Background Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in maintaining the balance between immunity and tolerance and, as such are a promising immunotherapy tool to induce immunity or to restore tolerance. The main challenge to harness the tolerogenic properties of DCs is to preserve their immature phenotype. We recently developed polyion complex micelles, formulated with double hydrophilic block copolymers of poly (methacrylic acid) and poly (ethylene oxide) blocks and able to entrap therapeutic molecules, that did not induce DC maturation. In the current study, the intrinsic destabilising membrane properties of the polymers were used to optimise endosomal escape property of the micelles in order to propose various strategies to restore tolerance.
Material and method PMAA- b-PEO copolymers with low (PMAA2100- b-PEO5000, PMAA3500- b-PEO5000) and high Mw (PMAA2500- b-PEO12000, PMAA16200- b-PEO30000) were used to formulate either OVA peptide-entrapped or siRNA-entrapped micelles. siRNA- and peptide-entrapment efficiency was monitored using fluorescent molecules. Peptide presentation was monitored using transgenic T cells and si-RNA silencing of target gene was followed by FACS.
Results On the first hand, we showed that high molecular weight (Mw) copolymer-based micelles were efficient to favour the release of the micelle-entrapped peptide into the endosomes, and thus to improve peptide presentation by immature (i) DCs. On the second hand, we put in evidence that low Mw copolymer-based micelles were able to favour the cytosolic release of micelle-entrapped small interferent RNAs, dampening the DCs immunogenicity.
Conclusion Therefore, we demonstrate the versatile use of polyionic complex micelles to preserve tolerogenic properties of DCs. Altogether, our results underscored the potential of such micelle-loaded iDCs as a therapeutic tool to restore tolerance in autoimmune diseases.
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