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Non-viral vectors for mRNA delivery primarily include lipid nanoparticles (LNPs) and polymers. While LNPs are known for their high mRNA delivery efficiency, they can induce excessive immune responses and cause off-target effects, potentially leading to side effects. In this study, we aimed to explore polymer-based mRNA delivery systems as a viable alternative to LNPs, focusing on their mRNA delivery efficiency and potential application in mRNA vaccines. We created a library of poly(β-amino ester) (PBAE) polymers by combining various amine monomers and acrylate monomers. Through screening this polymer library, we identified specific polymer nanoparticles (PNPs) that demonstrated high mRNA expression efficiency, with sustained mRNA expression for up to two weeks. Furthermore, the PNPs showed mRNA expression only at the injection site and did not exhibit liver toxicity. Additionally, when assessing immune activation, the PNPs significantly induced T-cell immune activation and were effective in the plaque reduction neutralization test. These results suggest that polymer-based mRNA delivery systems not only hold potential for use in mRNA vaccines but also show promise for therapeutic applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Highlights: [•] Dextran sulfate-b-poly(glycerol methacrylate) (DS-b-PGMA) copolymer is synthesized. [•] DS-coated superparamagnetic iron oxide nanoparticles (DS-SPIONs) were prepared. [•] DS-SPIONs showed high stability due to robust anchoring of PGMA segment on SPIONs. [•] DS-SPIONs were taken up by activated macrophages via receptor-mediated endocytosis. [•] DS-SPIONs produced contrast enhancement in the T 2-weighted MR cellular imaging. [ABSTRACT FROM AUTHOR]

Abstract: Amphiphilic hyaluronic acid conjugates were synthesized as a potential drug carrier by chemical conjugation of an amine-terminated hydrotropic oligomer, which has a unique ability to enhance the solubility of paclitaxel (PTX), to a hyaluronic acid (HA) backbone using carbodiimide chemistry. The physicochemical properties of the hydrotropic hyaluronic acid (HydroHA) conjugates were investigated using 1H NMR, dynamic light scattering, transmission electron microscopy (TEM), and fluorescence spectroscopy. HydroHA conjugates could form self-assembled nanoparticles in an aqueous medium because of hydrophobic interactions among hydrotropic oligomers. Their particle sizes were in the range of 274–356nm, depending on the degree of substitution (DS) of the hydrotropic oligomer. TEM images showed that particle morphology was spherical in shape. Critical aggregation concentrations of HydroHA conjugates ranged from 0.034 to 0.125mg/mL, which decreased with an increase in the DS of the hydrotropic oligomer. The HydroHA conjugates were selectively taken up by the cancer cell line (SCC-7) over-expressing CD44, a hyaluronic receptor. The nanoparticles could encapsulate PTX up to 20.7wt.% by the dialysis method. The in vitro release pattern of PTX from nanoparticles was significantly dependent on drug loading content, in which the release rate was lower for the nanoparticles that contained larger amounts of the drug. From the cytotoxicity test, it was found that the drug-loaded HydroHA nanoparticles exhibited stronger cytotoxicity to SCC-7 than to normal fibroblast cell (CV-1). These results suggest that HydroHA nanoparticles have potential as the carrier of PTX for cancer therapy. [Copyright &y& Elsevier]

Despite the success of immune checkpoint blockade (ICB) therapy in various cancers, its efficacy faces challenges in glioblastoma (GBM) due to the immunosuppressive cold-tumor microenvironment. The scarcity of tumor-infiltrating T cells and the suppression of T cell activity significantly limit therapeutic outcomes in GBM. Nitric oxide (NO) and reactive oxygen species (ROS) from tumor-associated myeloid cells (TAMCs) are key contributors to T cell suppression, reducing ICB therapy effectiveness. In this study, we developed NO-ROS scavenging micelles that effectively scavenge both NO and ROS, protecting T cells from their exhausting effects. This leads to a significant increase in T cell infiltration and activation. Moreover, when combined with αPD-1, the survival rate increases to 40 % up to 120 days, enhancing therapeutic efficacy compared to αPD-1 alone. This approach not only protects T cells from the inhibitory effects of NO and ROS but also has the potential to reshape the tumor microenvironment, overcoming T cell suppression in cold tumors. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is widely known as an effective vasodilator at low concentrations. Drug delivery systems combined with NO can dilate blood vessels surrounding tumor tissues, and the drug accumulation in tumors is accelerated by the enhanced permeability and retention effect, leading to an improvement in the anti-tumor effect. N-heterocyclic carbene-based NO donors (e.g., 1,3-bis-(2,4,6-trimethylphenyl)imidazolylidene nitric oxide (IMesNO) have been developed for stable NO storing in air and water, and NO release by thermolysis. Herein, we demonstrated on-demand NO release by high-intensity focused ultrasound (HIFU) as a stimulus, which generated high heat and exerted an ablation effect when treated in vivo. We demonstrated IMesNO to be a HIFU-responsive NO donor and its potential application in vivo using IMesNO-loaded micelles. Moreover, IMesNO-loaded micelles mixed with drug-loaded micelles (IMesNO/DOX@MCs) showed acceleration of drug accumulation in tumor sites and enhanced tumor growth inhibition. Thus, our findings suggest a potential clinical bioapplication of NO-releasing drug-loaded micelles owing to the therapeutic function of NO and HIFU treatment for anti-cancer therapy. [ABSTRACT FROM AUTHOR]