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mRNA antigens require powerful nanocarriers for efficient delivery, as well as immunomodulators for controlling their excessive immunogenicity. While lipid nanoparticles (LNPs) used in mRNA vaccines exhibited systemic toxicity, there is an urgent need for developing potential nanoparticles with strong immunoenhancing effects for mRNA antigens. Although natural polysaccharides as adjuvants assisted various types of antigens in triggering potent immune responses, they have been rarely investigated in mRNA vaccines. Here, we constructed four polysaccharide nanoparticles with different molecular weights (MWs) to deliver and protect mRNA antigens, and boosted antigen cross-presentation, DC maturation, CD4 + /CD8 + T cell responses and humoral immune responses. Importantly, the immunoenhancing capacities of polysaccharide nanoparticles were highly dependent on their MW properties. CS NPs with high MW initiated stimulator of interferon genes (STING)-mediated autophagy and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome signaling, consequently possessing superior mRNA antigen-specific immune responses in vitro and in vivo . In contrast, CS NPs with low MWs induced NLRP3 signaling without STING or autophagy activation, which failed to induce robust immune responses. Therefore, it uncovered the MW-dependent immunoenhancing effects and mechanism of polysaccharide nanoparticles, providing a platform for designing potential nanosized polysaccharide immunomodulators for mRNA vaccines.

A main pathogenic factor of atherosclerosis is the local oxidative stress microenvironment. Probucol (PU) has anti-inflammatory, antioxidative and hypolipidemic effects, showing great potential to treat atherosclerosis. However, its low bioavailability limits its development. Herein, PU was encapsulated to form RP-PU with star-shaped polymers and red blood cell membranes. Star-shaped polymers show lower solution viscosity, a smaller hydrodynamic radius and a higher drug loading content than linear polymers. RP-PU had a good sustained-release effect and excellent biocompatibility. RP-PU can be efficiently internalized by cells to improve biodistribution. ApoE -/- mice were treated with RP-PU, and the contents of lipids and related metabolic enzymes were effectively reduced. The collagen fibers in the aortic root sections were reduced by RP-PU compared with control and PU. Moreover, RP-PU inhibited foam cell formation, decreased ICAM-1 and MCP-1 expression and delayed lesion formation. Consequently, RP-PU biomimetic nanoparticles can be developed as an anti-atherosclerotic nanotherapeutic., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Stimulus-responsive polymer materials have attracted much attention as drug carriers because of the ability to deliver drugs to the active site. Reactive oxygen species (ROS) play crucial roles in cellular signaling and regulation of oxygen homeostasis. However, ROS are present in abnormally high levels in many pathological environments. Based on the above points, three-arm poly(lactic- co -glycolic acid)-PO-poly(ethylene glycol) (3s-PLGA-PO-PEG or simply PP) was synthesized by using peroxalate esters (PO) as hydrogen peroxide-responsive linkages. PP was used to deliver promote hematopoietic recovery drugs erythropoietin (EPO) and EPO nanoparticles (EPO NPs) were prepared. We established a hematopoietic system injury model by ionizing radiation (IR) and unexpectedly found the good therapeutic effect of blank PP. Moreover, the administration of EPO NPs obviously decreased IR-induced ROS in bone marrow cells (BMCs) and reconstituted hematopoietic stem cells in BMCs. This study reveals a novel ROS-responsive polymer material that could be employed to remove excess ROS in the lesion and promote the efficacy of drug therapy.

Lung cancer is one of the most rapidly growing malignancies in terms of morbidity and mortality. Although traditional treatments have been used for more than 50 years, it is still far from solving the problems of postoperative risks and systemic toxicity. Emerging targeting and immunotherapy are developing continuously and are gaining recognition; eventually, they face the inevitable challenge of drug resistance. Nanotechnology has several important effects on lung cancer treatment, owing to its unique properties. Several nanoparticle-based treatments have successfully become cancer treatments. Good biocompatibility with higher specific surface area can carry substantial amounts of lung cancer treatment medications while avoiding medication toxicity; editable and modified characteristics give rise to multifunctional nanomedicines; excellent photoelectric effects make lung cancer a multimodal treatment. This article summarizes the breakthroughs achieved by nanotechnology, targeted therapy, and immunotherapy, reflecting the importance and necessity of nanotechnology in the treatment of lung cancer., (© 2021 Wiley-VCH GmbH.)

