Rheumatoid arthritis (RA) is driven by complex immune dysregulation in which innate immune cells—including dendritic cells, macrophages, and neutrophils—play pivotal roles in initiating and amplifying synovial inflammation. Despite the central roles of these cells, conventional therapies often lack the precision to selectively target these specific cell subsets, leading to systemic off-target effects. In this context, nanotechnology offers a promising strategy to overcome these limitations by leveraging the unique phagocytic capacity and surface markers of innate immune cells for targeted delivery. Visual representation of nanoparticle-mediated immune and microenvironmental remodeling in RA

Tumor cell-derived small extracellular vesicles (TDEs) play a critical role in immune evasion, including the establishment of an immunosuppressive tumor microenvironment (TME), and form a substantial barrier to effective cancer immunotherapy. Here, we introduce the ExoPERM (pH-enabled rupture of exosome membranes) strategy, a pH-responsive system based on small extracellular vesicle (EV)-disrupting alpha-helical peptides that selectively target small EVs localized within the TME. By incorporating a pH-sensitive linker through PEGylation, this system ensures systemic stability while allowing the selective release of peptides within the mildly acidic TME. Mechanistic investigations revealed that the peptide preferentially ruptured small EVs at pH 6.5, effectively preventing EVs’ PD-L1 interactions with PD-1 on CD8⁺ T cells and contributing to the restoration of their effector functions. Furthermore, this targeted disruption significantly attenuated TDE-induced activation of cancer-associated fibroblasts, thereby remodeling the dense fibrotic stroma that physically restricts immune cell penetration. In vivo studies have demonstrated enhanced CD8⁺ T-cell tumor infiltration and activation, notably when combined with immune checkpoint blockade or adoptive T-cell transfer. These synergistic effects were robustly validated across murine melanoma and colorectal cancer models, successfully converting immunologically cold tumors into T-cell-inflamed hot tumors. The ExoPERM strategy provides a promising option for overcoming TDE-mediated resistance in cancer, suggesting a distinct approach to small EV inhibition.

A particle current generated by pumping in the absence of gradients in potential energy, density or temperature1 is associated with non-trivial dynamics. A representative example is charge pumping that is associated with the quantum Hall effect2 and the quantum anomalous Hall effect3. Spin pumping, the spin equivalent of charge pumping, refers to the emission of a spin current by magnetization dynamics4, 5, 6-7. Previous studies have focused solely on transversal spin pumping arising from classical dynamics, which corresponds to precessing atomic moments with constant magnitude. However, longitudinal spin pumping arising from quantum fluctuations, which correspond to a temporal change in the atomic moment's magnitude, remains unexplored. Here we experimentally investigate longitudinal spin pumping using iron-rhodium (FeRh), which undergoes a first-order antiferromagnet-to-ferromagnet phase transition during which the atomic moment's magnitude varies over time. By injecting a charge current into a FeRh/platinum bilayer, we induce a rapid phase transition of FeRh in nanoseconds, leading to the emission of a spin current to the platinum layer. The observed inverse spin Hall signal is about one order of magnitude larger than expected for transversal spin pumping, suggesting the presence of longitudinal spin pumping driven by quantum fluctuations and indicating its superiority over classical transversal spin pumping. Our result highlights the significance of quantum fluctuations in spin pumping and holds broad applicability in diverse angular momentum dynamics, such as laser-induced ultrafast demagnetization8, orbital pumping9,10 and quantum spin transfer11, 12-13.

Non-collinear antiferromagnets, such as Mn3Sn, stand out for their topological properties and potential in antiferromagnetic spintronics. This emerging field aims at harnessing ultrafast magnetization dynamics of antiferromagnets through spin torques. Here we report the time-resolved dynamics of Mn3Sn on a picosecond timescale, driven by an optically induced spin current pulse. Our results reveal that the magnetization of Mn3Sn tilts immediately after the spin current pulse and subsequently undergoes 70 GHz precession. This immediate tilting underscores the predominant role of damping-like torque stemming from spin current absorption by Mn3Sn. We also determine the spin coherence length of Mn3Sn to be approximately 15 nm. This value substantially exceeds that of ferromagnets, highlighting a distinct spin-dephasing process in non-collinear antiferromagnets. Our results hold promise for ultrafast applications of non-collinear antiferromagnets and enrich our understanding of their spin-transfer physics. An optically induced spin current pulse induces gigahertz magnetization dynamics in Mn3Sn with a spin coherence length of approximately 15 nm, which is longer than in ferromagnets.

