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.

Department of Chemical Engineering The University of Melbourne Parkville 3010 Victoria Australia

Dipartimento di Scienze e Tecnologie Chimiche Universita di Roma Tor Vergata Via Della Ricerca Scientifica 1 00133 Rome Italy

International Clinical Research Centre St Anne Hospital 656 91 Brno Czech Republic

Materials Characterization and Fabrication Platform Department of Chemical Engineering The University of Melbourne Parkville 3010 Victoria Australia

School of Cardiovascular and Metabolic Medicine and Sciences King's College London London SE5 9NU U K

School of Science RMIT University Melbourne 3000 Victoria Australia

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