Dataset Information

Cellular Uptake of siRNA-Loaded Nanocarriers to Knockdown PD-L1: Strategies to Improve T-cell Functions.

ABSTRACT: T-cells are a type of lymphocyte (a subtype of white blood cells) that play a central role in cell-mediated immunity. Currently, adoptive T-cell immunotherapy is being developed to destroy cancer cells. In this therapy, T-cells are harvested from a patient's blood. After several weeks of growth in culture, tumor-specific T-cells can be reinfused into the same cancer patient. This technique has proved highly efficient in cancer treatment. However, there are several biological processes that can suppress the anti-cancer responses of T-cells, leading to a loss of their functionality and a reduction of their viability. Therefore, strategies are needed to improve T-cell survival and their functions. Here, a small interfering RNA (siRNA)-loaded nanocarrier was used to knockdown PD-L1, one of the most important proteins causing a loss in the functionality of T-cells. The biocompatibility and the cellular uptake of siRNA-loaded silica nanocapsules (SiNCs) were investigated in CD8+ T-cells. Then, the PD-L1 expression at protein and at mRNA levels of the treated cells were evaluated. Furthermore, the effect of the PD-L1 knockdown was observed in terms of cell proliferation and the expression of specific biomarkers CD25, CD69 and CD71, which are indicators of T-cell functions. The results suggest that this siRNA-loaded nanocarrier showed a significant potential in the delivery of siRNA into T-cells. This in turn resulted in enhanced T-cell survival by decreasing the expression of the inhibitory protein PD-L1. Such nanocarriers could, therefore, be applied in adoptive T-cell immunotherapy for the treatment of cancer.

SUBMITTER: Thiramanas R

PROVIDER: S-EPMC7565787 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Cellular Uptake of siRNA-Loaded Nanocarriers to Knockdown PD-L1: Strategies to Improve T-cell Functions.

Thiramanas Raweewan R Li Mengyi M Jiang Shuai S Landfester Katharina K Mailänder Volker V

Cells 20200907 9

T-cells are a type of lymphocyte (a subtype of white blood cells) that play a central role in cell-mediated immunity. Currently, adoptive T-cell immunotherapy is being developed to destroy cancer cells. In this therapy, T-cells are harvested from a patient's blood. After several weeks of growth in culture, tumor-specific T-cells can be reinfused into the same cancer patient. This technique has proved highly efficient in cancer treatment. However, there are several biological processes that can s ...[more]

PMID: 32906726

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Project description:Current nucleic acid (NA) nanotherapeutic approaches face challenges because of shortcomings such as limited control on loading efficiency, complex formulation procedure involving purification steps, low load of NA cargo per nanoparticle, endosomal trapping, and hampered release inside the cell. When combined, these factors significantly limit the amount of biologically active NA delivered per cell in vitro, delivered dosages in vivo for a prolonged biological effect, and the upscalability potential, thereby warranting early consideration in the design and developmental phase. Here, we report a versatile nanotherapeutic platform, termed auropolyplexes, for improved and efficient delivery of small interfering RNA (siRNA). Semitelechelic, thiolated linear polyethylenimine (PEI) was chemisorbed onto gold nanoparticles to endow them with positive charge. A simple two-step complexation method offers tunable loading of siRNA at concentrations relevant for in vivo studies and the flexibility for inclusion of multiple functionalities without any purification steps. SiRNA was electrostatically complexed with these cationic gold nanoparticles and further condensed with polycation or polyethyleneglycol-polycation conjugates. The resulting auropolyplexes ensured complete complexation of siRNA into nanoparticles with a high load of ∼15,500 siRNA molecules/nanoparticle. After efficient internalization into the tumor cell, an 80% knockdown of the luciferase reporter gene was achieved. Auropolyplexes were applied intratracheally in Balb/c mice for pulmonary delivery, and their biodistribution were studied spatio-temporally and quantitatively by optical tomography. Auropolyplexes were well tolerated with ∼25% of the siRNA dose remaining in the lungs after 24 h. Importantly, siRNA was released from auropolyplexes in vivo and a fraction also crossed the air-blood barrier, which was then excreted via kidneys, whereas >97% of gold nanoparticles were retained in the lung. Linear PEI-based auropolyplexes offer a combination of successful endosomal escape and better biocompatibility profile in vivo. Taken together, combined chemisorption and complexation endow auropolyplexes with crucial biophysical attributes, enabling a versatile and upscalable nanogold-based platform for siRNA delivery in vitro and in vivo.

Dataset Information

Cellular Uptake of siRNA-Loaded Nanocarriers to Knockdown PD-L1: Strategies to Improve T-cell Functions.

Publications

Cellular Uptake of siRNA-Loaded Nanocarriers to Knockdown PD-L1: Strategies to Improve T-cell Functions.

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