Nanotechnology has shown great promise in treating diverse diseases. However, developing nanomedicine that can cure autoimmune diseases without causing systemic immunosuppression is still quite challenging. Herein, we propose an all-in-one nanomedicine comprising an autoantigen peptide and CRISPR-Cas9 to restore specific immune tolerance by engineering dendritic cells (DCs) into a tolerogenic phenotype, which can expand autoantigen-specific regulatory T (Treg) cells. In brief, we utilized cationic lipid-assisted poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles to simultaneously encapsulate an autoimmune-diabetes-relevant peptide (2.5mi), a CRISPR-Cas9 plasmid (pCas9) and three guide RNAs (gRNAs) targeting costimulatory molecules (CD80, CD86 and CD40). We demonstrated that the all-in-one nanomedicine was able to effectively codeliver these components into DCs, followed by simultaneous disruption of the three costimulatory molecules and presentationof 2.5mi peptide on the genome-edited DCs. The resulting tolerogenic DCs triggered the generation and expansion of autoantigen-specific Treg cells by presenting 2.5mi peptide to CD4+ T cells in the absence of costimulatory signals. Using autoimmune type 1 diabetes (T1D) as a typical disease model, we demonstrated that our nanomedicine prevented autoimmunity to islet components and inhibited T1D development. Our all-in-one nanomedicine achieved co-delivery of CRISPR-Cas9 and peptide to DCs, and could be easily applied to other autoimmune diseases by substitution of different autoantigen peptide. This study has recently been published in ACS Applied Materials & Interfaces (doi: 10.1021/acsami.0c10885.) titled “An All-in-One Nanomedicine Consisting of CRISPR-Cas9 and an Autoantigen Peptide for Restoring Specific Immune Tolerance”.
This work is supported by the National Key R&D Program of China, the National Natural Science Foundation of China andthe Program for Guangdong Introducing Innovative and Entrepreneurial Teams and so on.