Mannose-Functionalized “Pathogen-like” Polyanhydride Nanoparticles Target C-Type Lectin Receptors on Dendritic Cells

Abstract

Targeting pathogen recognition receptors on dendritic cells (DCs) offers the advantage of triggering specific signaling pathways to induce a tailored and robust immune response. In this work, we describe a novel approach to targeted antigen delivery by decorating the surface of polyanhydride nanoparticles with specific carbohydrates to provide "pathogen-like" properties that ensure nanoparticles engage C-type lectin receptors on DCs. The surface of polyanhydride nanoparticles was functionalized by covalent linkage of dimannose and lactose residues using an amine-carboxylic acid coupling reaction. Coculture of functionalized nanoparticles with bone marrow-derived DCs significantly increased cell surface expression of MHC II, the T cell costimulatory molecules CD86 and CD40, the C-type lectin receptor CIRE and the mannose receptor CD206 over the nonfunctionalized nanoparticles. Both nonfunctionalized and functionalized nanoparticles were efficiently internalized by DCs, indicating that internalization of functionalized nanoparticles was necessary but not sufficient to activate DCs. Blocking the mannose and CIRE receptors prior to the addition of functionalized nanoparticles to the culture inhibited the increased surface expression of MHC II, CD40 and CD86. Together, these data indicate that engagement of CIRE and the mannose receptor is a key mechanism by which functionalized nanoparticles activate DCs. These studies provide valuable insights into the rational design of targeted nanovaccine platforms to induce robust immune responses and improve vaccine efficacy. The use of vaccine adjuvants to activate the innate immune system is crucial to vaccine effectiveness. 1 Adjuvants can be used to enhance the efficacy of single dose vaccines and reduce the required antigen dose. The use of biodegradable polymer nanoparticles as vaccine delivery vehicles allows for effective delivery of payloads by parental or mucosal administration by protecting the antigen from harsh physiological conditions and enabling transport across biological barriers (e.g., mucus membranes). 2 Polyanhydride nanoparticles have shown excellent potential as vaccine carriers. 3À6 Encapsulation of protein antigens into polyanhydride particles stabilizes them and provides sustained azntigen release; 4,7 these particles also enhance the immune response by acting as an adjuvant. 3 Dendritic cells (DCs) are antigen presenting cells (APCs) that play a major role in connecting the innate and adaptive immune systems, a key step to inducing protective immunity. 8 DCs can sense and internalize antigen by a variety of mechanisms that trigger DC maturation and direct further interactions with other immune cells, including naive T cells. 1,9,10 Pattern recognition receptors (PRRs) on DCs detect the presence of a potential threat by interacting with pathogen-associated molecular patterns (PAMPs). 10,11 In particular, C-type lectin receptors (CLRs) are PRRs with highly conserved carbohydrate-recognition domains that bind sugar moieties (e.g., mannose, fuco...

Safety and Biocompatibility of Carbohydrate-Functionalized Polyanhydride Nanoparticles

“…Biodegradable nanoparticles possess promising characteristics in this regard by playing dual roles, both as adjuvants and delivery vehicles (5). In particular, polyanhydride particles have been demonstrated to induce enhanced expression of MHCs I and II on and stimulation of antigen-presenting cells (APCs), which are fundamental to initiating adaptive immune responses (6)(7)(8). After in vivo administration, the nanoparticles interact with a variety of cells, including APCs (9,10).…”

Role of targeting nanoparticles for cancer immunotherapy and imaging

“…Surface-functionalized mannose polyanhydride nanoparticles are reported to effectively activate DCs through mannose receptor. The dimannose-modified nanoparticles de mon strated the improved MHC II, CD86 and CD40 antigen presentation, increased CD206 and CIRE expression, higher level of pro-inflammatory IL-6 and TNF-α compared to non-modified nanoparticles [24] . Asparagine-glycine-arginine (NGR) cell-specific peptide is reported as a targeting ligand to target PEGylated polyplex to DC via enhanced phagocytosis.…”

“…Active targeting of antigens in DCs by nanoparticles can also be achieved by other targeting ligands, such as mannose or lactose residues, via endocytic receptor interaction to elicit robust vaccines [24] . Mannan (MN)-decorated PLGA-NPs showed an increased cellular uptake in DCs by both flow cytometry and confocal microscope [25] .…”

Dendritic Cells Interactions with the Immune System – Implications for Vaccine Development

“…The antigen or additional adjuvants can be incorporated by different strategies, such as encapsulated [101], and covalently [102] or non-covalently coupled to the particles [103]. In addition, the delivery of the products can be controlled, allowing a slow and continuous release, by pulses, or triggered by factors such as pH [104], electric or magnetic fields [105], temperature [106] or ionic strength [107].…”