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Erythrocyte-Driven Immunization Via Biomimicry of Their Natural Antigen-Presenting Function

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Erythrocyte-Driven Immunization Via Biomimicry of Their Natural Antigen-Presenting Function Erythrocyte-driven immunization via biomimicry of their natural antigen-presenting function Anvay Ukidvea,b,1, Zongmin Zhaoa,b,1, Alexandra Fehnela, Vinu Krishnana,b, Daniel C. Pana,b, Yongsheng Gaoa,b, Abhirup Mandala,b, Vladimir Muzykantovc,d, and Samir Mitragotria,b,2 aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; bWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; cDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; and dCenter for Translational Targeted Therapeutics and Nanomedicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 Edited by Chad A. Mirkin, Northwestern University, Evanston, IL, and approved June 15, 2020 (received for review February 14, 2020) Erythrocytes naturally capture certain bacterial pathogens in cir- including proteins (2–4), therapeutics (16), and nanoparticles culation, kill them through oxidative stress, and present them to the (17–19) have been attached to the erythrocyte surface or en- antigen-presenting cells (APCs) in the spleen. By leveraging this innate capsulated within erythrocytes (20) for various therapeutic ap- immune function of erythrocytes, we developed erythrocyte-driven plications. The attachment of cargo to the erythrocyte surface immune targeting (EDIT), which presents nanoparticles from the has been brought about by chemical conjugation (16), binding to surface of erythrocytes to the APCs in the spleen. Antigenic specific receptors like glycophorin A (4), sortagging (2), or passive nanoparticles were adsorbed on the erythrocyte surface. By engi- adsorption (19), without compromising their physiological function neering the number density of adsorbed nanoparticles, (i.e., the of oxygen transport. All previous approaches of hitchhiking on number of nanoparticles loaded per erythrocyte), they were pre- erythrocytes are based on induction of minimal perturbation to the dominantly delivered to the spleen rather than lungs, which is con- carrier erythrocytes, which has led to either their extended circu- ventionally the target of erythrocyte-mediated delivery systems. lation or capture in the capillary endothelia after injection (17, 19, Presentation of erythrocyte-delivered nanoparticles to the spleen 21). Here, we engineered a hitchhiking system that induces the led to improved antibody response against the antigen, higher cen- delivery of the attached nanoparticles predominantly to the spleen tral memory T cell response, and lower regulatory T cell response, instead of lungs to achieve cellular and humoral immunity, a process compared with controls. Enhanced immune response slowed down that we refer to as erythrocyte-driven immune targeting (EDIT). APPLIED BIOLOGICAL SCIENCES tumor progression in a prophylaxis model. These findings suggest that EDIT is an effective strategy to enhance systemic immunity. Results Synthesis and Characterization of Antigenic Cargo. Ovalbumin (OVA) biomimetic | spleen targeting | immunization | vaccination | was selected as a model antigen and was capped on the surface of erythrocyte hitchhiking 200-nm polystyrene carboxylate (PS-COOH) to generate protein- capped nanoparticles (NPs) that were attached to erythrocytes rythrocytes, accounting for over 80% of cells in the human (Fig. 2A). OVA was attached to 200-nm NPs using 1-ethyl-3-(3- Ebody, serve the primary function of oxygen delivery to tissues. dimethylaminopropyl)carbodiimide (EDC) chemistry, as previously In addition to oxygen transport, erythrocytes also perform several reported (22). Loading of OVA on NPs could be controlled over a additional functions that are of high immunological relevance. For wide range (SI Appendix,Fig.S1); however, an intermediate loading example, upon reaching the end of their natural lifespan, senescent of ∼43 μg/mg of particles was used for the remainder of the studies erythrocytes are phagocytosed in the spleen in a noninflammatory (Fig. 2B). OVA attachment to nanoparticles was confirmed by size pathway (1). This unique mechanism has been elegantly exploited and zeta-potential measurements. OVA attachment increased the to develop tolerance to antigens for applications in autoimmune hydrodynamic size of NPs from 191 to 234 nm (Fig. 2C). Further, disorders and reducing anti-drug antibody production (2–4). Spe- cifically, antigenic peptides, attached to erythrocyte membranes, Significance are captured in the spleen along with senescent erythrocytes, thus generating a tolerogenic response to antigens due to the non- Red blood cells perform the unique function of capturing cer- inflammatory pathway of capture