reach the pharmacological target in a highly specific way, leading to better drug bioavailability, efficacy and safety. Some of these delivery systems have shown promising results in animal models of PD not only when dopaminergic drugs are administered, but even more when neurotrophic factors are released. These latter compounds promote maturation and survival of dopaminergic neurons and can be exogenously administered in the form of pharmacological therapy or endogenously generated by non-pharmacological methods. In this sense, experimental exposure to enriched environments, a non-invasive strategy based on the combination of social and inanimate stimuli, enhances the production of neurotrophic factors and produces a neuroprotective effect in parkinsonian animals. In this review, we will discuss new nanodelivery systems in PD with a special focus on therapies that increase the release of neurotrophic factors.

Polypropylene sulphide coating on magnetic nanoparticles as a novel platform for excellent biocompatible, stimuli-responsive smart magnetic nanocarriers for cancer therapeutics.

Magnetic nanoparticle (MNP) delivery systems are promising for targeted drug delivery, imaging, and chemo-hyperthermia of cancer; however, their uses remain limited primarily due to their toxicity associated with reactive oxygen species (ROS) generation, targeted delivery, and biodegradation. Attempts employing polymer coatings to minimize the toxicity, along with other challenges, have had limited success. We designed a novel yet generic 'one-for-all' polypropylene sulphide (PPS) coated magnetic nano-delivery system (80 ± 15 nm) as a multi-faceted approach for significant biocompatibility improvement, loading of multiple drugs, ROS-responsive delivery, and combined chemo-hyperthermia therapy for biomedical applications. Three distinct MNP systems (15 ± 1 nm) were fabricated, coated with PPS polymer, and investigated to validate our hypothesis and design. Simultaneous degradation of MNPs and PPS coatings with ROS-scavenging characteristics boosted the biocompatibility of MNPs 2-3 times towards non-cancerous fibroblasts (NIH3T3) and human epithelial cells (HEK293). In an alternating magnetic field, PPS-MNPs (MnFe) had the strongest heating characteristics (SAR value of 240 W g-1). PPS-MNP drug-loaded NPs were efficiently internalised into cells and released 80% of the drugs under tumor microenvironment-mimicking (pH 5-7, ROS) conditions, and demonstrated effective chemo-hyperthermia (45 °C) application for breast cancer cells with 95% cell death in combined treatment vs. 55% and 30% cell death in only hyperthermia and chemotherapy respectively.

Enhanced immunogenicity induced by mRNA vaccines with various lipid nanoparticles as carriers for SARS-CoV-2 infection.

mRNA vaccines have emerged as a highly promising approach for preventing cancer and infectious diseases, attributed to their superior immunogenicity, rapid development speed, and quality-controlled scale production. While homologous mRNA vaccine administration is currently the most prevalent method employed in clinical settings, heterologous administration is a promising avenue worth exploring. In this report, two types of mRNA vaccine formulations for SARS-CoV-2 infection were developed based on different lipid nanoparticle (LNP) delivery systems, and heterologous and homologous mRNA vaccinations were administered to explore the levels of immune responses comparatively. First, five novel H-series ionizable lipids were synthesized and confirmed by NMR and MS. Subsequently, six SARS-CoV-2 receptor-binding domain (RBD) mRNA-encapsulated LNP formulations were prepared using a microfluidic mixer based on H-series and MC3 lipids. These formulations exhibited spherical structures with an average diameter ranging from 90-140 nm, as characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The safety of these formulations was confirmed in vitro by the cytotoxicity assay. Moreover, transfection assay, lysosomal escape test, and western blot, and in vivo biodistribution analyses collectively demonstrated that lipids H03 and MC3 exhibited superior in vitro and in vivo delivery efficacy in comparison to other H-series lipids. Notably, H03-Fluc mRNA exhibited an approximately 2.2-fold higher in vivo bioluminescence signal intensity than MC3-Fluc mRNA. Additionally, evaluation of humoral immunity demonstrated that homologous H03-mRNA vaccination elicited an immune response that was approximately 3-fold higher than that of homologous MC3-mRNA vaccination. More significantly, the heterologous H03-mRNA/MC3-mRNA vaccination elicited an immune response that was approximately 2-3-fold higher than that of homologous H03-mRNA vaccination and 6-9-fold higher than that of homologous MC3-mRNA vaccination, without any observable adverse effects. These results suggest that heterologous mRNA vaccination is superior to homologous mRNA vaccination and may be attributed to differences in LNP carriers. Therefore, our research may inspire further exploration of different delivery systems to enhance mRNA-based therapeutics.

