Murine and Non-Human Primate Dendritic Cell Targeting Nanoparticles for in Vivo Generation of Regulatory T-Cells

Abstract

Porous silicon nanoparticles (pSiNP), modified to target dendritic cells (DC), provide an alternate strategy for the delivery of immunosuppressive drugs. Here, we aimed to develop a DC-targeting pSiNP displaying c-type lectin, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), and CD11c monoclonal antibodies. The in vivo tracking of these fluorescent DC-targeting nanoparticles was assessed in both C57BL/6 mice and common marmosets ( Callithrix jacchus) by intravenous injection (20 mg/kg). Rapamycin and ovalbumin (OVA) peptide loaded pSiNP were employed to evaluate their ability to generate murine CD4CD25FoxP3 regulatory T-cells in vivo within OVA sensitized mice. In vivo, pSiNP migrated to the liver, kidneys, lungs, and spleen in both mice and marmosets. Flow cytometry confirmed pSiNP uptake by splenic and peripheral blood DC when functionalized with targeting antibodies. C57BL/6 OVA sensitized mice injected with CD11c-pSiNP loaded with rapamycin + OVA produced a 5-fold higher number of splenic regulatory T-cells compared to control mice, at 40 days post-pSiNP injection. These results demonstrate the importance of the immobilized targeting antibodies to enhance cellular uptake and enable the in vivo generation of splenic regulatory T-cells.

Immunomodulatory Nanosystems

“…2019, 6,1900101 HA-NP CD44 and TLR4 on macrophages - [295] Dextran-dexamethasone prodrug Lectin and scavenger receptor on macrophages Esterase [44] Au NP IL-4 -- [296] MSNP IL-4 -- [297] MTC cross-linked with miRNA-146b Mannose receptor on BMDMs - [298] Silica nanoparticle conjugated with KGM -Mannose receptor on BMDMs - [299] RGD-coated Au NP protected by a magnetic nanocage -- [300] Modulation of Tregs Au NP Hyperforin -- [301] Au NP Hexapeptide -- [302] PLGA NP Protein or peptide antigens and rapamycin -- [303] PLA-PLGA NP PLP and rapamycin -- [304] Porous silicon nanoparticle Rapamycin and OVA peptide CD11c on DCs - [36] PLGA NP Anti-CD3 Ab PNAd on HEV - [42] PLGA NP Diabetogenic peptide -- [305] Iron oxide nanoparticle T1D-relevant peptide-MHC class I complexe -- [306] Iron oxide nanoparticle Diabetogenic antigen peptide-MHC class II complex -- [307] PLGA NP IL-2 and TGF-β Biotin on CD4+ T cells - [308] Obesity increases the M1 macrophage infiltration in adipose tissue and promotes the secretion of pro-inflammatory cytokines, such as TNF-α and IL-6, which lead to high risk of glucose intolerance and insulin resistance. Sci.…”

“…[36] Specifically, rapamycin-and OVA peptide-loaded porous silicon nanoparticles were endowed with murine DC-targeting ability by surface coupling with CD11c Ab. For example, Stead et al proposed a nanoparticle-based method for generation of Tregs in vivo with the purpose of inhibiting chronic graft rejection after organ transplantation.…”

“…One strategy to improve the localization of encapsulated cargoes in target tissues or cells is chemical modification of nanoparticles with targeting moieties. For example, nanomaterials decorated with DEC‐205 antibody (Ab), CD40 Ab, CD11c Ab, or mannose can be preferentially internalized by dendritic cells (DCs) through receptor‐mediated endocytosis . Similarly, folate, lectins, and CD44 are utilized for recognition by corresponding receptors overexpressed on macrophages .…”

Encapsulation of Human Natural and Induced Regulatory T‐Cells in IL‐2 and CCL1 Supplemented Alginate‐GelMA Hydrogel for 3D Bioprinting

“…[ 63 ] To further enhance Treg numbers, low‐dose rapamycin could be added as an additional bioactive factor, [ 64 ] utilizing recently developed rapamycin‐loaded porous silicon nanoparticles. [ 65,66 ] Moreover, peripheral blood CCR8 + T‐cells were highly enriched with Tregs, and CCL1‐supplemented hydrogel was shown to specifically induce chemotaxis of these cells, providing an insight into the cellular microenvironment in humans upon utilization of CCL‐1‐supplemented hydrogel. Lastly, the findings from Treg encapsulation translated into the 3D bioprinting system as bioprinted Tregs were viable and functional, and protected co‐printed murine islets from xenoresponse mediated by human PBMCs.…”

Emerging approaches and technologies in transplantation: the potential game changers

“…In their approach, the investigators fabricated liposomal carriers carrying an antigen (OVA) and the B cell targeting ligand CD22 (Siglec-G), with rapamycin trapped in the lipid layer, and they demonstrated that stable B-cell tolerance to OVA can be achieved by treatment with this liposome formulation. 54 In another study, Stead et al 55 developed porous silicon-based NPs targeting dendritic cells (DCs). These NPs were conjugated with DC-specific intercellular adhesion molecule-3grabbing nonintegrin (DC-SIGN), CD11c monoclonal antibodies and rapamycin.…”