Cancer immunotherapy represents a remarkable breakthrough in oncology. However, the efficacy of existing therapeutic modalities is observed in only a subset of patients, highlighting the need for further advancements. Tumor-derived small extracellular vesicles (T-sEVs), nano-sized extracellular vesicles secreted by cancer cells, have been the focus of significant interest as contributors to immunotherapy resistance. T-sEVs serve as biomarkers and therapeutic targets owing to their roles in mediating intercellular communication, promoting tumor progression and metastasis, and fostering immunosuppressive microenvironments that hinder immunotherapy. However, when appropriately utilized and their unique properties leveraged, T-sEVs exhibit therapeutic potential. This review explores the potential of T-sEVs as a multifaceted therapeutic option for enhancing cancer immunotherapies. It overviews the emerging research trends and applications of three main therapeutic strategies: eliminating immunosuppressive T-sEVs, utilizing T-EVs as drug carriers with tumor-targeting capabilities, and exploiting T-EVs as antigenic platforms to enhance anticancer immunity. In conclusion, the review provides insights into the potential clinical applications of T-sEV-based therapies and discusses future directions for their development.

We develop a theory of adiabatic orbital pumping, highlighting qualitative differences from spin pumping. An oscillating magnetic field pumps not only orbital angular momentum current, but also orbital angular position current. The latter, which has no spin counterpart, underscores the incompleteness of existing orbital torque theories. Importantly, both types of orbital currents can be detected as transverse electric voltages, which contain considerable second-harmonic components unlike in spin pumping. Moreover, orbital currents can be pumped by lattice dynamics that carry phonon angular momentum, implying that orbital currents can, in turn, induce phonon angular momentum. Our Letter open up new possibilities for generating orbital currents and provides a broader understanding of the interplay between spin, orbital, and phonon dynamics.

The abnormal tumor vasculature acts as the physical and functional barrier to the infiltration and activity of effector T cells, leading to the low response rate of immune checkpoint inhibitors (ICIs). Herein, antiangiogenic extracellular vesicles that enable normalization of the tumor-associated vasculature were prepared to potentiate the efficacy of ICIs. Small extracellular vesicles were exploited as the delivery platform to protect the antiangiogenic protein, pigment epithelium-derived factor (PEDF), from proteolytic degradation. Along with the physicochemical characteristics of the PEDF-enriched extracellular vesicles (P-EVs), their inhibitory effects on migration, proliferation, and tube formation of endothelial cells were investigated in vitro. In tumor-bearing mice, it was confirmed that, compared to bare PEDFs, P-EVs efficiently reduced vessel leakiness, improved blood perfusion, and attenuated hypoxia. Consequently, when combined with anti-PD-1 antibodies, P-EVs remarkably augmented the antitumor immunity, as evidenced by increased infiltration of CD8+ T cells and reduced regulatory T cells. These results suggest that P-EVs are promising therapeutics for tumors refractory to ICIs.

Cancer immunotherapy, aimed at reinvigorating the immune system to induce a lasting anticancer response, has emerged as a promising approach for counteracting the evasive tactics of cancer cells. This study delves into the innovative realm of stimuli-responsive polymeric nanomedicines in the context of cancer immunotherapy. By capitalizing on the intricate landscape of the tumor microenvironment (TME), which orchestrates immune suppression and tumor progression, stimuli-responsive nanomedicines offer a tailored strategy to enhance therapeutic interventions. The aberrant features of the TME, which include factors such as low pH, inflammation, oxidative stress, and enzyme overexpression, serve as triggers for intelligent delivery systems facilitated by functional polymers. This dynamic approach has the potential to overcome the challenges faced by traditional nanoparticle-based immunotherapy techniques, presenting a platform to precisely optimize drug delivery within the tumor locale. As the synergistic interaction between stimuli-responsive polymeric nanomedicines and the TME unfolds, a novel horizon emerges to advance the efficacy of cancer immunotherapy while mitigating its associated limitations.

