o:28460 Cellulose Nanocrystals as a Versatile Platform for Regulation of Myeloid Cell Immunogenicity Celulozni nanokristali kao pogodna platforma za regulaciju imunogenosti mijeloidnih ćelija en ABSTRACT Phosphonates possess a great potential for the therapy of bone tumours due to their inhibitory potential for osteoclasts. The delivery of phosphonates via cellulose nanocrystals (CNCs) seems a promising approach for their increased efficacy in target tissues. However, the immunological effects of these conjugates have not been investigated thoroughly. Here we modified used wood-based native (n)CNC, oxidized (ox-CNC) and phosphonate (3 AminoPropylphosphonic Acid (ApA))-conjugated CNC to test their physicochemical properties and immunomodulatory potential. Modification of CNC increased their elasticity module and hardness, which resulted in their reduced internalization by phagocytic cells. The non-toxic doses of native and modified CNC displayed different immunomodulatory properties in models of human peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (moDCs). Namely, nCNC displayed a tolerogenic potential upon internalization by MoDCs, as judged by their capacity to up-regulate IDO-1, PDL1, ILT3 and IL27 expression, and potentiate their capacity to induce FoxP3+ regulatory T cells when present during the differentiation of monocytes into MoDCs. These properties make nCNC promising in the treatment of chronic inflammatory diseases such as autoimmunity and transplantation. In contrast, ApA-CNC induced oxidative stress and autophagy in MoDCs and up-regulated maturation markers on MoDCs, including CD83, CD86, NLRP3, IL-1β and IL-12 production. Consequently, ApA-CNC-treated MoDCs displayed an increased allostimulatory potential and Th1/CTL polarizing activity in co-cultures with T cells. We found that the stimulatory effects of ApA-CNC on MoDCs were mediated via GABA-B receptor and down-regulation of cAMP levels in MoDCs, as the blockage of the receptor diminished the effects of ApA-CNC. Moreover, the Th1 polarizing and allostimulatory capacity of MoDCs differentiated with ApA-CNC were preserved upon LPS and IFN-γ treatment, which correlated with late expression of R2 subunit of GABA-B receptor during MoDCs differentiation. Therefore, the delivery of ApA via CNC induces potent DC-mediated Th1 polarization which could be harnessed for development new treatment of bone malignancies. This research was supported by the Ministry of Education, Science and Technological Development (Contract No. 451- 03-68/2020-14/ 200020) and the Science Fund of the Republic of Serbia (PROMIS, #6062673, Nano-MDSC-Thera). 1552099 10.11159/nddte22.149 1552101 2371-5308 2023-03-29T12:10:43.220Z 44 yes 46 Sergej Tomić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia doktor bioloških nauka 0000-0003-2570-1295 Vanja Kokol University of Maribor, Faculty of Mechanical Engineering, Maribor, Slovenia person Miodrag Čolić Serbian Academy of Sciences and Arts, Belgrade, Serbia person Petar Uskoković University of Belgrade, Faculty for Technology and Metallurgy, Serbia person Dragana Vučević University of Defence, Medical Faculty of the Military Medical Academy, Belgrade, Serbia person Dušica Stojanović University of Belgrade, Faculty for Technology and Metallurgy, Serbia person Miloš Vasiljević University of East Sarajevo, Medical Faculty Foča, Foča, Bosnia and Herzegovina person Marina Bekić University of Belgrade, Institute for the Application of Nuclear Energy INEP, Serbia person 0000-0002-6945-4241 application/pdf 382920 https://phaidrabg.bg.ac.rs/o:28460 no yes 18 70 92000004 11A29 11A2904 11A41 Proceedings of the 7th World Congress on Recent Advances in Nanotechnology (RAN’22) Avestia publishing 2022