Despite the clinically proven efficacies of immune checkpoint blockades, including anti‐cytotoxic T lymphocyte‐associated protein 4 antibody (αCTLA‐4), the low response rate and immune‐related ...adverse events (irAEs) in cancer patients represent major drawbacks of the therapy. These drawbacks of αCTLA‐4 therapy are mainly due to the suboptimal activation of tumor‐specific cytotoxic T lymphocytes (CTLs) and the systemic nonspecific activation of T cells. To overcome such drawbacks, αCTLA‐4 is delivered by dendritic cell‐derived nanovesicles presenting tumor antigens (DCNV‐TAs) that exclusively interact with tumor‐specific T cells, leading to selective activation of tumor‐specific CTLs. Compared to conventional αCTLA‐4 therapy, treatment with αCTLA‐4‐conjugated DCNV‐TAs significantly inhibits tumor growth and reduces irAEs in syngeneic tumor‐bearing mice. This study demonstrates that the spatiotemporal presentation of both αCTLA‐4 and tumor antigens enables selective activation of tumor‐specific T cells and potentiates the antitumor efficacy of αCTLA‐4 without inducing systemic irAEs.
Anti‐cytotoxic T lymphocyte‐associated protein 4 antibody (αCTLA‐4)‐conjugated and tumor antigen (TA)‐loaded nanovesicles derived from dendritic cells can facilitate spatiotemporal delivery of TA and αCTLA‐4 to tumor‐specific T cells. This leads to selective activation of tumor‐reactive T cells, effective inhibition of tumor growth and prevention of immune‐related adverse events, improving the current immune checkpoint blockade therapies.
A high triplet energy host is developed using a silane moiety, 9‐(4‐(triphenylsilyl)dibenzob,dfuran‐2‐yl)‐9H‐carbazole (SiDBFCz), is designed through extensive density functional theory (DFT) ...calculations to obtain appropriate hole and electron injection barriers. The chemical hardness and the charge transport characteristics are comprehensively investigated to realize a bipolar host with high triplet energy over 2.9 eV for deep blue phosphorescent organic light‐emitting diodes (PHOLEDs). The synthesized SiDBFCz clearly exhibits the bipolar characteristics especially with emitter molecules doped. An external quantum efficiency over 19 % without any microcavity optimization is achieved thanks to the good charge balance in the SiDBFCz PHOLED. The device lifetime of the SiDBFCz PHOLED is improved more than 1000 %, compared to the unipolar control devices at an initial luminance of 500 cd m−2. The dramatic enhancement of the operational stability of the deep blue PHOLED is also thoroughly investigated in terms of electrochemical stability of host molecules in charged or excited states. The results clearly indicate that the device lifetime is strongly correlated with the bond dissociation energy and the activation energy for the bond dissociation reaction in triplet excited state.
High efficiency and dramatic improvement of device lifetime were simultaneously and successfully realized with a silane‐based bipolar host, SiDBFCz. The dramatic enhancement of the operational stability was attributed to the bond dissociation energy and the activation energy for the bond dissociation reaction in the triplet excited state.
Poor O2 supply to the infiltrated immune cells in the joint synovium of rheumatoid arthritis (RA) up-regulates hypoxia-inducible factor (HIF-1α) expression and induces reactive oxygen species (ROS) ...generation, both of which exacerbate synovial inflammation. Synovial inflammation in RA can be resolved by eliminating pro-inflammatory M1 macrophages and inducing anti-inflammatory M2 macrophages. Because hypoxia and ROS in the RA synovium play a crucial role in the induction of M1 macrophages and reduction of M2 macrophages, herein, we develop manganese ferrite and ceria nanoparticle-anchored mesoporous silica nanoparticles (MFC-MSNs) that can synergistically scavenge ROS and produce O2 for reducing M1 macrophage levels and inducing M2 macrophages for RA treatment. MFC-MSNs exhibit a synergistic effect on O2 generation and ROS scavenging that is attributed to the complementary reaction of ceria nanoparticles (NPs) that can scavenge intermediate hydroxyl radicals generated by manganese ferrite NPs in the process of O2 generation during the Fenton reaction, leading to the efficient polarization of M1 to M2 macrophages both in vitro and in vivo. Intra-articular administration of MFC-MSNs to rat RA models alleviated hypoxia, inflammation, and pathological features in the joint. Furthermore, MSNs were used as a drug-delivery vehicle, releasing the anti-rheumatic drug methotrexate in a sustained manner to augment the therapeutic effect of MFC-MSNs. This study highlights the therapeutic potential of MFC-MSNs that simultaneously generate O2 and scavenge ROS, subsequently driving inflammatory macrophages to the anti-inflammatory subtype for RA treatment.