Immunotherapy is moving to the frontier of cancer treatment. Drug delivery systems (DDSs) have greatly advanced the development of cancer immunotherapeutic regimen and combination treatment. DDSs can spatiotemporally present tumor antigens, drugs, immunostimulatory molecules, or adjuvants, thus enabling the modulation of immune cells including dendritic cells (DCs) or T-cells directly in vivo and thereby provoking robust antitumor immune responses. Cancer vaccines, immune checkpoint blockade, and adoptive cell transfer have shown promising therapeutic efficiency in clinic, and the incorporation of DDSs may further increase antitumor efficiency while decreasing adverse side effects. This review focuses on the use of nano-, micro-, and macroscale DDSs for co-delivery of different immunostimulatory factors to reprogram the immune system to combat cancer. Regarding to nanoparticle-based DDSs, we emphasize the nanoparticle-based tumor immune environment modulation or as an addition to gene therapy, photodynamic therapy, or photothermal therapy. For microparticle or capsule-based DDSs, an overview of the carrier type, fabrication approach, and co-delivery of tumor vaccines and adjuvants is introduced. Finally, macroscale DDSs including hydrogels and scaffolds are also included and their role in personalized vaccine delivery and adoptive cell transfer therapy are described. Perspective and clinical translation of DDS-based cancer immunotherapy is also discussed. We believe that DDSs hold great potential in advancing the fundamental research and clinical translation of cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Immunotherapy is moving to the frontier of cancer treatment. Drug delivery systems (DDSs) have greatly advanced the development of cancer immunotherapeutic regimen and combination treatment. In this comprehensive review, we focus on the use of nano-, micro-, and macroscale DDSs for the co-delivery of different immunostimulatory factors to reprogram the immune system to combat cancer. We also propose the perspective on the development of next-generation DDS-based cancer immunotherapy. This review indicates that DDSs can augment the antitumor T-cell immunity and hold great potential in advancing the fundamental research and clinical translation of cancer immunotherapy by simultaneously delivering dual or multiple immunostimulatory drugs., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Subunit vaccines that are designed based on recombinant antigens or peptides have shown promising potential as viable substitutes for traditional vaccines due to their better safety and specificity. However, the induction of adequate in vivo immune responses with appropriate effectiveness remains a major challenge for vaccine development. More recently, the implementation of a nanoparticle-based antigen delivery system has been considered a promising approach to improve the in vivo efficacy for subunit vaccine development. Thus, we have designed and prepared a nanoparticle-based antigen delivery system composed of three-armed PLGA, which is conjugated to PEG via the peroxalate ester bond (3s-PLGA-PO-PEG) and PEI as a cationic adjuvant (PPO NPs). It is known that during a foreign pathogen attack, NADPH, an oxidase, of the host organism is activated and generates an elevated level of reactive oxygen species, hydrogen peroxide (H2O2) primarily, as a defensive mechanism. Considering the sensitivity of the peroxalate ester bond to H2O2 and the cationic property of PEI for the induction of immune responses, this 3s-PLGA-PO-PEG/PEI antigen delivery system is expected to be both ROS responsive and facilitative in antigen uptake without severe toxicity that has been reported with cationic adjuvants. Indeed, our results demonstrated excellent loading capacity and in vitro stability of the PPO NPs encapsulated with the model antigen, ovalbumin (OVA). Co-culturing of bone marrow dendritic cells with the PPO NPs also led to enhanced dendritic cell maturation, antigen uptake, enhanced lysosomal escape, antigen cross-presentation and in vitro CD8+ T cell activation. In vivo experiments using mice further revealed that the administration of the PPO nanovaccine induced robust OVA-specific antibody production, upregulation of splenic CD4+ and CD8+ T cell proportions as well as an increase in memory T cell generation. In summary, we report here a ROS-triggered nanoparticle-based antigen delivery system that could be employed to promote the in vivo efficacy of vaccine-induced immune responses.

