Stimuli-Responsive Biomaterials for Vaccines and Immunotherapeutic Applications

Abstract

The immune system is the key target for vaccines and immunotherapeutic approaches aimed at blunting infectious diseases, cancer, autoimmunity, and implant rejection. However, systemwide immunomodulation is undesirable due to the severe side effects that typically accompany such strategies. In order to circumvent these undesired, harmful effects, scientists have turned to tailorable biomaterials that can achieve localized, potent release of immune-modulating agents. Specifically, "stimuli-responsive" biomaterials hold a strong promise for delivery of immunotherapeutic agents to the disease site or disease-relevant tissues with high spatial and temporal accuracy. This review provides an overview of stimuli-responsive biomaterials used for targeted immunomodulation. Stimuli-responsive or "environmentally responsive" materials are customized to specifically react to changes in pH, temperature, enzymes, redox environment, photo-stimulation, molecule-binding, magnetic fields, ultrasound-stimulation, and electric fields. Moreover, the latest generation of this class of materials incorporates elements that allow for response to multiple stimuli. These developments, and other stimuli-responsive materials that are on the horizon, are discussed in the context of controlling immune responses.

Keywords: biomaterials; environmentally‐responsive materials; immunotherapies; stimuli‐responsive materials; vaccines.

Figure 1

Immunological cascade following vaccine injection. In the peripheral tissue, the vaccine gets taken up by resident immature DCs, inducing maturation. B cells with affinity toward the vaccine antigen will begin producing IgM Abs for a temporary initial adaptive response. Mature DCs traffic to the LN where they present the vaccine antigens to select CD4+ and CD8+ T cells. Clonally selected T and B cells undergo rapid proliferation and differentiate into T_fh cells and antigen‐specific plasma cells that form the core of cellular and humoral immunity, respectively. Following this immune response, long‐lasting memory T and B cells remain in the body to provide adaptive immunity against “secondary” exposure from the real pathogen threat.

Figure 2

Overview of the different types of stimuli‐responsive biomaterials for vaccine and immunotherapeutic delivery. The stimulus can come from an external source including electric field, light, magnetic field, and ultrasound signal. Alternatively, intrinsic stimuli found within intracellular compartments or specific tissues can also be used to activate materials. These stimuli include reductive environments, changes in pH, enzymatic cleavage, and temperature change. Certain types of materials respond to stimuli that can be found intrinsically or externally, such as therapies sensitive to multiple stimuli and molecule‐responsive hydrogels that can react to intrinsic or exogenous analytes.

Figure 3

A) Schematic of a pH‐responsive anti‐cancer immunotherapy. Tumor‐specific peptides are loaded into MGlu‐HPG polymer‐modified liposomes, which are taken up by DCs in lymphoid tissues. In response to endosomal/lysosomal acidic pH levels, these particles release the peptide into the cytosol of the DCs via membrane fusion, allowing for MHC class I loading of the peptide and a stronger immune response than if the peptide was administered alone. B,C) Mice were immunized through treatment of OVA‐I solution (open circles), OVA‐I‐loaded liposomes (closed circles), OVA‐II solution (open triangles), OVA‐II‐loaded liposomes (closed triangles), and OVA‐loaded liposomes (closed squares) 14 and 7 days before tumor cell inoculation against OVA antigen. pH‐responsive liposome formulations showed higher resistance to tumor growth and increased survival. Adapted with permission.^{[ 21 ]} Copyright 2016, Multidisciplinary Digital Publishing Institute.

Figure 4

A) Diagram showing a redox‐responsive anti‐cancer immunotherapy consisting of PSSN10 micelles for co‐delivery of the IDO inhibitor NLG919 (NLG) and loaded DOX. Introduction of the micelles into the cytoplasm of tumor cells blocks immune suppressive pathways through NLG and induces cytotoxicity through DOX. B,C) PSSN10 micelles induce an increase in CD4+ and CD8+ T cell proliferation in the presence of tumor cells comparable to free NLG and positive control conditions. D,E) PSSN10 micelles loaded with DOX prevent tumor growth and increase survival rate in a mouse model when compared to free DOX, DOXIL (clinical liposomal form of DOX), unloaded PSSN10, and untreated conditions. Adapted with permission.^{[ 37 ]} Copyright 2017, Nature.

Figure 5

A) Design of a photo‐responsive NP therapy (RA⁺NPs) that allows for triggered release of RA within leukemia cells. B) Leukemia cells were either treated or untreated with RA⁺NPs, then encapsulated in Matrigel and implanted in mice. Light therapy successfully induced differentiation of leukemia cells in the RA⁺NP‐treated group shown by CD11b‐positive populations. Adapted with permission.^{[ 48 ]} Copyright 2017, Nature.

Figure 6

Example of a molecule‐responsive immunotherapy. A) This treatment consists of a vaccine‐loaded PEG hydrogel crosslinked using the protein gyrase B (GyrB) and coumermycin. Upon addition of the antibiotic novobiocin, the GyrB binds to novobiocin, undoing the crosslink and allowing for triggered release of the vaccine. B) Visual confirmation of hydrogel degradation upon novobiocin treatment. C–E) Mice given a primary vaccine then booster vaccine via hydrogel activated by novobiocin showed increased anti‐hepatitis B (HB) Abs, lower percentages of HB‐positive cell, and lower amounts of secreted HB antigen. Adapted with permission.^{[ 56 ]} Copyright 2013, Nature.

Figure 7

Ultrasound‐responsive drug delivery through PSPLBC. A) PSPLBCs release paclitaxel at a faster rate while exposed to ultrasound. B) Disruption of PSPLBCs confirmed through microscopy. C–G) PSPLBs displayed high antitumor efficacy shown through reduced tumor volume, higher % tumor growth inhibition (TGI), lower normalized body weight, and increased percent survival. Adapted with permission.^{[ 63 ]} Copyright 2018, Nature.

Figure 8

Hypothetical multi‐responsive drug delivery system. The proposed particle would respond to MMP2 enzyme cleavage to activate a cell penetrating domain, allowing for entry into the intracellular space of the tumor cell. The drug load would be delivered upon further activation via intracellular reductive activity, low pH, and external electric or ultrasound signals.