The unique biological characteristics and promising clinical potential of extracellular vesicles (EVs) have galvanized EV applications for regenerative medicine. Recognized as important mediators of ...intercellular communication, naturally secreted EVs have the potential, as innate biotherapeutics, to promote tissue regeneration. Although EVs have emerged as novel therapeutic agents, challenges related to the clinical transition have led to further functionalization. In recent years, various engineering approaches such as preconditioning, drug loading, and surface modification have been developed to potentiate the therapeutic outcomes of EVs. Also, limitations of natural EVs have been addressed by the development of artificial EVs that offer advantages in terms of production yield and isolation methodologies. In this review, an updated overview of current techniques is provided for the functionalization of natural EVs and recent advances in artificial EVs, particularly in the scope of regenerative medicine.
Extracellular vesicles (EVs) have made a meteoric rise as a safer and more efficacious alternative to cell therapy in the last decade. This review provides an updated overview of current techniques for the functionalization of natural EVs and recent advances in artificial EVs, particularly in the scope of regenerative medicine.
To demonstrate potent efficacy, a cancer vaccine needs to activate both innate and adaptive immune cells. Personalized cancer vaccine strategies often require the identification of patient‐specific ...neoantigens; however, the clonal and mutational heterogeneity of cancer cells presents inherent challenges. Here, extracellular nanovesicles derived from alpha‐galactosylceramide‐conjugated autologous acute myeloid leukemia (AML) cells (ECNV‐αGC) are presented as a personalized therapeutic vaccine that activates both innate and adaptive immune responses, bypassing the need to identify patient‐specific neoantigens. ECNV‐αGC vaccination directly engages with and activates both invariant natural killer T (iNKT) cells and leukemia‐specific CD8+ T cells in mice with AML, thereby promoting long‐term anti‐leukemic immune memory. ECNV‐αGC sufficiently serves as an antigen‐presenting platform that can directly activate antigen‐specific CD8+ T cells even in the absence of dendritic cells, thereby demonstrating a multifaceted cellular mechanism of immune activation. Moreover, ECNV‐αGC vaccination results in a significantly lower AML burden and higher percentage of leukemia‐free survivors among cytarabine‐treated hosts with AML. Human AML‐derived ECNV‐αGCs activate iNKT cells in both healthy individuals and patients with AML regardless of responsiveness to conventional therapies. Together, autologous AML‐derived ECNV‐αGCs may be a promising personalized therapeutic vaccine that efficiently establishes AML‐specific long‐term immunity without requiring the identification of neoantigens.
An autologous extracellular nanovesicle vaccine derived from alpha‐galactosylceramide‐conjugated acute myeloid leukemia (AML) cells directly activates both innate immune cells and AML‐specific CD8+ T cells without having to define tumor antigens. It induces strong antitumor immune memory and synergizes with chemotherapy to prevent relapse in hosts with AML. Thus, it can be developed as a platform for personalized vaccines in humans.