Belinostat loaded lipid-polymer hybrid nanoparticulate delivery system for breast cancer: improved pharmacokinetics and biodistribution in a tumor model.

Despite various treatment modalities for breast cancer, it still persists as one of the most diagnosed types of cancer in females. The recent investigations in the epigenetics of breast cancer reveal several aberrations in the expression levels of various HDAC enzymes. Henceforth, the present work entails the formulation and characterization of a lipid polymer-based hybrid nanoparticulate (LPN) system for delivery of an epigenetic modulator drug, Belinostat, for its clinical application in breast cancer. The size of Belinostat nanoparticles prepared using a modified hot homogenization method was found to be 166.6 ± 19.95 nm with an encapsulation efficiency of 94.5 ± 5.1%. In vitro characterization for cytotoxicity, cellular uptake, and protein expression in two different breast cancer cells, 4T1 and MCF 7, revealed the superiority of the formulation in comparison with the free drug in MCF 7 cells. Subsequently, the behaviour of the formulation in in vivo settings of healthy and breast cancer xenograft bearing animals was analyzed using pharmacokinetic and biodistribution studies. The results revealed that the formulation demonstrated multi-fold improvement in the pharmacokinetic parameters in tumor bearing animals when compared with the free drug while no difference in pharmacokinetic behaviour was observed in healthy animals indicating the altered biodistribution and specificity of the formulation in breast tumor. This was confirmed by the biodistribution studies exhibiting 20-fold improved uptake and retention of the nanoparticulate formulation in tumor tissues of the animal model at the end of 4 h. Thus, the developed LPN system holds potential to act as a novel drug delivery system for Belinostat with several advantages over the free drug.

Paclitaxel-loaded cubosome lipid nanocarriers stabilised with pH and hydrogen peroxide-responsive steric stabilisers as drug delivery vehicles.

Responsive nanoparticle delivery systems hold great potential for next-generation chemotherapeutic treatment with reduced off-target side effects. In this work, we formulated responsive lipid-based cubosomes loaded with paclitaxel (PTX) as a model drug and stabilised by novel amphiphilic block copolymers (ABCs) containing the pH-responsive poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) and/or the hydrogen peroxide (H2O2)-responsive poly(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acrylate) (PTBA) blocks. The results showed that these cubosomes with a particle size of around 250 nm exhibited excellent PTX encapsulation efficiency of up to 60% and had the ability to control the release rate of the drug in response to pH and H2O2 changes. Specifically, compared to the physiological pH of 7.4, PTX was released faster from the cubosome carriers when exposed to pH 5.5 and/or 50 mM H2O2 conditions, which are pathological conditions found in a tumour microenvironment. In vitro cytotoxicity and cell uptake studies further investigated the cellular interactions of these cubosomes. It was found that cubosomes containing PTX had more toxic effects than the control free PTX sample. Compared to cubosomes stabilised by the non-responsive block copolymer Pluronic® F127, the ABC-stabilised cubosomes also had higher cell internalisation efficiency demonstrated by the cytoplasmic fluorescence intensities using confocal microscopy. These results demonstrated that ABCs containing responsive moieties can stabilise lipid cubosomes and enhance controlled release of poorly soluble chemotherapeutics and cellular uptake.

Development of a cationic polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticle system for enhanced intracellular delivery of biologics.

