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Journal of Controlled Release :... Sep 2023Natural killer (NK) cells participate in the immune system by eliminating cancer and virally infected cells through germline-encoded surface receptors. Their...
Natural killer (NK) cells participate in the immune system by eliminating cancer and virally infected cells through germline-encoded surface receptors. Their independence from prior activation as well as their significantly lower toxicity have placed them in the spotlight as an alternative to T cells for adoptive cell therapy (ACT). Engineering NK cells with mRNA has shown great potential in ACT by enhancing their tumor targeting and cytotoxicity. However, mRNA transfection of NK cells is challenging, as the most common delivery methods, such as electroporation, show limitations. Therefore, an alternative non-viral delivery system that enables high mRNA transfection efficiency with preservation of the cell viability would be beneficial for the development of NK cell therapies. In this study, we investigated both polymeric and lipid nanoparticle (LNP) formulations for eGFP-mRNA delivery to NK cells, based on a dimethylethanolamine and diethylethanolamine polymeric library and on different ionizable lipids, respectively. The mRNA nanoparticles based on cationic polymers showed limited internalization by NK cells and low transfection efficiency. On the other hand, mRNA-LNP formulations were optimized by tailoring the lipid composition and the microfluidic parameters, resulting in a high transfection efficiency (∼100%) and high protein expression in NK cells. In conclusion, compared to polyplexes and electroporation, the optimized LNPs show a greater transfection efficiency and higher overall eGFP expression, when tested in NK (KHYG-1) and T (Jurkat) cell lines, and cord blood-derived NK cells. Thus, LNP-based mRNA delivery represents a promising strategy to further develop novel NK cell therapies.
Topics: Humans; RNA, Messenger; Transfection; Killer Cells, Natural; Nanoparticles; Neoplasms; Polymers
PubMed: 37567506
DOI: 10.1016/j.jconrel.2023.08.014 -
Advanced Drug Delivery Reviews Oct 2023The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only... (Review)
Review
The minimally-invasive and painless nature of microneedle (MN) application has enabled the technology to obviate many issues with injectable drug delivery. MNs not only administer therapeutics directly into the dermal and ocular space, but they can also control the release profile of the active compound over a desired period. To enable prolonged delivery of payloads, various MN types have been proposed and evaluated, including dissolving MNs, polymeric MNs loaded or coated with nanoparticles, fast-separable MNs hollow MNs, and hydrogel MNs. These intricate yet intelligent delivery platforms provide an attractive approach to decrease side effects and administration frequency, thus offer the potential to increase patient compliance. In this review, MN formulations that are loaded with various therapeutics for long-acting delivery to address the clinical needs of a myriad of diseases are discussed. We also highlight the design aspects, such as polymer selection and MN geometry, in addition to computational and mathematical modeling of MNs that are necessary to help streamline and develop MNs with high translational value and clinical impact. Finally, up-scale manufacturing and regulatory hurdles along with potential avenues that require further research to bring MN technology to the market are carefully considered. It is hoped that this review will provide insight to formulators and clinicians that the judicious selection of materials in tandem with refined design may offer an elegant approach to achieve sustained delivery of payloads through the simple and painless application of a MN patch.
Topics: Humans; Skin; Drug Delivery Systems; Polymers; Needles; Administration, Cutaneous
PubMed: 37597586
DOI: 10.1016/j.addr.2023.115055 -
Nature Nanotechnology Mar 2024Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges...
Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air-liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles.
