Precision Nanovaccines for Potent Vaccination

Abstract

Compared with traditional vaccines, nanoparticulate vaccines are especially suitable for delivering antigens of proteins, peptides, and nucleic acids and facilitating lymph node targeting. Moreover, apart from improving pharmacokinetics and safety, nanoparticulate vaccines assist antigens and molecular adjuvants in crossing biological barriers, targeting immune organs and antigen-presenting cells (APC), controlled release, and cross-presentation. However, the process that stimulates and orchestrates the immune response is complicated, involving spatiotemporal interactions of multiple cell types, including APCs, B cells, T cells, and macrophages. The performance of nanoparticulate vaccines also depends on the microenvironments of the target organs or tissues in different populations. Therefore, it is necessary to develop precise nanoparticulate vaccines that accurately regulate vaccine immune response beyond simply improving pharmacokinetics. This Perspective summarizes and highlights the role of nanoparticulate vaccines with precise size, shape, surface charge, and spatial management of antigen or adjuvant for a precision vaccination in regulating the distribution, targeting, and immune response. It also discusses the importance of the rational design of nanoparticulate vaccines based on the anatomical and immunological microstructure of the target tissues. Moreover, the target delivery and controlled release of nanovaccines should be taken into consideration in designing vaccines for achieving precise immune responses. Additionally, it shows that the nanovaccines remodel the suppressed tumor environment and modulate various immune cell responses which are also essential.

Figure 1

Schematic illustration of the influence of size on lymphatic transportation.

Figure 2

(A) The density and distribution of antigens or adjuvants affect the recognition of pattern recognition receptors (PRRs) on the cell surface. (B) High adjuvant density particles induced stronger humoral and Th1 immune responses. (C) Traditional nanoparticles activate downstream immune responses by carrying excess CpG to achieve binding to toll-like receptor 9 (TLR9). The nanoparticles precisely modified with CpG at specific distances are capable of inducing comparable or stronger immune responses than conventional particles at the lowest dose. Reproduced with permission from ref (51). Copyright 2015 Springer Nature.

Figure 3

(A) Schematic of changing the LNP formulation and (B) the structure of ionizable lipid. (C) Alter the head, linker, or tail of ionizable lipids can change the tissue selecting targeting.

Figure 4

Schematic of the different routes for vaccination. The picture was created with BioRender.com.

Figure 5

(A) Schematic of HFMD nanovaccine preparation by FNC technic. (B) TNF-α or CpG as adjuvants promotes cell uptake by BMDCs. (C) Nanovaccine enhanced LN targeting. (D) The IFN-γ, IL-4 and IL-2 secreted in serum postvaccination of different forms of vaccines. Reproduced with permission from ref (97). Copyright 2018 ACS Publications.

Figure 6

(A) Schematic of cationic molecular bottlebrushes (MBBs) with tuned AR and loaded with anionic CpG by electrostatic interactions. (B) AFM images of three MBBs loaded with CpG. (C) Proximal LNs observed with IVIS imaging after SC injection. (D) Confocal images of CD11c⁺ cells extracted from popliteal LNs at 24 h after injection. The cell nucleus was stained with Hoechst 33342 (blue), TLR9 was stained using anti-TLR9-FITC (green), and LAMP-1 was stained using anti-LAMP1-Cy3 (red). In merged images, N, T, L, and C indicate the nucleus, TLR9, LAMP-1, and CpG, respectively (scale bar, 5 μm). (E) HBsAg levels in the blood were detected after different formulation therapy. (F) HBsAg positive ratio of HBV carrier mice was evaluated after different formulation therapy. Reproduced with permission from ref (103). Copyright 2021 ACS Publications.

Figure 7

(A) Schematic of the tannic acid-modified nanoadjuvant and nanopaclitaxel targeting metastatic lymph node. (B) Images of building popliteal LN metastasis model and injection of PNP or PNP-TA in situ. (C) INP-TA distribution in inguinal lymph nodes at 24 h postinjection (color bar scale of radiant efficiency) (D) INP-TA showed enhanced enrichment in LNs via conduits targeting. (E) Representative images of tumor therapy with PNP, PNP-TA, INP and INP-TA, and monitoring the metastasis inhibition of LNs and lungs. (F) HE staining of lungs from the mice of different treated groups. Abbreviations, INP: IMQ nanoadjuvant; PNP: PTX nanoparticle; INP-TA: Tannic acid supported INP; PNP-TA: Tannic acid-supported PNP; TAA: Tumor-associated antigen; LECs: Lymphatic endothelial cells; SCS: Subcapsular sinus. Reproduced with permission from ref (104). Copyright 2022 ELSEVIER.

Figure 8

(A) Synthetic strategy diagram of the self-degradable poly(β-amino ester)s and the nanovaccine (p(S+O)) formulation. (B) Schematic of the nanovaccine promoting cytosolic delivery of antigen and agonist. (C) p(S+O) promoted OVA and 2′3′-cGAMP escaped from endosome. (D) Representative flow cytometry plots of SIINFEKL-tetramer⁺ CD8⁺ T cells on day 19 post the first vaccination. (E) Average tumor volume. Reproduced with permission from ref (105). Copyright 2022 ELSEVIER.

Figure 9

Microneedle assistant nanovaccine activated γδ T cells to combat tumors. (A) Schematic of the MN nanovaccine preparation. γδ T cells in (B) skin and (C) tumor postvaccination. (D) RNA levels of related chemokines genes in tumors and (E) spleen stimulated by MN nanovaccine. (F) MN_LCTMV significantly inhibited Luc-4T1 tumor growth. Reproduced with permission from ref (106). Copyright 2023 Wiley Online Library.

Figure 10

Nanovaccine combined with anti-PD-L1 remodeling the TME. (A) Schematic of the EBV-associated nanovaccine combined with anti-PD-L1 for tumor therapy. (B) Nanovaccine adjuvanted by CpG (NA1C) elicited a biased immune response. (C) NA1C synergized with anti-PD-L1 downregulated MDSC in TME. The Tregs in (D) PBMC and (E) TME were downregulated. (F) NA1C combined with anti-PD-L1 showed potent efficiency for tumor eradication. Reproduced with permission from ref (108). Copyright 2020 ELSEVIER.

Figure 11

Nanovaccine promoted TLS formation to inhibit tumor progress. (A) Schematic of the Mn²⁺ assistant nanovaccine codelivered EBNA1 antigen and CpG for tumor therapy. (B) Nanovaccine promoted cell internalization and cytosolic delivery of CpG and Mn²⁺. (C) Nanovaccine elicited a strong STING pathway response and (D, E) showed a potent tumor inhibition (F) HE staining showed the TLS formation using the Mn²⁺ assistant nanovaccine. Reproduced with permission from ref (109). Copyright 2023 ACS Publications.