Nanocarrier-based immunotherapy for viral diseases

Abstract

The global morbidity and mortality associated with viral diseases pose a major threat to public health security and cause significant economic losses worldwide. Developing novel prophylactic and therapeutic interventions remains an urgent priority in contemporary virology research. Immunotherapy, initially developed for cancer treatment, has shown satisfactory efficacy in the management of viral infections. However, the clinical application of immunotherapy is still constrained by its inherent limitations, including poor stability, inadequate targeting ability, and systemic toxicity. Nanocarriers have emerged as a promising platform to address these challenges, with features such as protecting active substances from enzymatic degradation, delivering active substances specifically to the site of infection via ligand modification, and controlling the release behavior of active substances so as to maintain their controlled and therapeutic concentrations. Therefore, the combination of immunotherapy and nanocarriers is expected to overcome the shortcomings of immunotherapy and significantly improve their therapeutic efficacy. In this review, the classification, application, and combination of immunotherapy with nanocarriers in viral diseases are summarized. The challenges and the future prospects of this combination are also discussed.

Keywords: Immune checkpoint inhibitors; Immunotherapy; Nanocarriers; T-cell immunotherapy; Vaccine; Viral diseases.

Graphical abstract

Fig. 1

Mechanisms of actions of three mainly immunotherapies: vaccines, immune checkpoint inhibitors, and cell therapy. The mechanism of vaccine action is that after vaccines containing antigen enters into the body, B cells recognize the antigen, differentiate into plasma cells, and produce specific antibodies, who neutralize the pathogen and prevent it from invading the cell. The mechanism of immune checkpoint inhibitor action is to block inhibitory signals or pathway and enhance T-cell activation and proliferation. The mechanism of action of T-cell therapy is to modify the patient's or donor's T-cells in vitro so that they can specifically recognize the antigen after being infused back and kill the target cells or regulate the immune microenvironment through the secretion of cytokines.

Fig. 2

Four vaccine mechanisms of action. (a) Mechanism of action of attenuated or inactivated vaccines (Domínguez-Andrés et al., 2020). Copyright 2020, adapted with permission from Domínguez-Andrés et al. under the Creative Commons Attribution-Non Commercial License. (b) Mechanism of action of the carrier vaccines (Machhi et al., 2021b). Copyright 2021, adapted with permission from Machhi et al. under the Creative Commons Attribution-Non Commercial License. (c) Mechanism of action of nucleic acid vaccines (DNA vaccines and mRNA vaccines) (Machhi et al., 2021b). Copyright 2021, adapted with permission from Machhi et al. under the Creative Commons Attribution-Non Commercial License. (d) Mechanism of action of the recombinant protein vaccines. Courtesy of the authors (Pollet et al., 2021a). Copyright 2021, adapted with permission from Pollet et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 3

Dual roles of immune checkpoint inhibitors in HIV. On the one hand, they activate HIV expression in latently infected CD4⁺ T cells. On the other hand, they enhance HIV-specific CD8⁺ T-cell function. PD-1: Programmed death-1; PD-L1: Programmed death ligand-1; SHP2: Src homology 2 domain-containing tyrosine phosphatase 2; TCR: T-cell receptor; LCK: lymphocyte-specific protein tyrosine kinase; ZAP-70: zeta-chain-associated protein kinase-70; MHC: major histocompatibility complex (Gubser et al., 2022). Copyright 2022, adapted with permission from Gubser et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 4

Formats of TCR and CAR. Structure of an endogenous or genetically engineered T cell receptor (TCR)-CD3 complex (left). Generations of chimeric antigen receptors (CARs) and their structural differences (right). First-generation (1st Gen) CARs only consist of a single-chain variable fragment (scFV), a hinge domain/spacer, and an intracellular CD3 ζ signaling domain. Second- (2nd Gen) and third-generation (3rd Gen) CARs include one or two costimulatory domains, respectively. Fourth-generation (4th Gen) CARs or T cells redirected for antigen-unrestricted cytokine-initiated killings (TRUCKs) include a transgenic expression cassette for nuclear factor of activated T-cells (NFAT)-mediated transgene expression. Next-generation CARs include a truncated intracellular domain of cytokine receptors with a STAT-binding motif for JAK/STAT signaling (Hiltensperger and Krackhardt, 2023). Copyright 2023, adapted with permission from Hiltensperger and Krackhardt under the Creative Commons Attribution-Non Commercial License.

Fig. 5

The mode of action of BNT162b2 in vivo (Li et al., 2022a). Copyright 2022, adapted with permission from Li et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 6

Cell-specific genome editing with antibody-targeted Cas9-EDVs (Hamilton et al., 2024).Copyright 2024, adapted with permission from Hamilton et al. under the Creative Commons Attribution-Non Commercial License.