In Vivo Insulin Peptide Autoantigen Delivery by Mannosylated Sodium Alginate Nanoparticles Delayed but Could Not Prevent the Onset of Type 1 Diabetes in Nonobese Diabetic Mice

Type 1 diabetes (T1D) is an autoimmune subtype of diabetes, mainly caused by the immune attack of self-insulin-producing cells. Immune modulation that delays the onset of T1D is able to reduce diabetic complications and mortality. We have previously reported that mannosylated sodium alginate nanoparticles (MAN-ALG) exhibited excellent dendritic cell targeting and in vivo antigen delivery efficacy. To investigate the role of MAN-ALG in an autoimmune context, we loaded the MAN-ALG with Ins2(9-23), a T1D autoantigen [MAN-ALG(PEP)], for T1D immune tolerance induction in nonobese diabetic (NOD) mice. We observed the delayed onset of T1D occurrence and some degree of blood glucose reduction accompanied by a larger islet area, attributable to augmented T-regulatory cell proportion in mice treated with MAN-ALG(PEP). However, MAN-ALG was also found to elicit lysosomal escape and cross-presentation of Ins2(9-23) in bone marrow-derived dendritic cells, leading to the immune activation of Ins2(9-23)-recognizing T cells and destruction of Ins2(9-23)-expressing islet cells. This dual impact resulted in delayed but a nonpreventive effect of MAN-ALG(PEP) on the T1D onset in NOD mice. Considering the potent immune stimulatory property of MAN-ALG, cautions should be implemented when using alginate-based biomaterials in an autoimmune context. Moreover, it is also noted that regarding the in vivo outcome of immune therapies, biomaterial-based delivery systems and their detailed role on immune regulation need to be examined.