Controlled Delivery of Single or Multiple Antigens in Tolerogenic Nanoparticles Using Peptide-Polymer Bioconjugates

Abstract

Polymeric nanoparticles (NPs) have demonstrated their potential to induce antigen (Ag)-specific immunological tolerance in multiple immune models and are at various stages of commercial development. Association of Ag with NPs is typically achieved through surface coupling or encapsulation methods. However, these methods have limitations that include high polydispersity, uncontrollable Ag loading and release, and possible immunogenicity. Here, using antigenic peptides conjugated to poly(lactide-co-glycolide), we developed Ag-polymer conjugate NPs (acNPs) with modular loading of single or multiple Ags, negligible burst release, and minimally exposed surface Ag. Tolerogenic responses of acNPs were studied in vitro to decouple the role of NP size, concentration, and Ag loading on regulatory T cell (Treg) induction. CD4CD25Foxp3 Treg induction was dependent on NP size, but CD25 expression of CD4 T cells was not. NP concentration and Ag loading could be modulated to achieve maximal levels of Treg induction. In relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a murine model of multiple sclerosis, acNPs were effective in inhibiting disease induced by a single peptide or multiple peptides. The acNPs provide a simple, modular, and well-defined platform, and the NP physicochemical properties offer potential to design and answer complex mechanistic questions surrounding NP-induced tolerance.

Intravascular innate immune cells reprogrammed via intravenous nanoparticles to promote functional recovery after spinal cord injury

“…i.v.-administered NPs are thought to bind to circulating immune cells via scavenger receptors such as MARCO. NPs with a diameter of 500 nm were selected based on our previous work with autoimmune disease (30) and a greater internalization due in part to binding affinity for immune cells and flow patterns within the blood (12). Previous studies reported that neither resident microglia nor T lymphocytes express scavenger receptors such as MARCO (31), thus indicating that NPs target selectively circulating immune cells that would normally infiltrate a SCI.…”

Nanoparticles for the Induction of Antigen-Specific Immunological Tolerance

“…Coupling antigens to spleen cells through ethylenecarbodiimide (ECDI) fixation has been shown to induce their apoptosis and treatments with these dead cell-peptide conjugates confers tolerance to the antigen in many preclinical models. This approach has been used to treat various diseases, including animal models of EAE and T1D ( 94 , 95 ). A similar strategy has been employed to target disease-relevant antigens to erythrocytes in vivo .…”

In vivo reprogramming of immune cells: Technologies for induction of antigen-specific tolerance

“…Previous studies using Ag-SP demonstrated the dependence of the spleen for tolerance induction [82], however, prophylactic tolerance induction by PLGA(Ag) particles was not solely dependent on the spleen [70]. Pearson et al developed Ag-polymer conjugate PLGA (acNP) particles that displayed modular Ag loading (up to 150 μg peptide per mg particle), low burst release, and minimally exposed surface Ag [94]. In vitro, acNPs were effective at inducing Tregs in a co-culture model of BMDCs, naïve OTII T cells, and TGF-p1.…”

“…(F) Corresponding cumulative clinical score for mice treated with particles (n = 5). Differences between disease courses of different treatment groups were analyzed for statistical significance using the Kruskal-Wallis test (one-way ANOVA non-parametric test) with Dunn's multiple comparisons test (p < 0.05) [94]. …”