unique to erythrocytes. tain pathogens in blood and presenting them to the immune Recently, erythrocytes have been implicated in another inter- cells in the spleen. We developed a strategy based on this in- esting and contrasting innate immune function (5, 6). Specifically, nate immune function of red blood cells to deliver vaccine they capture immune complexes and bacteria in circulation on their nanoparticles to the spleen. This biomimetic strategy induced a surface and hand them to Kupffer cells in the liver and professional strong vaccination response without the need for foreign antigen-presenting cells (APCs) in the spleen without the capture of adjuvants. the carrier erythrocyte (7–11). Bacterial species in the blood such as Staphylococcus and Propionibacterium attach to erythrocyte mem- Author contributions: A.U., Z.Z., and S.M. designed research; A.U., Z.Z., A.F., V.K., D.C.P., brane due to electrostatic attraction and are killed by oxycytosis by Y.G., and A.M. performed research; A.U., Z.Z., V.K., D.C.P., and Y.G. contributed new reagents/analytic tools; A.U. and Z.Z analyzed data; and A.U., Z.Z., V.M., and S.M. the carrier erythrocyte. Thereafter, erythrocytes hand them over to wrote the paper. the cells in the liver and spleen, without themselves being seques- Competing interest statement: A.U., Z.Z., and S.M. are inventors on a patent application tered (9, 12). While the exact mechanism of selective cargo uptake that covers aspects of the technology described in this manuscript. The patent application by APCs is unclear, transient membrane alteration induced by the is assigned to and managed by Harvard University. bacterial cargo is implicated in the increased cross talk between the This article is a PNAS Direct Submission. erythrocytes and APCs (13, 14). Here, we leverage this innate and Published under the PNAS license. unique ability of erythrocytes to present antigens in the spleen to 1A.U. and Z.Z. contributed equally to this work. develop a biomimetic strategy for generating cellular and humoral 2To whom correspondence may be addressed. Email: [email protected]. immune responses to antigens (Fig. 1). This article contains supporting information online at https://www.pnas.org/lookup/suppl/ Attachment of molecules to erythrocytes has been leveraged doi:10.1073/pnas.2002880117/-/DCSupplemental. for several biomedical applications (15). A range of payloads First published July 14, 2020. www.pnas.org/cgi/doi/10.1073/pnas.2002880117 PNAS | July 28, 2020 | vol. 117 | no. 30 | 17727–17736 Downloaded by guest on September 29, 2021 Fig. 1. Schematic for engineering a handoff of nanoparticles at the spleen via erythrocyte hitchhiking. (A) Protein-capped polymeric nanoparticles used for the study (different sizes, materials, or coated with different proteins). (B) The number of nanoparticles loaded on erythrocytes was tuned for protein loading and to induce temporary up-regulation of phosphatidylcholine. (C) Intravenous injection of hitchhiked nanoparticles leads to high discharge in the spleen. (D) Up-regulated phosphatidylcholine and masking CD47 improves interactions with antigen-presenting cells in the spleen. (E) Improved erythrocyte interactions facilitate nanoparticle uptake by the APCs while the erythrocytes return back to the circulation. (F) Handoff of nanoparticles at the spleen improves both humoral and cellular immune responses. conjugation of the carboxylate groups on the NPs was also evident the dendritic cells and consequently activate them (SI Appen- from the decrease in zeta potential from −40.4 to −21.4 mV dix,Fig.S3). All particles were monodispersed and showed (Fig. 2D). OVA conjugation did not affect NP polydispersity excellent internalization by and activation of dendritic cells. (Fig. 2E). This was further confirmed by performing scanning Though bare nanoparticles are themselves capable of maturating electron microscopy (SEM). SEM images of plain and conju- the cells (23), they are not of specific consequence in assessing the gated nanoparticles show monodisperse nanoparticles (Fig. 2F) benefits of hitchhiking OVA-NPs and hence were not included in in both cases, indicating that OVA conjugation had a negligible the study. effect on polydispersity. Apart from characterization of physicochemical properties, we Engineering Nanoparticle–Erythrocyte Hitchhiking to Achieve a Handoff also characterized the OVA-NPs for internalization by and ac- in the Spleen. Hitchhiking of nanoparticles occurs through two steps tivation of dendritic cells. Both OVA and OVA-NPs were taken that are physical in nature (17, 19, 24): adsorption of nanoparticles up by dendritic cells (SI Appendix, Fig. S2A). However, OVA- on the erythrocyte surface to initiate contact, and spreading of the NPs were taken up in significantly
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