Intracellular delivery of proteins, peptides and biologics is an emerging field which has the potential to provide novel opportunities to target intracellular proteins, previously deemed 'undruggable'. However, the delivery of proteins intracellularly remains a challenge. Here, we present a cationic nanoparticle delivery system for enhanced cellular delivery of proteins through use of a polyethyleneimine and poly-(lactic-co-glycolic acid) polymer blend. Cationic nanoparticles were shown to provide increased cellular uptake compared to anionic and neutral nanoparticles, successfully delivering Variable New Antigen Receptors (vNARs), entrapped within the nanoparticle core, to the cell interior. vNARs were identified as ideal candidates for nanoparticle entrapment due to their remarkable stability. The optimised 10% PEI-PLGA nanoparticle formulation displayed low toxicity, was uniform in size and possessed appropriate cationic charge to limit cellular toxicity, whilst being capable of escaping the endo/lysosomal system and delivering their cargo to the cytosol. This work demonstrates the ability of cationic nanoparticles to facilitate intracellular delivery of vNARs, novel biologic agents with potential utility towards intracellular targets.

Administration methods of lipid-based nanoparticle delivery systems for cancer treatment.

As nano medications have developed in the recent four decades, nano-delivery systems have been applied in treating various diseases and are especially common in cancer treatment. Nano-delivery systems could target cancer-associated cells, enhance the accuracy and efficacy of treatment, and reduce systemic side effects. Among the many drugs on nano-carriers, the load system of lipid-based nanoparticles has the brightest prospect due to the high level of biocompatibility, biodegradability, loading capability, and immunogenicity. Previous reviews have comprehensively introduced their effects and progress. However, most of them did not provide great attention to practical applications. This article will focus on different intake methods, which decide the biological process of drugs. This suggests that we can modify lipid-based nano-delivery systems according to how they are capable of prolonging the half-life span and magnifying therapy effects in treating cancer. Besides, we put forth the problems that should be further studied in the future and their probable solutions.

Principles of Nanoparticle Delivery to Solid Tumors.

The effective treatment of patients with cancer hinges on the delivery of therapeutics to a tumor site. Nanoparticles provide an essential transport system. We present 5 principles to consider when designing nanoparticles for cancer targeting: (a) Nanoparticles acquire biological identity in vivo, (b) organs compete for nanoparticles in circulation, (c) nanoparticles must enter solid tumors to target tumor components, (d) nanoparticles must navigate the tumor microenvironment for cellular or organelle targeting, and (e) size, shape, surface chemistry, and other physicochemical properties of nanoparticles influence their transport process to the target. This review article describes these principles and their application for engineering nanoparticle delivery systems to carry therapeutics to tumors or other disease targets.

Efficient delivery of VEGF-A mRNA for promoting diabetic wound healing via ionizable lipid nanoparticles

Diabetes is often accompanied by chronic non-healing wounds, and vascularendothelial growth factor A (VEGF-A) is crucial in the treatment of chronic diabetic wounds. However, the application of VEGF-A protein in clinic is limited due to poor absorption and short half-life of protein macromolecule. Herein, we employed an emerging protein replacement therapy by delivering VEGF-A mRNA into the body to express the desired protein to accelerate diabetic wound healing. Primarily, VEGF-A mRNA was synthesized by an in vitro transcription (IVT) method and encapsulated with an ionizable lipid-mediated nanoparticles (LNP) delivery system via a microfluidic method. The resultant LNP/VEGF-A mRNA were characterized by using dynamic light scattering (DLS) and transmission electron microscope(TEM). The nanoparticles have regular spherical morphology with an average particle size of 101.17 nm, a narrow polydispersity (PDI) of 0.17 and negative Zeta potential of −3.05 mV. The bioactivities of the nanoparticles formulation were evaluated against HUVEC cells through cell proliferation, migration and tube formation assays. It was found that the LNP/VEGF-A mRNA nanoparticles could promote endothelial cell proliferation. In addition, they exhibited successful mRNA delivery and high VEGF-A protein expression in vitro and in vivo by means of Western Blot assay and in vivo imaging system (IVIS). Finally, C57BL/6 diabetic mice model was established and intradermally treated with the LNP/VEGF-A mRNA nanoparticles. It was found that the LNP/VEGF-A mRNA treated wounds were almost healed after 14 days with an average wound area of 2.4 %, compared with the PBS group of 21.4 %. Apparently, the nanoparticles formulation was able to significantly expedite diabetic wound healing. The histological analysis containing H&E, Masson’s trichrome staining and CD31 further confirmed the healing efficacy and low toxicity of the formulation. Taken together, the LNP/VEGF-A mRNA nanoparticles can be taken up by cells to express protein effectively and improve diabetic wound healing, which might have potential application in the treatment of chronic diabetic wounds as a protein replacement therapy.