Topics: Excipients; Cell Differentiation; Nanoparticles; Polymers; RNA, Messenger; RNA, Small Interfering
PubMed: 37985700
DOI: 10.1038/s41565-023-01548-3 -
Biosensors Aug 2023Surveillance of viral pathogens in both point-of-care and clinical settings is imperative to preventing the widespread propagation of disease-undetected viral outbreaks... (Review)
Review
Surveillance of viral pathogens in both point-of-care and clinical settings is imperative to preventing the widespread propagation of disease-undetected viral outbreaks can pose dire health risks on a large scale. Thus, portable, accessible, and reliable biosensors are necessary for proactive measures. Polymeric microparticles have recently gained popularity for their size, surface area, and versatility, which make them ideal biosensing tools. This review cataloged recent investigations on polymeric microparticle-based detection platforms across eight virus families. These microparticles were used as labels for detection (often with fluorescent microparticles) and for capturing viruses for isolation or purification (often with magnetic microparticles). We also categorized all methods by the characteristics, materials, conjugated receptors, and size of microparticles. Current approaches were compared, addressing strengths and weaknesses in the context of virus detection. In-depth analyses were conducted for each virus family, categorizing whether the polymeric microparticles were used as labels, for capturing, or both. We also summarized the types of receptors conjugated to polymeric microparticles for each virus family.
Topics: Point-of-Care Systems; Polymers
PubMed: 37622906
DOI: 10.3390/bios13080820 -
International Journal of Molecular... Nov 2023The definition of the term biopolymer is often controversial, and there is no clear distinction between "biopolymers", "bioplastics", and "bio-based polymers" [...].
The definition of the term biopolymer is often controversial, and there is no clear distinction between "biopolymers", "bioplastics", and "bio-based polymers" [...].
Topics: Biopolymers; Polymers
PubMed: 38003441
DOI: 10.3390/ijms242216251 -
Nature Communications Aug 2023Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers,...
Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers, the existence of complicated intracorporal interferences, and the demand for extra external stimulations hinder their further biological applications. Herein, a nanocompartment-confined strategy that provides a confined and secluded environment for monomer enrichment and isolation is developed to achieve high polymerization efficiency, reduce the interference from external environment, and realize broad-spectrum polymerizations in living systems. For exogenous photopolymerization, the light-mediated free-radical polymerization of sodium 4-styrenesulfonate induces a 2.7-fold increase in the reaction rate with the protection of a confined environment. For endogenous hydrogen peroxide-responsive polymerization, p‑aminodiphenylamine hydrochloride embedded in a nanocompartment not only performs a 6.4-fold higher reaction rate than that of free monomers, but also activates an effective second near-infrared photoacoustic imaging-guided photothermal immunotherapy at tumor sites. This nanocompartment-confined strategy breaks the shackles of conventional polymerization, providing a universal platform for in vivo synthesis of polymers with diverse structures and functions.
Topics: Polymerization; Hydrogen Peroxide; Immunotherapy; Polymers
PubMed: 37634028
DOI: 10.1038/s41467-023-40935-1 -
Cell Death and Differentiation Jan 2024Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is...
Mixed lineage kinase-like protein (MLKL) forms amyloid-like polymers to promote necroptosis; however, the mechanism through which these polymers trigger cell death is not clear. We have determined that activated MLKL translocates to the lysosomal membrane during necroptosis induction. The subsequent polymerization of MLKL induces lysosome clustering and fusion and eventual lysosomal membrane permeabilization (LMP). This LMP leads to the rapid release of lysosomal contents into the cytosol, resulting in a massive surge in cathepsin levels, with Cathepsin B (CTSB) as a significant contributor to the ensuing cell death as it cleaves many proteins essential for cell survival. Importantly, chemical inhibition or knockdown of CTSB protects cells from necroptosis. Furthermore, induced polymerization of the MLKL N-terminal domain (NTD) also triggers LMP, leading to CTSB release and subsequent cell death. These findings clearly establish the critical role of MLKL polymerization induced lysosomal membrane permeabilization (MPI-LMP) in the process of necroptosis.
