Immunosuppressive Polymeric Nanoparticles Targeting Dendritic Cells Alleviate Lupus Disease in Fcgr2b-/- Mice by Mediating Antigen-Specific Immune Tolerance.

Dendritic cells (DCs) are the most potent antigen-presenting cells that have multifaceted functions in the control of immune activation and tolerance. Hyperresponsiveness and altered tolerogenicity of DCs contribute to the development and pathogenesis of system lupus erythematosus (SLE); therefore, DC-targeted therapies aimed at inducing specific immune tolerance have become of great importance for the treatment of SLE. This study developed a new nanoparticle (NP) containing a biodegradable PDMAEMA-PLGA copolymer for target-oriented delivery to DCs in situ. PDMAEMA-PLGA NPs provided sustained drug release and exhibited immunosuppressive activity in FLT3L and GM-CSF-derived bone marrow in conventional DCs (BM-cDCs). PDMAEMA-PLGA NPs improved dexamethasone capability to convert wild-type and Fcgr2b-/- BM-cDCs from an immunogenic to tolerogenic state, and BM-cDCs treated with dexamethasone-incorporated PDMAEMA-PLGA NPs (Dex-NPs) efficiently mediated regulatory T cell (Treg) expansion in vitro. Dex-NP therapy potentially alleviated lupus disease in Fcgr2b-/- mice by mediating Foxp3+ Treg expansion in an antigen-specific manner. Our findings substantiate the superior efficacy of DC-targeted therapy using the PDMAEMA-PLGA NP delivery system and provide further support for clinical development as a potential therapy for SLE. Furthermore, PDMAEMA-PLGA NP may be a versatile platform for DC-targeted therapy to induce antigen-specific immune tolerance to unwanted immune responses that occur in autoimmune disease, allergy, and transplant rejection.

The combined magnetic field and iron oxide-PLGA composite particles: Effective protein antigen delivery and immune stimulation in dendritic cells.

Superparamagnetic iron oxide nanoparticles (SPIONs) have received much attention in drug and biomolecule delivery systems. Here, we report a delivery system using the combination of a magnetic field and the relatively biocompatible composite particles of poly(lactic-co-glycolic acid) and SPIONs (SPION-PLGA particles) for protein delivery to bone-marrow derived primary dendritic cells (BM-DCs). SPIONs with the diameter of ∼10 nm were synthesized via thermal decomposition of iron(III) oleate. The SPIONs and bovine serum albumin (BSA) were encapsulated in PLGA particles of two different diameters, 300 and 500 nm. The obtained SPIONs-PLGA nanocomposites exhibited superparamagnetic character, showed low cytotoxicity and were well taken up in macrophage and BM-DCs under an external magnetic field. In addition, the nanocomposites were tested for immune induction in BM-DCs. This combined SPION-PLGA carrier and an external magnetic field can significantly enhance BM-DC maturation by upregulating MHC II, CD80 and CD86 expression. Immune response induction by this strategy is verified through a significant upregulation of the IL-12 and IFN-γ production. Moreover, no activation of BM-DCs to secrete pro-inflammatory cytokine TNF-α was observed for all particles. We anticipate these findings to be a starting point for vaccine researches involving the combined magnetic field and SPION-PLGA composite particles.