Antibody-Free Glycogen Nanoparticles Engage Human Immune T Cells for Intracellular Delivery of Small Drugs or mRNA

TY - JOUR

T1 - Antibody-Free Glycogen Nanoparticles Engage Human Immune T Cells for Intracellular Delivery of Small Drugs or mRNA

AU - Fernandes, Soraia

AU - Quattrociocchi, Miriam

AU - Cassani, Marco

AU - Savazzi, Giulio

AU - Johnson, Darryl

AU - Forte, Giancarlo

AU - Caruso, Frank

AU - Cavalieri, Francesca

N1 - Publisher Copyright: © 2024 American Chemical Society.

PY - 2024/10/22

Y1 - 2024/10/22

N2 - T cells play a major role in immune defense against viral infections and diseases such as cancer. Accordingly, developing nanoparticle (NP) systems to effectively deliver therapeutics to T cells is of interest. However, NP-mediated delivery of drugs to T cells is challenging because of the nonphagocytic nature of T cells. To engage T cells and induce cellular internalization, NPs are typically decorated with specific receptor-targeting antibodies, often using laborious and costly procedures. Herein, we report that natural glycogen NPs (i.e., nanosugars) with different sizes (20-80 nm) and surface charges (neutral and positively charged) engage Jurkat T cells, undergo intracellular trafficking, and release encapsulated drug without the use of receptor-targeting antibodies. Specifically, glycogen-resveratrol constructs are employed to reactivate HIV-1 latently infected Jurkat T cells (J-Lat A2) and trigger proviral expression. Both neutral and positively charged glycogen NPs engage with J-Lat A2 cells. Large (84 ± 29 nm) and positively charged (23 ± 5 mV) NPs, denoted phytoglycogen-ethylenediamine (PGEDA) NPs, readily associate with the cell membrane and are internalized (60%) in J-Lat A2 cells but remain confined in the endocytic vesicles, with moderate reactivation of latent HIV-1 (4.7 ± 0.5%). Conversely, small (21 ± 5 nm) and positively charged (10 ± 6 mV) NPs, bovine glycogen-EDA (BGEDA) NPs, associate slowly with T cells but show nearly 100% internalization and efficient endosomal escape properties, resulting in 1.5-fold higher reactivation of latent HIV-1 in T cells. PGEDA NPs and BGEDA NPs are also internalized by primary human T cells (>90% cell association) and enable the transfection of mRNA, with BGEDA NPs showing a 2-fold higher transfection than PGEDA NPs. This work highlights the potential of BGEDA NPs for the effective intracellular delivery of small-molecule drugs and mRNA in T cells.

AB - T cells play a major role in immune defense against viral infections and diseases such as cancer. Accordingly, developing nanoparticle (NP) systems to effectively deliver therapeutics to T cells is of interest. However, NP-mediated delivery of drugs to T cells is challenging because of the nonphagocytic nature of T cells. To engage T cells and induce cellular internalization, NPs are typically decorated with specific receptor-targeting antibodies, often using laborious and costly procedures. Herein, we report that natural glycogen NPs (i.e., nanosugars) with different sizes (20-80 nm) and surface charges (neutral and positively charged) engage Jurkat T cells, undergo intracellular trafficking, and release encapsulated drug without the use of receptor-targeting antibodies. Specifically, glycogen-resveratrol constructs are employed to reactivate HIV-1 latently infected Jurkat T cells (J-Lat A2) and trigger proviral expression. Both neutral and positively charged glycogen NPs engage with J-Lat A2 cells. Large (84 ± 29 nm) and positively charged (23 ± 5 mV) NPs, denoted phytoglycogen-ethylenediamine (PGEDA) NPs, readily associate with the cell membrane and are internalized (60%) in J-Lat A2 cells but remain confined in the endocytic vesicles, with moderate reactivation of latent HIV-1 (4.7 ± 0.5%). Conversely, small (21 ± 5 nm) and positively charged (10 ± 6 mV) NPs, bovine glycogen-EDA (BGEDA) NPs, associate slowly with T cells but show nearly 100% internalization and efficient endosomal escape properties, resulting in 1.5-fold higher reactivation of latent HIV-1 in T cells. PGEDA NPs and BGEDA NPs are also internalized by primary human T cells (>90% cell association) and enable the transfection of mRNA, with BGEDA NPs showing a 2-fold higher transfection than PGEDA NPs. This work highlights the potential of BGEDA NPs for the effective intracellular delivery of small-molecule drugs and mRNA in T cells.

KW - endosomal escape

KW - glycogen nanoparticles

KW - human immune T cells

KW - mRNA delivery

KW - resveratrol

UR - http://www.scopus.com/inward/record.url?scp=85206437002&partnerID=8YFLogxK

U2 - 10.1021/acsnano.4c09156

DO - 10.1021/acsnano.4c09156

M3 - Article

C2 - 39392742

AN - SCOPUS:85206437002

SN - 1936-0851

VL - 18

SP - 28910

EP - 28923

JO - ACS Nano

JF - ACS Nano

IS - 42

ER -