Topics: Protein Kinases; Necroptosis; Polymerization; Lysosomes; Polymers; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37996483
DOI: 10.1038/s41418-023-01237-7 -
Annals of Botany Jul 2023Silicon and aluminium oxides make the bulk of agricultural soils. Plants absorb dissolved silicon as silicic acid into their bodies through their roots. The silicic acid... (Review)
Review
BACKGROUND
Silicon and aluminium oxides make the bulk of agricultural soils. Plants absorb dissolved silicon as silicic acid into their bodies through their roots. The silicic acid moves with transpiration to target tissues in the plant body, where it polymerizes into biogenic silica. Mostly, the mineral forms on a matrix of cell wall polymers to create a composite material. Historically, silica deposition (silicification) was supposed to occur once water evaporated from the plant surface, leaving behind an increased concentration of silicic acid within plant tissues. However, recent publications indicate that certain cell wall polymers and proteins initiate and control the extent of plant silicification.
SCOPE
Here we review recent publications on the polymers that scaffold the formation of biogenic plant silica, and propose a paradigm shift from spontaneous polymerization of silicic acid to dedicated active metabolic processes that control both the location and the extent of the mineralization.
CONCLUSION
Protein activity concentrates silicic acid beyond its saturation level. Polymeric structures at the cell wall stabilize the supersaturated silicic acid and allow its flow with the transpiration stream, or bind it and allow its initial condensation. Silica nucleation and further polymerization are enabled on a polymeric scaffold, which is embedded within the mineral. Deposition is terminated once free silicic acid is consumed or the chemical moieties for its binding are saturated.
Topics: Silicon Dioxide; Silicic Acid; Silicon; Plants; Polymers
PubMed: 37094329
DOI: 10.1093/aob/mcad056 -
Toxins Jan 2024Mycotoxins are toxic metabolites of molds which can contaminate food and beverages. Because of their acute and chronic toxicity, they can have harmful effects when... (Review)
Review
Mycotoxins are toxic metabolites of molds which can contaminate food and beverages. Because of their acute and chronic toxicity, they can have harmful effects when ingested or inhaled, posing severe risks to human health. Contemporary analytical methods have the sensitivity required for contamination detection and quantification, but the direct application of these methods on real samples is not straightforward because of matrix complexity, and clean-up and preconcentration steps are needed, more and more requiring the application of highly selective solid-phase extraction materials. Molecularly imprinted polymers (MIPs) are artificial receptors mimicking the natural antibodies that are increasingly being used as a solid phase in extraction methods where selectivity towards target analytes is mandatory. In this review, the state-of-the-art about molecularly imprinted polymers as solid-phase extraction materials in mycotoxin contamination analysis will be discussed, with particular attention paid to the use of mimic molecules in the synthesis of mycotoxin-imprinted materials, to the application of these materials to food real samples, and to the development of advanced extraction methods involving molecular imprinting technology.
Topics: Humans; Polymers; Mycotoxins; Molecularly Imprinted Polymers; Antibodies; Beverages
PubMed: 38251263
DOI: 10.3390/toxins16010047 -
Science Advances Apr 2024Molecular strain can be introduced to influence the outcome of chemical reactions. Once a thermodynamic product is formed, however, reversing the course of a...
Molecular strain can be introduced to influence the outcome of chemical reactions. Once a thermodynamic product is formed, however, reversing the course of a strain-promoted reaction is challenging. Here, a reversible, strain-promoted polymerization in cyclic DNA is reported. The use of nonhybridizing, single-stranded spacers as short as a single nucleotide in length can promote DNA cyclization. Molecular strain is generated by duplexing the spacers, leading to ring opening and subsequent polymerization. Then, removal of the strain-generating duplexers triggers depolymerization and cyclic dimer recovery via enthalpy-driven cyclization and entropy-mediated ring contraction. This reversibility is retained even when a protein is conjugated to the DNA strands, and the architecture of the protein assemblies can be modulated between bivalent and polyvalent states. This work underscores the utility of using DNA not only as a programmable ligand for assembly but also as a route to access restorable bonds, thus providing a molecular basis for DNA-based materials with shape-memory, self-healing, and stimuli-responsive properties.
Topics: Polymerization; DNA; Cyclization; Thermodynamics; Nucleic Acid Conformation
PubMed: 38657068
DOI: 10.1126/sciadv.ado8020