Two-dimensional (2D) materials have served as key platforms for exploring novel phenomena and innovative applications, driven by their reduced dimensionality. The existing library of 2D materials includes carbon-based and transition metal-based systems. However, oxygen-based 2D materials are missing. Oxygen, the most abundant element on Earth with a higher electronegativity than carbon, holds the potential to introduce unprecedented functionalities in 2D materials. Here we report the experimental realization of a 2D oxygen crystal with a highly ordered honeycomb structure, termed “oxylene”, formed on an ultraflat Cu(111) surface with exceptional resistance to oxidation. Scanning tunneling microscopy and density functional theory studies reveal that oxylene consists of oxygen atom clusters occupying both face-centered cubic (fcc) and hexagonal closed-packed (hcp) sites with a 4×4 periodicity on the Cu(111) surface. Furthermore, oxylene exhibits distinct magnetic ordering due to the magnetic octupole moments of oxygen atoms. Symmetry analysis suggests that oxylene exhibits linear responses that are observed in the noncollinear antiferromagnetic Weyl semimetal Mn3Sn. Our discovery of oxylene provides intriguing opportunities for exploiting its unique electric and magnetic properties, as well as harnessing oxygen’s high reactivity in 2D form.

We develop a theory of orbital pumping, which corresponds to the emission of orbital currents from orbital dynamics. This phenomenon exhibits two distinct characteristics compared to spin pumping. Firstly, while spin pumping generates solely spin (angular momentum) currents, orbital pumping yields both orbital angular momentum currents and orbital angular position currents. Secondly, lattice vibrations induce orbital dynamics and associated orbital pumping as the orbital angular position is directly coupled to the lattice. These pumped orbital currents can be detected as transverse electric voltages via the inverse orbital(-torsion) Hall effect, stemming from orbital textures. Our work proposes a new avenue for generating orbital currents and provides a broader understanding of angular momentum dynamics encompassing spin, orbital, and phonon.

Exosomes are extracellular vesicles secreted by eukaryotic cells and have been extensively studied for their surface markers and internal cargo with unique functions. A deeper understanding of exosomes has allowed their application in various research areas, particularly in diagnostics and therapy. Exosomes have great potential as biomarkers and delivery vehicles for encapsulating therapeutic cargo. However, the limitations of bare exosomes, such as rapid phagocytic clearance and non-specific biodistribution after injection, pose significant challenges to their application as drug delivery systems. This review focuses on exosome-based drug delivery for treating rheumatoid arthritis, emphasizing pre/post-engineering approaches to overcome these challenges. This review will serve as an essential resource for future studies to develop novel exosome-based therapeutic approaches for rheumatoid arthritis. Overall, the review highlights the potential of exosomes as a promising therapeutic approach for rheumatoid arthritis treatment.

Tumour-derived exosomes (T-EXOs) impede immune checkpoint blockade therapies, motivating pharmacological efforts to inhibit them. Inspired by how antiviral curvature-sensing peptides disrupt membrane-enveloped virus particles in the exosome size range, we devised a broadly useful strategy that repurposes an engineered antiviral peptide to disrupt membrane-enveloped T-EXOs for synergistic cancer immunotherapy. The membrane-targeting peptide inhibits T-EXOs from various cancer types and exhibits pH-enhanced membrane disruption relevant to the tumour microenvironment. The combination of T-EXO-disrupting peptide and programmed cell death protein-1 antibody-based immune checkpoint blockade therapy improves treatment outcomes in tumour-bearing mice. Peptide-mediated disruption of T-EXOs not only reduces levels of circulating exosomal programmed death-ligand 1, but also restores CD8 + T cell effector function, prevents premetastatic niche formation and reshapes the tumour microenvironment in vivo. Our findings demonstrate that peptide-induced T-EXO depletion can enhance cancer immunotherapy and support the potential of peptide engineering for exosome-targeting applications.