Nano Functional Food: Opportunities, Development, and Future Perspectives.

A functional food is a kind of food with special physiological effects that can improve health status or reduce illness. However, the active ingredients in functional foods are usually very low due to the instability and easy degradation of some nutrients. Therefore, improving the utilization rate of the effective ingredients in functional food has become the key problem. Nanomaterials have been widely used and studied in many fields due to their small size effect, high specific surface area, high target activity, and other characteristics. Therefore, it is a feasible method to process and modify functional food using nanotechnology. In this review, we summarize the nanoparticle delivery system and the food nanotechnology in the field of functional food. We also summarize and prospect the application, basic principle, and latest development of nano-functional food and put forward corresponding views.

Novel core-shell nanoparticles: Encapsulation and delivery of curcumin using guanidine hydrochloride-induced oleosome protein self-assembly

Guanidine hydrochloride (GuHCl) was used to disassemble and reassemble oleosome proteins (OP) to encapsulate curcumin inside OP core-shell structures, improving its stability and bioavailability. The effect of GuHCl on the structure of OP indicated that OP disassembly and reassembly primarily involved the breakage and formation of hydrogen bonds. The extrinsic-protein subunits in OP were completely disassembled by GuHCl (5 M); after GuHCl removal by dialysis, the disassembled subunits were re-linked with intrinsic-protein subunits, encapsulating curcumin during the reassembly process. Curcumin preferentially bound with extrinsic protein of OP (through hydrogen bonding and hydrophobic interactions) to form protein-nanoparticle shells, while intrinsic-protein formed hydrophobic cores that encapsulated curcumin; the final curcumin encapsulation efficiency was 22.56 μm/mg. Additionally, the curcumin-OP nanoparticles exhibited high stability and bioavailability (44.7%), and sustained-release behavior with GuHCl (5 M). This study elucidates and develops OP structures and could guide the development of high-efficiency nanoparticle delivery systems for hydrophobic nutrient carriers.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Urgency and necessity of Epstein-Barr virus prophylactic vaccines.

Epstein-Barr virus (EBV), a γ-herpesvirus, is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them was able to prevent EBV infection and no vaccine has been approved to date. Current efforts focus on antigen selection, combination, and design to improve the efficacy of vaccines. EBV glycoproteins such as gH/gL, gp42, and gB show excellent immunogenicity in preclinical studies compared to the previously favored gp350 antigen. Combinations of multiple EBV proteins in various vaccine designs become more attractive approaches considering the complex life cycle and complicated infection mechanisms of EBV. Besides, rationally designed vaccines such as virus-like particles (VLPs) and protein scaffold-based vaccines elicited more potent immune responses than soluble antigens. In addition, humanized mice, rabbits, as well as nonhuman primates that can be infected by EBV significantly aid vaccine development. Innovative vaccine design approaches, including polymer-based nanoparticles, the development of effective adjuvants, and antibody-guided vaccine design, will further enhance the immunogenicity of vaccine candidates. In this review, we will summarize (i) the disease burden caused by EBV and the necessity of developing an EBV vaccine; (ii) previous EBV vaccine studies and available animal models; (iii) future trends of EBV vaccines, including activation of cellular immune responses, novel immunogen design, heterologous prime-boost approach, induction of mucosal immunity, application of nanoparticle delivery system, and modern adjuvant development.

Self-Assembly of Tunable Intrinsically Disordered Peptide Amphiphiles.