Conventional approaches to developing therapeutic cancer vaccines that primarily activate tumor‐specific T cells via dendritic cells (DCs) often demonstrate limited efficacy due to the suboptimal ...activation of these T cells. To address this limitation, here a therapeutic cancer nanovaccine is developed that enhances T cell responses by interacting with both DCs and T cells. The nanovaccine is based on a cancer cell membrane nanoparticle (CCM‐MPLA) that utilizes monophosphoryl lipid A (MPLA) as an adjuvant. To allow direct interaction between the nanovaccine and tumor‐specific T cells, anti‐CD28 antibodies (aCD28) are conjugated onto CCM‐MPLA, resulting in CCM–MPLA–aCD28. This nanovaccine activates tumor‐specific CD8+ T cells in both the presence and absence of DCs. Compared with nanovaccines that interact with either DCs (CCM–MPLA) or T cells (CCM–aCD28), CCM–MPLA–aCD28 induces more potent responses of tumor‐specific CD8+ T cells and exhibits a higher antitumor efficacy in tumor‐bearing mice. No differences in T cell activation efficiency and therapeutic efficacy are observed between CCM–MPLA and CCM–aCD28. This approach may lead to the development of effective personalized therapeutic cancer vaccines prepared from autologous cancer cells.
A nanovaccine comprising cancer cell membrane, monophosphoryl lipid A, and anti‐CD28 antibodies (named CCM–MPLA–aCD28) activates tumor‐specific CD8+ T cells by interacting with both dendritic cells (DCs) and naïve T cells. CCM–MPLA–aCD28 exhibits higher efficacy in tumor‐specific T cell activation and tumor inhibition than nanovaccines that interact with either DCs (CCM–MPLA) or naïve T cells (CCM–aCD28).
Here, it is shown that graphene oxide (GO) can be utilized as both a cell‐adhesion substrate and a growth factor protein‐delivery carrier for the chondrogenic differentiation of adult stem cells. ...Conventionally, chondrogenic differentiation of stem cells is achieved by culturing cells in pellets and adding the protein transforming growth factor‐β3 (TGF‐β3), a chondrogenic factor, to the culture medium. However, pellets mainly provide cell‐cell interaction and diffusional limitation of TGF‐β3 may occur inside the pellet both of these factors may limit the chondrogenic differentiation of stem cells. In this study, GO sheets (size = 0.5–1 μm) were utilized to adsorb fibronectin (FN, a cell‐adhesion protein) and TGF‐β3 and were then incorporated in pellets of human adipose‐derived stem cells (hASCs). The hybrid pellets of hASC‐GO enhanced the chondrogenic differentiation of hASCs by adding the cell‐FN interaction and supplying TGF‐β3 effectively. This method may provide a new platform for stem cell culture for regenerative medicine.
Graphene oxide can be used as both a cell‐adhesion substrate and a growth factor delivery carrier for the chondrogenic differentiation of adult stem cells.
Chimeric antigen receptor‐T (CAR‐T) cell immunotherapy has shown impressive clinical outcomes for hematologic malignancies. However, its broader applications are challenged due to its complex ex vivo ...cell‐manufacturing procedures and low therapeutic efficacy against solid tumors. The limited therapeutic effects are partially due to limited CAR‐T cell infiltration to solid tumors and inactivation of CAR‐T cells by the immunosuppressive tumor microenvironment. Here, a facile approach is presented to in vivo program macrophages, which can intrinsically penetrate solid tumors, into CAR‐M1 macrophages displaying enhanced cancer‐directed phagocytosis and anti‐tumor activity. In vivo injected nanocomplexes of macrophage‐targeting nanocarriers and CAR‐interferon‐γ‐encoding plasmid DNA induce CAR‐M1 macrophages that are capable of CAR‐mediated cancer phagocytosis, anti‐tumor immunomodulation, and inhibition of solid tumor growth. Together, this study describes an off‐the‐shelf CAR‐macrophage therapy that is effective for solid tumors and avoids the complex and costly processes of ex vivo CAR‐cell manufacturing.
Chimeric antigen receptor (CAR)‐T cell therapy is costly and challenged for solid tumor treatment. An approach is presented toward in vivo programming of macrophages into CAR‐M1 macrophages to overcome the challenges. In vivo injection of nanocomplexes of macrophage‐targeting nanocarrier and CAR‐M1 macrophage‐inducing DNA generate CAR‐M1 macrophages that facilitate CAR‐mediated cancer phagocytosis, anti‐tumor immunomodulation, and inhibition of solid tumor growth.