We theoretically demonstrate the spin swapping effect of band structure origin in centrosymmetric ferromagnets. It is mediated by an orbital degree of freedom but does not require inversion asymmetry or impurity spin-orbit scattering. Analytic and tight-binding models reveal that it originates mainly from k points where bands with different spins and different orbitals are nearly degenerate, and thus it has no counterpart in normal metals. First-principle calculations for centrosymmetric 3d transition-metal ferromagnets show that the spin swapping conductivity of band structure origin can be comparable in magnitude to the intrinsic spin Hall conductivity of Pt. Our theory generalizes transverse spin currents generated by ferromagnets and emphasizes the important role of the orbital degree of freedom in describing spin-orbit-coupled transport in centrosymmetric materials.

Electrical conduction in magnetic materials depends on their magnetization configuration, resulting in various magnetoresistances (MRs). The microscopic mechanisms of MR have so far been attributed to either an intrinsic or extrinsic origin, yet the contribution and temperature dependence of either origin has remained elusive due to experimental limitations. In this study, we independently probed the intrinsic and extrinsic contributions to the anisotropic MR (AMR) of a permalloy film at varying temperatures using temperature-variable terahertz time-domain spectroscopy. The AMR induced by the scattering-independent intrinsic origin was observed to be approximately 1.5% at T = 16 K and is virtually independent of temperature. In contrast, the AMR induced by the scattering-dependent extrinsic contribution was approximately 3% at T = 16 K but decreased to 1.5% at T = 155 K, which is the maximum temperature at which the AMR can be resolved using THz measurements. Our results experimentally quantify the temperature-dependent intrinsic and extrinsic contributions to AMR, which can stimulate further theoretical research to aid the fundamental understanding of AMR.

Immune checkpoint therapy (ICT), which reinvigorates cytotoxic T cells, provides clinical benefits as an alternative to conventional cancer therapies. However, its clinical response rate is too low to treat an immune-excluded tumor, owing to the presence of abundant stromal elements impeding the penetration of immune cells. Here, we report that macitentan, a dual endothelin receptor antagonist approved by the FDA to treat pulmonary arterial hypertension, can be repositioned to modulate the desmoplastic tumor microenvironment (TME). In the 4T1 orthotopic tumor model, the polymeric nanoparticles bearing macitentan (M-NPs) prevent fibrotic progression by regulating the function of cancer-associated fibroblasts, attenuate the biogenesis of cancer cell-derived exosomes, and modulate the T cell subsets and distribution in TME. These results demonstrate that the M-NPs effectively reorganize the immunosuppressive TME by targeting the endothelin-1 axis and consequently exhibit synergistic antitumor effects in combination with ICT.

Although tolerogenic dendritic cell-derived exosomes (TolDex) have emerged as promising therapeutics for rheumatoid arthritis (RA), their clinical applications have been hampered by their poor in vivo disposition after systemic administration. Herein, we report the development of stimuli-responsive TolDex that induces lesion-specific immunoregulation in RA. Responsiveness to reactive oxygen species (ROS), a physiological stimulus in the RA microenvironment, was conferred on TolDex by introducing a thioketal (TK) linker-embedded poly(ethylene glycol) (PEG) on TolDex surface via hydrophobic insertion. The detachment of PEG following overproduction of ROS facilitates the cellular uptake of ROS-responsive TolDex (TKDex) into activated immune cells. Notably, TolDex and TKDex downregulated CD40 in mature dendritic cells (mDCs) and regulated secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) at the cellular level. In the collagen-induced arthritis (CIA) mouse model, PEG prolonged the blood circulation of TKDex following intravenous administration and enhanced their accumulation in the joints. In addition, TKDex decreased IL-6, increased transforming growth factor-A and induced the CD4(+)CD25(+)Foxp3(+) regulatory T cells in CIA mice. Overall, ROS-responsive TolDex might have potential as therapeutic agents for RA. Statement of significance Tolerogenic dendritic cell-derived exosomes (TolDex) are emerging immunoregulators of autoimmune diseases, including rheumatoid arthritis (RA). However, their lack of long-term stability and low targetability are still challenging. To overcome these issues, we developed reactive oxygen species (ROS)-responsive TolDex (TKDex) by incorporating the ROS-sensitive functional group-embedded poly(ethylene glycol) linker into the exosomal membrane of TolDex. Surface-engineered TKDex were internalized in mature DCs because of high ROS-sensitivity and enhanced accumulation in the inflamed joint in vivo. Further, for the first time, we investigated the potential mechanism of action of TolDex relevant to CD40 downregulation and attenuation of tumor necrosis factor (TNF)-alpha secretion. Our strategy highlighted the promising nanotherapeutic effects of stimuli-sensitive TolDex, which induces immunoregulation. (C) 2021 Published by Elsevier Ltd on behalf of Acta Materialia Inc.