Intrinsically disordered peptide amphiphiles (IDPAs) present a novel class of synthetic conjugates that consist of short hydrophilic polypeptides anchored to hydrocarbon chains. These hybrid polymer-lipid block constructs spontaneously self-assemble into dispersed nanoscopic aggregates or ordered mesophases in aqueous solution due to hydrophobic interactions. Yet, the possible sequence variations and their influence on the self-assembly structures are vast and have hardly been explored. Here, we measure the nanoscopic self-assembled structures of four IDPA systems that differ by their amino acid sequence. We show that permutations in the charge pattern along the sequence remarkably alter the headgroup conformation and consequently alter the pH-triggered phase transitions between spherical, cylindrical micelles and hexagonal condensed phases. We demonstrate that even a single amino acid mutation is sufficient to tune structural transitions in the condensed IDPA mesophases, while peptide conformations remain unfolded and disordered. Furthermore, alteration of the peptide sequence can render IDPAs to become susceptible to enzymatic cleavage and induce enzymatically activated phase transitions. These results hold great potential for embedding multiple functionalities into lipid nanoparticle delivery systems by incorporating IDPAs with the desired properties.

Inhaled platelet vesicle-decoyed biomimetic nanoparticles attenuate inflammatory lung injury.

Acute lung injury (ALI) is an inflammatory response which causes serious damages to alveolar epithelia and vasculature, and it still remains high lethality and mortality with no effective treatment. Based on the inflammatory homing of platelets and cell membrane cloaking nanotechnology, in this study we developed a biomimetic anti-inflammation nanoparticle delivery system for ALI treatment. PM@Cur-RV NPs were designed by combining the poly (lactic-co-glycolic acid) nanoparticles (NPs) coated with platelet membrane vesicles (PM) for the purpose of highly targeting delivery of curcumin (Cur) and resveratrol (RV) to inflammatory lungs. PM@Cur-RV NPs showed good biocompatibility and biosafety both in vitro and in vivo. Accumulation of NPs into lung tract was observed after inhaled NPs. Remarkably, the inhalation of PM@Cur-RV NPs effectively inhibited lung vascular injury evidenced by the decreased lung vascular permeability, and the reduced proinflammatory cytokine burden in an ALI mouse model. The analysis of infiltrated macrophages in the lungs showed that the Cur-RV-modulated macrophage polarized towards M2 phenotype and the decreased histone lactylation might contribute to their anti-inflammation effects. Together, this work highlights the potential of inhalation of biomimetic nanoparticle delivery of curcumin and resveratrol for the treatment of pulmonary diseases.

Alternative Pharmacological Strategies for the Treatment of Alzheimer's Disease: Focus on Neuromodulator Function.

Alzheimer's disease (AD) is a neurodegenerative disorder, comprising 70% of dementia diagnoses worldwide and affecting 1 in 9 people over the age of 65. However, the majority of its treatments, which predominantly target the cholinergic system, remain insufficient at reversing pathology and act simply to slow the inevitable progression of the disease. The most recent neurotransmitter-targeting drug for AD was approved in 2003, strongly suggesting that targeting neurotransmitter systems alone is unlikely to be sufficient, and that research into alternate treatment avenues is urgently required. Neuromodulators are substances released by neurons which influence neurotransmitter release and signal transmission across synapses. Neuromodulators including neuropeptides, hormones, neurotrophins, ATP and metal ions display altered function in AD, which underlies aberrant neuronal activity and pathology. However, research into how the manipulation of neuromodulators may be useful in the treatment of AD is relatively understudied. Combining neuromodulator targeting with more novel methods of drug delivery, such as the use of multi-targeted directed ligands, combinatorial drugs and encapsulated nanoparticle delivery systems, may help to overcome limitations of conventional treatments. These include difficulty crossing the blood-brain-barrier and the exertion of effects on a single target only. This review aims to highlight the ways in which neuromodulator functions are altered in AD and investigate how future therapies targeting such substances, which act upstream to classical neurotransmitter systems, may be of potential therapeutic benefit in the sustained search for more effective treatments.

Colostrum-derived exosome based system: The next-generation nucleic acid delivery system with enhanced biosafety?

Wallen et al. employed a colostrum exosome-based nanoparticle delivery system, exosome-PEI matrix (EPM), to help develop a flexible, testable therapeutic model system. Based on this system, plasmid DNA and small interfering RNA (siRNA) were delivered into in vitro cell lines and in vivo. Three essential severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins—spike glycoprotein, nucleocapsid, and replicase—were expressed to mimic the expression of the viral genome; certain siRNAs were found to silence their matched proteins with 80%–95% efficiency, indicating their therapeutic potential.