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Drug Delivery to the Immune System: Immunotherapies and Vaccines 449
chitosan to form nanospheres. Intranasal administration in a
murine RSV infection model induces significant immune responses,
reducing viral titers. Other nanocarriers, like metallic oxide particles
and synthetic polymers, offer the potential for multivalent vaccine
constructs [
systems (BNDDS) have
biomedical research in the past few years. The low immunogenicity,
low toxicity, high tumor targeting, and good biocompatibility of
the biofilm are organically integrated with the flexibility and versatility of the nanocarrier in this new biomimetic platform, which uses
bio-nanotechnology to encapsulate synthetic NPs within a biomimetic membrane. This h
precision tumor therapy
technology approaches, CM-coated
NP surfaces by co-extrusion, freezing-thawing/ultrasound, extrusion/ultrasound, and stirring. Cell membranes of Bacteria [
RBC [
for delivering nano-drugs. This innovative adaptive nano-drug targeting platform can effectively evade immune system surveillance
and clearance, extending the duration of drug circulation in the
body and accomplishing specific delivery of nano-drugs in response
to specific CMs [
Microspheres and lipospheres are utilized for vaccine delivery
due to the intestine’s imperfect barrier to small particles. These
particles serve as carriers for antigens, making them suitable for
controlled-release vaccine purposes. Entrapped antigens within
these particles, when absorbed by M-cells, can induce immunity.
Microscopic particles smaller than 10 μm can swiftly reach the
gut-associated lymphoid tissue (GALT) within an hour when orally
administered. Particle size is important in microparticulate systems,
affecting uptake, release, and immune responses. Small microspheres (<10 μm) deliver antigen quickly to phagocytic cells,
while larger particles require disintegration for uptake. Combining
both sizes can mimic the pulsatile release of antigens, resembling
prime and booster shots in immunization [
polyanhydrides, specifically poly(fumaric-co-sebacic) anhydride,
ranging from 0.5 to 5 μm, were detected within one hour postingestion and remained visible in the Peyer’s patch for up to 24 h
following oral administration [
34
]. Biofilm-mediated biomimetic nano-drug delivery
emerged as a major area of interest for
as promising applications in the field of
[
16]. Further, using biomimetic and nano-
NPs (CM-NPs) encapsulate
12],
13], platelets [21], etc. were used for developing camouflage
56].
38]. Microspheres of
15].
15 Biomimicry
Biomolecules like antibodies, aptamers, peptides, and small molecules coat nanoparticles for specific cell binding. Bioconjugated
NPs have improved pharmacokinetics and distribution but are
recognized as foreign and cleared by the body. To evade clearance,
researchers explore biomimetic approaches. These include synthetic
450 Santanu Pal et al.
16 Micellar Systems
NPs mimicking natural structures and NPs disguised by natural
structures. Both strategies hold promises for improving cancer
therapy with reduced side effects and better-targeted delivery
62]. Using collagen-mimetic peptide-coated polymeric scaffolds
[
to deliver antigen-specific T cells directly to tumors indicates the
potential of these biomaterials to boost immunotherapy effectiveness against solid tumors [
loaded with immunotherapeutics and coated with antibody fragments, were used to target circulating T cells. Delivering these
nanoparticles by binding to endogenous immune cells induced
stronger antitumor effects than direct drug administration [
Micelles, self-aggregated clusters of amphiphilic surfactant molecules used as antigen carriers, encapsulate antigens for delivery.
Methods include oral smallpox vaccine production using micelles,
omega-3 fatty acids, and nanoparticles, while combining a genetically defective vaccinia virus with micelles enhances bioavailability
and immunity. Mucosal cytotoxic T-lymphocyte response induction was noticed with micelles [
lizing micelles in transmucosal delivery demonstrate bioadhesive
properties and effective agent delivery.
58]. Further, polymeric nanoparticles,
49].
3]. Additionally, formulations uti-
17 Hydrogels
Hydrogels are hydrophilic polymeric networks that can absorb
large volumes of water, thereby causing swelling and shrinkage to
enable controlled drug release. They appear to be a promising drug
delivery vehicle because of their porous and compatible nature with
aqueous environments. They can be prepared as microparticles,
nanoparticles, films, slabs, and coatings for various biomedical
needs. Hydrogels that are designed to deliver drugs by diffusionbased method use a matrix or reservoir through mesh or pores of a
hydrogel. The hydrogel membrane producing capsules, spheres, or
slabs is coated on a drug-containing core, which has more concentration in the center of the system that helps in constant drug
release. The matrix system works by the macromolecular pores or
mesh, whereas the reservoir delivery system produces constant
drug release that is time-independent [
hydrogels have been developed that can be used as ocular drug
delivery carriers. These hydrogels can remain in the lacrimal canal,
which offers comfort for the patient being soft with a high swelling
capacity. Whether the punctal-plug system should be used permanently or temporarily will be decided by the material used, silicone
or collagen, respectively. The commonly used hydrogel for
Covalently crosslinked
36].
