6 research outputs found
Transformable DNA nanocarriers for plasma membrane targeted delivery of cytokine
Direct delivery of cytokines using nanocarriers holds great promise for cancer therapy. However, the nanometric scale of the vehicles made them susceptible to size-dependent endocytosis, reducing the plasma membrane-associated apoptosis signalling. Herein, we report a tumor microenvironment-responsive and transformable nanocarrier for cell membrane targeted delivery of cytokine. This formulation is comprised of a phospholipase A2 (PLA2) degradable liposome as a shell, and complementary DNA nanostructures (designated as nanoclews) decorated with cytokines as the cores. Utilizing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a model cytokine, we demonstrate that the TRAIL loaded DNA nanoclews are capable of transforming into nanofibers after PLA2 activation. The nanofibers with micro-scaled lengths efficiently present the loaded TRAIL to death receptors on the cancer cell membrane and amplified the apoptotic signalling with reduced TRAIL internalization
Enhanced Cancer Immunotherapy by Microneedle Patch-Assisted Delivery of Anti-PD1 Antibody
Despite recent advances in melanoma
treatment through the use of
anti-PD-1 (aPD1) immunotherapy, the efficacy of this method remains
to be improved. Here we report an innovative self-degradable microneedle
(MN) patch for the sustained delivery of aPD1 in a physiologically
controllable manner. The microneedle is composed of biocompatible
hyaluronic acid integrated with pH-sensitive dextran nanoparticles
(NPs) that encapsulate aPD1 and glucose oxidase (GOx), which converts
blood glucose to gluconic acid. The generation of acidic environment
promotes the self-dissociation of NPs and subsequently results in
the substantial release of aPD1. We find that a single administration
of the MN patch induces robust immune responses in a B16F10 mouse
melanoma model compared to MN without degradation trigger or intratumoral
injection of free aPD1 with the same dose. Moreover, this administration
strategy can integrate with other immunomodulators (such as anti-CTLA-4)
to achieve combination therapy for enhancing antitumor efficacy
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Synergistic Transcutaneous Immunotherapy Enhances Antitumor Immune Responses through Delivery of Checkpoint Inhibitors
Despite
the promising efficacy of immunoregulation in cancer therapy,
the clinical benefit has been restricted by inefficient infiltration
of lymphocytes in the evolution of immune evasion. Also, immune-related
adverse events have often occurred due to the off-target binding of
therapeutics to normal tissues after systematic treatment. In light
of this, we have developed a synergistic immunotherapy strategy that
locally targets the immunoinhibitory receptor programmed cell death
protein 1 (PD1) and immunosuppressive enzyme indoleamine 2,3-dioxygenase
(IDO) for the treatment of melanoma through a microneedle-based transcutaneous
delivery approach. The embedded immunotherapeutic nanocapsule loaded
with anti-PD1 antibody (aPD1) is assembled from hyaluronic acid modified
with 1-methyl-dl-tryptophan (1-MT), an inhibitor of IDO.
This formulation method based on the combination strategy of “drug
A in carriers formed by incorporation of drug B” facilitates
the loading capacity of therapeutics. Moreover, the resulting delivery
device elicits the sustained release and enhances retention of checkpoint
inhibitors in the tumor microenvironment. Using a B16F10 mouse melanoma
model, we demonstrate that this synergistic treatment has achieved
potent antitumor efficacy, which is accompanied by enhanced effective
T cell immunity as well as reduced immunosuppression in the local
site
Dynamic Pneumococcal Genetic Adaptations Support Bacterial Growth and Inflammation during Coinfection with Influenza
Streptococcus pneumoniae (pneumococcus) is one of the primary bacterial pathogens that complicates influenza virus infections. These bacterial coinfections increase influenza-associated morbidity and mortality through a number of immunological and viral-mediated mechanisms, but the specific bacterial genes that contribute to postinfluenza pathogenicity are not known. Here, we used genome-wide transposon mutagenesis (Tn-Seq) to reveal bacterial genes that confer improved fitness in influenza virus-infected hosts. The majority of the 32 genes identified are involved in bacterial metabolism, including nucleotide biosynthesis, amino acid biosynthesis, protein translation, and membrane transport. We generated mutants with single-gene deletions (SGD) of five of the genes identified, SPD1414, SPD2047 (cbiO1), SPD0058 (purD), SPD1098, and SPD0822 (proB), to investigate their effects on in vivo fitness, disease severity, and host immune responses. The growth of the SGD mutants was slightly attenuated in vitro and in vivo, but each still grew to high titers in the lungs of mock- and influenza virus-infected hosts. Despite high bacterial loads, mortality was significantly reduced or delayed with all SGD mutants. Time-dependent reductions in pulmonary neutrophils, inflammatory macrophages, and select proinflammatory cytokines and chemokines were also observed. Immunohistochemical staining further revealed altered neutrophil distribution with reduced degeneration in the lungs of influenza virus-SGD mutant-coinfected animals. These studies demonstrate a critical role for specific bacterial genes and for bacterial metabolism in driving virulence and modulating immune function during influenza-associated bacterial pneumonia.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Transformable DNA nanocarriers for plasma membrane targeted delivery of cytokine
Direct delivery of cytokines using nanocarriers holds great promise for cancer therapy. However, the nanometric scale of the vehicles made them susceptible to size-dependent endocytosis, reducing the plasma membrane-associated apoptosis signalling. Herein, we report a tumor microenvironment-responsive and transformable nanocarrier for cell membrane targeted delivery of cytokine. This formulation is comprised of a phospholipase A2 (PLA2) degradable liposome as a shell, and complementary DNA nanostructures (designated as nanoclews) decorated with cytokines as the cores. Utilizing the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a model cytokine, we demonstrate that the TRAIL loaded DNA nanoclews are capable of transforming into nanofibers after PLA2 activation. The nanofibers with micro-scaled lengths efficiently present the loaded TRAIL to death receptors on the cancer cell membrane and amplified the apoptotic signalling with reduced TRAIL internalization