Background: To address the issue of delivery of proteins, a six-arm copolymer, six-arm poly (ε-caprolactone)-poly(ethylene glycol) (6S-PCL-PEG), was synthesized by a simple two-step reaction. Thereafter, the application of 6S-PCL-PEG as a protein carrier was evaluated., Materials and Methods: A six-arm copolymer, six-arm poly(ε-caprolactone) (6S-PCL), was synthesized by ring-opening polymerization, with stannous octoate as a catalyst and inositol as an initiator. Then, poly(ethylene glycol) (PEG) was linked with 6S-PCL by oxalyl chloride to obtain 6S-PCL-PEG. Hydrogen-1 nuclear magnetic resonance spectrum, Fourier-transform infrared spectroscopy, and gel-permeation chromatography were conducted to identify the structure of 6S-PCL-PEG. The biocompatibility of the 6S-PCL-PEG was evaluated by a cell counting kit-8 assay. Polymeric nanoparticles (NPs) were prepared by a water-in-oil-in-water double emulsion (W 1 /O/W 2 ) solvent evaporation method. The size distribution and zeta potential of NPs were determined by dynamic light scattering. Transmission electron microscopy was used to observe the morphology of NPs. Drug-loading capacity, encapsulation efficiency, and the release behavior of ovalbumin (OVA)-loading NPs were tested by the bicinchoninic acid assay kit. The stability and activity of OVA released from NPs were detected and the uptake of NPs was evaluated by NIH-3T3 cells., Results: All results indicated the successful synthesis of amphiphilic copolymer 6S-PCL-PEG, which possessed excellent biocompatibility and could formulate NPs easily. High drug-loading capacity and encapsulation efficiency of protein NPs were observed. In vitro, OVA was released slowly and the bioactivity of OVA was maintained for over 28 days., Conclusion: 6S-PCL-PEG NPs prepared in this study show promising potential for use as a protein carrier., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Currently, development of subunit vaccine based on recombinant antigens or peptides has gradually become an important alternative option for traditional vaccine. However, induction of potent immune response with desired efficacy remains a major challenge. The nanoparticle-based antigen delivery system has been considered a potential carrier system to improve the efficacy of subunit vaccine. In the present study, we have designed an immune-stimulatory delivery system by conjugating three-armed PLGA to PEG via the peroxalate ester bond which is sensitive to hydrogen peroxide (H 2 O 2 ), a major reactive oxygen species (ROS). Hyaluronic acid (HA), a ligand for CD44 receptors was also modified onto the outer shell of the 3s-PLGA-PEG nanoparticles to promote immune cell uptake. For in vitro and in vivo immune response assessment, a model antigen ovalbumin (OVA) was enclosed within the core of the 3s-PLGA-PEG nanoparticles to form 3s-PLGA-PO-PEG/HA nanoparticles (PHO NPs). Our results showed that the PHO NPs enhanced dendritic cell maturation, antigen uptake, and antigen presentation in vitro, likely due to enhanced lysosomal escape. In vivo experiments further revealed that the PHO nanovaccine robustly promoted OVA-specific antibody production and T cell response accompanied by modest stimulation of memory T cells. In summary, the ROS-responsive PHO NPs with modified HA may be an effective vehicle antigen delivery system to promote antigen-induced immune response.