Drug Delivery to the Immune System: Immunotherapies and Vaccines 451
18 Edible Vaccines
ophthalmic drug delivery systems is polyethylene glycol. The delivery system that causes drug release in response to environmental
changes remains ideal as there is controlled release and side effects
are not seen in off-target sites. In the therapy of diseases like
diabetes and cancer, which are characterized by changes in physiology, particularly in various stages of disease, a sensitive drug delivery system that responds to changes in temperature, pH, glucose
concentration, and ionic strength proves to be
Manipulation of the polymer composition is done to make it
responsive to environmental stimuli [
were designed to degrade in response
in the tumor microenvironment for the sustained release of a
combination of chemotherapy and immunotherapy, demonstrating
that hydrogels can enable high-precision control over the release
kinetics of a combination of therapeutics simultaneously [
Edible vaccines were produced through gene cloning and plant
transformation [
immune responses. Studies have demonstrated the expression of
various antigens in plants, including Streptococcus mutants surface
protein antigen A (SpaA) in tobacco. Animal trials have validated
the antigenicity of plant-derived vaccines, such as hepatitis B surface
antigen from tobacco and lettuce, bacterial diarrhea antigen from
tobacco and potato, Norwalk virus antigen from potato, and footand-mouth disease antigen from Arabidopsis [
14]. They can induce both mucosal and systemic
5]. Injectable hydrogels
to reactive oxygen species
advantageous.
65].
50, 63].
19 Plant-Derived Viruses
The use of plant viruses as carriers for immunogens began with the
discovery that an epitope from foot-and-mouth disease virus
(FMDV) could be expressed in cowpea mosaic virus (CPMV).
Plant viruses, such as cowpea mosaic virus (CPMV), have been
effective carriers for vaccines since 1994. Studies show that plantvirus-derived epitopes from HIV-1, mouse zona pellucida, and
rabies virus induce antibody production in mice, while a plantvirus-derived canine parvovirus epitope provided complete protection in a mink challenge trial [
20 Melt-in Mouth Strips
These strips, designed to dissolve in a child’s mouth, contain
immunogens aimed at protecting against rotavirus infection, a
common cause of severe diarrhea and vomiting in children. The
63].
452 Santanu Pal et al.
current rotavirus vaccine is available in liquid or freeze-dried forms,
requiring refrigeration for transport and storage, which makes it
costly for use in impoverished areas. Additionally, newborns sometimes struggle to consume the liquid vaccine, a challenge less likely
with a strip that adheres to and dissolves on the tongue within a
minute (John Hopkins).
21 Transdermal Delivery
Microneedle-based transdermal delivery systems offer a highly
modular approach for local immunotherapy, exploiting both
biological and remotely triggered stimuli for controlled drug
release. Delivery systems consist of a degradable microneedle
patch, which can painlessly penetrate the skin to reach the immune
cell-rich epidermis to deliver immunotherapeutic. They deliver the
drugs directly to the blood capillary, which facilitates active absorption as these microneedles are short and thin. Considering the drug
type and dose, objective, and targets for use, the fabrication of a
microneedle system has been studied and can be fabricated with
photolithography and laser-mediated techniques. For
manufacturing metal or polymer microneedles, laser-mediated fabrication techniques are commonly used. Moreover, micro stereolithography, 3D printing, and two-photon polymerization are also
used for various microneedle preparations [
patches were designed to degrade and locally deliver anti-PD-1
antibodies in response to the acidic tumor microenvironment,
demonstrating that pH-responsive materials can enable precise
control over the local delivery of immunotherapeutics. Microneedles typically consist of a biodegradable polymer, such as hyaluronic
acid, and are loaded with pH-sensitive nanoparticles that contain
anti-PD-1 [
within the patch, as well as the biocompatibility of the delivery
system, will require further studies to assess clinical translatability.
23]. Microneedle
64]. Evaluation of the bioavailability of therapeutics
22 Delivery of Nucleic Acids
Intracellular immunotherapy delivery systems face hurdles of extracellular and intracellular barriers. Nucleic acids, being negatively
charged, require secondary agents for cellular uptake, with DNA
vaccines facing the additional challenge of crossing cellular and
nuclear membranes for transcription in the nucleus. mRNA, while
requiring only cytosolic penetration for protein translation, faces
rapid degradation without proper modifications or delivery systems
[
32, 45, 71].
nucleic acid-based vaccine and immunotherapy delivery. Nanoparticle systems overcome endosomal entrapment, aiding cytoplasmic
delivery. Materials facilitating endosomal disruption enable nucleic
Recent delivery advancements address challenges in
Drug Delivery to the Immune System: Immunotherapies and Vaccines 453
acid release. Intracellular agonists, limited to local administration
due to toxicity, require protection until reaching the target cells’
cytosol. These innovations promise safer, more effective cancer
immunotherapies with potential clinical impact.
