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Vaccines induce specific immunity through antigen uptake and processing. However, while nanoparticle vaccines have elevated uptake, the impact of intracellular protein release and how this affects processing and downstream responses are not fully understood. Herein, we reveal how tuning unmodified antigen release rate, specifically through modulation of metal–organic framework (MOF) pore size, influences the type and extent of raised adaptive immunity. We use two MOFs in the NU-100x series with 1.4 nm difference in pore diameter, employ facile postsynthesis loading to achieve significant internalization of model protein antigen ovalbumin (ca.1.4 mg/mg), and observe distinct antigen release and intracellular processing profiles influenced by MOF pore size. We investigate how this difference in release biases downstream CD8+, TH1, and TH2 T cell responses. Ovalbumin-loaded NU-1003 induced 1.8-fold higher CD8+:CD4+T cell proliferation ratio and displayed 2.2-fold greater ratio of CD4+TH1:TH2 cytokines compared to ovalbumin-loaded NU-1000. Antigen released from NU-1000 in vivo exhibited stronger antigen-specific IgG responses, which is dependent on CD4+T cells (up to ninefold stronger long-term antibody production and 5.9-fold higher IgG1:IgG2a ratio), compared to NU-1003. When translated to wild-type SARS-CoV-2 receptor-binding domain (RBD) protein, RBD-loaded NU-1000 induced 60.5-fold higher IgG1:IgG2a compared to NU-1003. Wild-type RBD-loaded NU-1000 immunization also induced a greater breadth of epitope recognition compared to NU-1003, as evidenced by increased binding antibodies to the Omicron RBD variant. Overall, this work highlights how antigen release significantly influences immunity induced by vaccines and offers a path to employ unmodified antigen release kinetics to drive personalized protective responses.
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This content will become publicly available on July 1, 2026
Exponentially Decreasing Antigen Release Reduces Inflammatory Markers in an Antigen‐Specific Manner
ABSTRACT Vaccine development requires innovative approaches to improve immune responses while reducing the number of immunizations. In this study, we explore the impact of controlled antigen release on immune activation and regulation using programmable infusion pumps and biodegradable biomaterials in OT‐II and wild‐type mice to understand the adaptive immune response through controlled antigen delivery in the absence of adjuvant. Ovalbumin (OVA) was delivered via an exponentially decreasing profile, mimicking clearance of infection, and an exponentially increasing profile, mimicking induction of infection. Exponentially decreasing OVA delivery through infusion pumps promoted regulatory T‐cell (Treg) activation in secondary lymphoid organs and suppressed pro‐inflammatory T‐helper type 17 (Th17) responses in blood. An exponentially increasing OVA profile enhanced central memory T‐cell (TCM) populations in submandibular blood and humoral immune responses in cardiac blood serum, demonstrating distinct immune modulation based on release kinetics. OVA was also delivered using a biodegradable PLGA‐PEG‐PLGA (PPP) depot, which provided controlled OVA release in an exponentially decreasing pattern. PPP‐OVA treatment significantly reduced the frequency of pro‐inflammatory T‐helper type 1 (Th1) cells while increasing CD25+FOXP3+Treg cells in the spleen. Moreover, to identify T‐cell populations that most accurately characterize the divergence in Treg and T‐helper response to OVA kinetics, a Sequential Feature Selection (SFS) algorithm with Machine Learning (ML) models was used. ML algorithms identified gMFI of RORγt+as a key feature in submandibular blood and the ratio of gMFI of FOXP3+to GATA3+as the marker that was significantly changed by treatments in inguinal lymph nodes (iLN) when infusion pumps were used to deliver OVA. In addition, ML‐based SFS identified CD25+FOXP3+regulatory T cells as the most important feature, influencing the expression of other cell types in both inguinal lymph nodes (iLN) and spleen when PPP was used to deliver OVA. This finding suggests that the exponentially decreasing profile may generate anti‐inflammatory responses. Overall, these findings suggest that controlled antigen delivery enhances immune regulation and memory T cells, providing new insights into immune responses mediated by the release kinetics.
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- Award ID(s):
- 2323532
- PAR ID:
- 10658860
- Publisher / Repository:
- Wiley Online Library and biorxiv
- Date Published:
- Journal Name:
- Journal of Biomedical Materials Research Part A
- Volume:
- 113
- Issue:
- 7
- ISSN:
- 1549-3296
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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