Although T‐cell therapy is a remarkable breakthrough in cancer immunotherapy, the therapeutic efficacy is limited for solid tumors. A major cause of the low efficacy is T‐cell exhaustion by ...immunosuppressive mechanisms of solid tumors, which are mainly mediated by programmed death‐ligand 1 (PD‐L1) and transforming growth factor‐beta (TGF‐β). Herein, T‐cell‐derived nanovesicles (TCNVs) produced by the serial extrusion of cytotoxic T cells through membranes with micro‐/nanosized pores that inhibit T‐cell exhaustion and exhibit antitumoral activity maintained in the immunosuppressive tumor microenvironment (TME) are presented. TCNVs, which have programmed cell death protein 1 and TGF‐β receptor on their surface, block PD‐L1 on cancer cells and scavenge TGF‐β in the immunosuppressive TME, thereby preventing cytotoxic‐T‐cell exhaustion. In addition, TCNVs directly kill cancer cells via granzyme B delivery. TCNVs successfully suppress tumor growth in syngeneic‐solid‐tumor‐bearing mice. Taken together, TCNV offers an effective cancer immunotherapy strategy to overcome the tumor's immunosuppressive mechanisms.
T‐cell‐derived nanovesicles (TCNVs) are produced from activated CD8+ T cells for cancer immunotherapeutics. TCNVs exhibit inhibition of solid tumor growth through blocking immunosuppressive molecules in the tumor microenvironment, aiding in maintaining the cytotoxic T cells’ antitumor activity. Moreover, TCNVs kill tumor cells directly. Therefore, TCNV offers an effective cancer immunotherapy strategy to overcome the solid tumor's immunosuppressive mechanisms.
Alzheimer's disease (AD), the most common cause of dementia, is a complex condition characterized by multiple pathophysiological mechanisms including amyloid‐β (Aβ) plaque accumulation and ...neuroinflammation in the brain. The current immunotherapy approaches, such as anti‐Aβ monoclonal antibody (mAb) therapy, Aβ vaccines, and adoptive regulatory T (Treg) cell transfer, target a single pathophysiological mechanism, which may lead to unsatisfactory therapeutic efficacy. Furthermore, Aβ vaccines often induce T helper 1 (Th1) cell‐mediated inflammatory responses. Here, a nanovaccine composed of lipid nanoparticles loaded with Aβ peptides and rapamycin is developed, which targets multiple pathophysiological mechanisms, exhibits the combined effects of anti‐Aβ antibody therapy and adoptive Aβ‐specific Treg cell transfer, and can overcome the limitations of current immunotherapy approaches for AD. The Nanovaccine effectively delivers rapamycin and Aβ peptides to dendritic cells, produces both anti‐Aβ antibodies and Aβ‐specific Treg cells, removes Aβ plaques in the brain, alleviates neuroinflammation, prevents Th1 cell‐mediated excessive immune responses, and inhibits cognitive impairment in mice. The nanovaccine shows higher efficacy in cognitive recovery than an Aβ vaccine. Unlike anti‐Aβ mAb therapy and adoptive Treg cell transfer, both of which require complicated and costly manufacturing processes, the nanovaccine is easy‐to‐prepare and cost‐effective. The nanovaccines can represent a novel treatment option for AD.
Rapamycin‐incorporated lipid nanoparticle containing amyloid‐β (LNP‐R/Aβ) attenuates neuroinflammation and improves cognitive function in a transgenic rodent model of Alzheimer's disease (AD) by inducing tolerogenic dendritic cells and Aβ‐specific regulatory T cells, and generating anti‐amyloid antibodies. Furthermore, LNP‐R/Aβ reduces T helper 1 cells in AD brains, implying lower risks of meningitis, which is the major reason for the failure of conventional Aβ vaccines.