The orbital Hall effect describes the generation of the orbital current flowing in a perpendicular direction to an external electric field, analogous to the spin Hall effect. As the orbital current carries the angular momentum as the spin current does, injection of the orbital current into a ferromagnet can result in torque on the magnetization, which provides a way to detect the orbital Hall effect. With this motivation, we examine the current-induced spin-orbit torques in various ferromagnet/heavy metal bilayers by theory and experiment. Analysis of the magnetic torque reveals the presence of the contribution from the orbital Hall effect in the heavy metal, which competes with the contribution from the spin Hall effect. In particular, we find that the net torque in Ni/Ta bilayers is opposite in sign to the spin Hall theory prediction but instead consistent with the orbital Hall theory, which unambiguously confirms the orbital torque generated by the orbital Hall effect. Our finding opens a possibility of utilizing the orbital current for spintronic device applications, and it will invigorate researches on spin-orbit-coupled phenomena based on orbital engineering.

Most studies of the Rashba effect have focused on interfacial Rashba spin–orbit coupling. Recently, bulk Rashba materials have attracted considerable interest owing to their potential to enhance the Rashba spin–orbit torque. By employing a bulk Rashba material, GeTe, as a spin–orbit channel in GeTe/NiFe bilayers, a large field-like spin–orbit torque up to 15.8 mT/(10 7 A cm −2 ) is measured. This value is one of the largest reported field-like torques and is attributed to the interfacial spin–orbit coupling being enhanced by the bulk Rashba effect in the GeTe channel. Furthermore, the large field-like torque is maintained even for a 20-nm-thick NiFe layer. This unconventional dependence on the thickness of both the GeTe and NiFe layers cannot be described by conventional theory, but it is believed to stem from the additional bulk Rashba effect-induced term. The large field-like torque over a wide range of ferromagnet thicknesses results in scalable in-plane spin–orbit torque devices. This result calls for a further theoretical study on spin transport in heterostructures, including bulk Rashba materials.

Department of Physics, KAIST, Daejeon 34141, South Korea Department of Materials Science and Engineering and KI for Nanocentury, KAIST, Daejeon 34141, South Korea Center for Scientific Instrumentation, KBSI, Daejeon 34133, South Korea Department of Materials Science & Engineering, Korea University, Seoul 02841, South Korea KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, South Korea

Despite their potent antitumor activity, clinical application of immune checkpoint inhibitors has been significantly limited by their poor response rates (<30%) in cancer patients, primarily due to immunosuppressive tumor microenvironments. As a representative immune escape mechanism, cancer-derived exosomes have recently been demonstrated to exhaust CD8+ cytotoxic T cells. Here, it is reported that sulfisoxazole, a sulfonamide antibacterial, significantly decreases the exosomal PD-L1 level in blood when orally administered to the tumor-bearing mice. Consequently, sulfisoxazole effectively reinvigorates exhausted T cells, thereby eliciting robust antitumor effects in combination with anti-PD-1 antibody. Overall, sulfisoxazole regulates immunosuppression through the inhibition of exosomal PD-L1, implying its potential to improve the response rate of anti-PD-1 antibodies.