Complete reendothelialization followed by inhibition of smooth muscle cell (SMC) proliferation is considered as an effective therapeutic option to prevent restenosis. We have designed poly(lactide-co-glycolide)-loaded bilayered nanoparticles (NPs) with the ability to sequentially release vascular endothelial growth factor (VEGF)-encoding plasmids from the outer layer and paclitaxel (PTX) from the core to promote endothelial regeneration as well as prevent restenosis. Comparing with conventional NPs, which release VEGF plasmid and PTX simultaneously, we expect that the bilayered NPs could release the VEGF plasmid more rapidly, followed by a delayed release of PTX, resulting in an efficient VEGF gene transfection, which ideally could promote reendothelialization and inhibit excessive SMC growth. Indeed, in the present study, we have observed efficient gene transfection using a model plasmid as well as cell growth attenuation in vitro using Chinese hamster ovary cells. Therapeutic efficacy of the bilayered NPs on restenosis was further evaluated in vivo using a rabbit model of atherosclerosis. The bilayered NPs were administered locally via balloon angioplasty to the injured aortic wall through perfusion. Twenty-eight days after the NP administration, rabbits treated with the bilayered NPs exhibited rapid reendothelialization and inhibition of restenosis, as demonstrated by histological analysis. Increased level of VEGF and decreased level of C-reactive protein, a biological marker that is closely related to atherosclerosis, were also observed from animals treated with the bilayered NPs, implicating ameliorated atherosclerosis. Our results suggest that the VEGF plasmid-/PTX-loaded bilayered NPs exert a beneficial impact on atherosclerotic restenosis by sequentially releasing VEGF and PTX in vivo.

Excessive and uncontrollable inflammatory responses in alveoli can dramatically exacerbate pulmonary disease progressions through vigorous cytokine releases, immune cell infiltration and protease-driven tissue damages. It is an urgent need to explore potential drug strategies for mitigating lung inflammation. Protease-activated receptor 2 (PAR2) as a vital molecular target principally participates in various inflammatory diseases via intracellular signal transduction. However, it has been rarely reported about the role of PAR2 in lung inflammation. This study applied CRISPR-Cas9 system encoding Cas9 and sgRNA (pCas9-PAR2) for PAR2 knockout and fabricated an anionic human serum albumin-based nanoparticles to deliver pCas9-PAR2 with superior inflammation-targeting efficiency and stability (TAP /pCas9-PAR2). TAP /pCas9-PAR2 robustly facilitated pCas9-PAR2 to enter and transfect inflammatory cells, eliciting precise gene editing of PAR2 in vitro and in vivo. Importantly, PAR2 deficiency by TAP /pCas9-PAR2 effectively and safely promoted macrophage polarization, suppressed pro-inflammatory cytokine releases and alleviated acute lung inflammation, uncovering a novel value of PAR2. It also revealed that PAR2-mediated pulmonary inflammation prevented by TAP /pCas9-PAR2 was mainly dependent on ERK-mediated NLRP3/IL-1 β and NO/iNOS signalling. Therefore, this work indicated PAR2 as a novel target for lung inflammation and provided a potential nanodrug strategy for PAR2 deficiency in treating inflammatory diseases. TAP/ pCas9-PAR2 alleviated acute lung inflammation through ERK/NLRP3/IL-1 β and NO/iNOS signalling via genome editing of PAR2. [Display omitted] [ABSTRACT FROM AUTHOR]

Pt-Based catalysts for the methanol oxidation reaction (MOR) are highly susceptible to poisoning due to the surface adsorption of reaction intermediates such as COads. Depositing Pt nanoparticles (NPs) on Ni(OH)2 to fabricate Pt–Ni(OH)2 interfaces is considered as a promising method to improve the stability of Pt-based catalysts because Ni(OH)2 could facilitate water dissociation in alkaline electrolytes to form OH adspecies and assist in the oxidative removal of COads on adjacent Pt sites. However, this supported structure rather limited Pt–Ni(OH)2 interfaces because only a small fraction of the Pt NP surface could come into contact with Ni(OH)2. Herein, this work has addressed a simple and efficient strategy to engineer novel-structure catalysts by tuning the properties of the interface of Pt-based NPs with high-index facets (HIFs). Pt1Ni1–Ni(OH)2 nanoparticles (NPs) were synthesized through Ni(OH)2 partially covering the HIFs of monodisperse Pt1Ni1 concave nanocubes (CNCs) in situ. Pt–Ni(OH)2 interfaces were characterized and over 40% of the Pt surface active sites fall within the periphery of Ni(OH)2. Thanks to the synergy of HIFs and abundant Pt–Ni(OH)2 interfaces, Pt1Ni1–Ni(OH)2 NPs exhibited remarkable catalytic performance towards the MOR in alkaline solution. [ABSTRACT FROM AUTHOR]