Biomaterials engineering to stimulate antigen-specific T cells

Using nanoparticles as an artificial antigen presentation cell (aAPC), with surface-conjugated antigen in the context of an MHC molecule and co-stimulating molecules (Signals 1 and 2), we developed the first quantitative analysis of particle size effect on aAPCs with both Signals 1 and 2 based on T cell biology and identified an optimal size range for higher efficiently. Recently, we developed a hyaluronic acid hydrogel-based artificial T-cell stimulation matrix that incorporates matrix stiffness cue and T cell proliferation Signal 3 to synergize with the Signals 1 and 2 for ex vivo and in vivo T cell activation and proliferation.

Representative Publications:

  1. Hickey JW, Vicente FP, Howard GP, Mao HQ, Schneck JP. Biologically inspired design of nanoparticle artificial antigen-presenting cells for immunomodulation. Nano Letters. 17(11): 7045–7054 (2017). PMCID: PMC6709596; PMID: 28994285.
  2. Hickey JW, Isser AY, Vicente FP, Warner SB, Mao HQ, Schneck JP. Efficient magnetic enrichment of antigen-specific T cells by engineering particle properties. Biomaterials. 187: 105–116 (2018). PMCID: PMC6284398; PMID: 30312851
  3. Hickey JW, Dong Y, Chung JW, Salathe SF, Pruitt HC, Li X, Chang C, Fraser AK, Bessell CA, Ewald AJ, Gerecht S, Mao HQ, Schneck JP. Engineering an artificial T-cell stimulating matrix for immunotherapy. Advanced Materials. 31(23): e1807359 (2019). PMCID: PMC8601018; PMID: 30968468.
  4. [Cover] Hickey JW, Isser A, Salathe SF, Gee KM, Hsiao MH, Shaikh W, Uzoukwu NC, Bieler JG, Mao HQ, Schneck JP. Adaptive Nanoparticle Platforms for High Throughput Expansion and Detection of Antigen-Specific T cells. Nano Lett. 20(9): 6289–6298 (2020). doi: 10.1021/acs.nanolett.0c01511. PMID: 32594746.

Lymph draining polyelectrolyte complex nanoparticles for vaccine delivery

We developed nanovaccines to potentiate immune responses by site-specific drainage to lymph nodes. Using a nanovaccine encapsulating VP1 protein antigen from enterovirus 71, which causes hand-foot-mouth disease (HFMD) and tumor necrosis factor-α (TNFα) or CpG as an adjuvant, we showed rapid drainage to proximal and distal lymph nodes and subsequently induced strong immune activation and conferred effective protection against lethal virus challenge. We have also developed similar nanoparticles for plasmid DNA encoding antigen and microparticles for prolonged release of antigen, working towards a single dose vaccine.

Representative Publications:

  1. Qiao D, Liu L, Chen Y, Xue C, Gao Q, Mao HQ, Leong KW, Chen Y. Potency of a scalable nanoparticulate subunit vaccine. Nano Lett. 18(5): 3007-3016 (2018). doi: 10.1021/acs.nanolett.8b00478. PMID: 29694053.
  2. Howard GP, Verma G, Ke X, Thayer WM, Hamerly T, Baxter VK, Lee JE, Dinglasan RR, Mao HQ. Critical size limit of biodegradable nanoparticles for enhanced lymph node trafficking and paracortex penetration. Nano Research. 12(4): 837–844 (2019). PMCID: PMC7747954; PMID: 33343832.
  3. Howard GP, Bender NG, Khare P, López-Gutiérrez B, Nyasembe V, Weiss WJ, Simecka JW, Hamerly T, Mao HQ, Dinglasan RR. Immunopotentiation by lymph-node targeting of a malaria transmission-blocking nanovaccine. Front. Immunol. 12: 729086 (2021). doi: 10.3389/fimmu.2021.729086. PMID: 34512663.
  4. Wilson KL, Howard GP, Coatsworth H, Dinglasan RR, Mao HQ, Plebanski M. Biodegradable PLGA-b-PEG Nanoparticles Induce T Helper 2 (Th2) Immune Responses and Sustained Antibody Titers via TLR9 Stimulation. Vaccines. 8(2): 261. doi: 10.3390/vaccines8020261 (2020). PMID: 32485944.
  5. Ke X, Howard GP, Tang H, Cheng B, Saung MT, Santos JL, Mao HQ. Physical and chemical profiles of nanoparticles for lymphatic targeting. Advanced Drug Delivery Reviews. 151-152: 72–93. (2019) doi: 10.1016/j.addr.2019.09.005. PMID: 31626825.