DNA vaccine delivery strategies utilize various physical methods such as tattooing, gene guns, electroporation, ultrasound, and
laser energy (such as electrical, ultrasonic, or laser beams) to induce
a temporary alteration in cell membrane permeability, facilitating
the uptake of immunogenic DNA into cells. Cell membrane permeability returns to normal once the applied energy is removed
after a brief duration.
Gene gun technology facilitates the direct entry of DNA into
cells by bombarding target DNA, as demonstrated in a study comparing intradermal gene gun vaccination to intramuscular injection,
showing higher antigen-specific IgG titers with gene gun immunization due to direct delivery into target cells, despite using a smaller
dose of DNA [
Tattooing serves as a physical method to inject DNA into skin
cells, showing stronger and faster immune responses compared to
intramuscular injection when delivering human papillomavirus type
16 (HPV16) DNA alone [
Electroporation involves applying electrical pulses to create
transient pores in the skin, facilitating DNA entry; it has shown
safety and efficacy in delivering therapeutic DNA vaccines, like
Chron Vac-C, in clinical studies and is being explored for various
cancers in ongoing trials [
Ultrasound disr
poration, and when combined with microbubble echo contrast
agents, it enhances gene transfection efficiency. Although utilized
to deliver proteins, its application in antigen deliver y to dendritic
cells for cancer immunotherapy remains unexplored.
31].
41].
4].
cell membranes to facilitate DNA incor-
upts
23 mRNA Delivery
Dendrimer systems have been utilized to deliver large therapeutic
payloads such as replicon mRNA, which can substantially amplify
the production of encoded protein. This was demonstrated in
various applications, including vaccines for H1N1 influenza, Toxo-
plasma gondii, and Ebola virus [
nanoparticles engineered to transport mRNA vaccines to immune
cells, stimulating robust cytotoxic T-cell responses [
Fur
ther, nanoparticles are designed to adjust their negative charge,
allowing them to selectively target dendritic cells upon systemic
administration. In mouse models of cancer, this delivery method
induced enduring type I interferon-dependent immunity. Furthermore, in a phase I clinical trial involving melanoma patients, it
stimulated strong and specific T-cell responses against
antigens [26].
6]. A collection of ionizable lipid
37] (Fig. 5).
454 Santanu Pal et al.
Fig. 5 Schematic diagram of mRNA vaccine delivery mechanism. (Created by using BIORENDER)
Unlike a conventional bolus vaccination, the implantable scaffolds created a physical environment in vivo that secreted and
presented antigens and stimulatory signals to dendritic cells over
2 weeks [
69].
24 Delivery of Cytokines
25 DC Targeting
The major challenge with the systemic delivery of cytokines is their
rapid clearance, resulting in sub-optimal therapeutic effects. High
concentrations and repeated dosing must be used to offset the
clearance rate, often resulting in toxic and life-threatening side
effects such as systemic inflammation and increased vascular permeability [
cytokines in either lipid or polymeric particles. By packaging the
cytokines in a particle, their half-life can be increased because they
can be released over time and protected from degradation
70]. Implantable polymeric scaffolds were designed to release
[
cytokines to recruit host dendritic cells and present cancer antigens
and danger signals to activate those cells to generate specific and
protective antitumor immunity [
Receptors expressed on the surface of DCs, such as Fc receptors
(FcRs) and C-type lectin receptors (CLRs), can be targeted by
conjugating their respective ligands onto antigen-containing NPs
and MPs, increasing the specificity of delivery to DCs and potentially skewing the subsequent processing of the antigen toward a
Th1 or Th2 response [
exhibit immunostimulatory properties when formed into nanoparticles. Toll-like receptor 4 (TLR4) and nuclear factor κB (NF-κB)
24, 28]. One way to overcome this is by delivering these
1].
19]. Ammonio methacrylate copolymers
Drug Delivery to the Immune System: Immunotherapies and Vaccines 455
have been identified as key players in dendritic cell (DC) activation
in response to nanoparticles containing quaternary ammonium
groups. Further, in mice models with colorectal tumors, injecting
these copolymer nanoparticles around the tumor led to significant
anticancer effects and improved survival rates [
these, nanoparticles formed from polyanhydrides have recently
been investigated for their potential immune-stimulating effects
as drug delivery vehicles [
2, 4, and 5 and results
with DCs [
60].
26 Drug Delivery Targeting T Cells
T cells with surface-conjugated synthetic nanoparticles loaded with
adjuvants enhanced donor cell stimulation and tumor elimination
while minimizing systemic toxicity compared to free adjuvants
administered systemically [
used to target T cells in circulation and reprogram them to express
leukemia-recognizing CAR genes as an alternative to ex vivo CAR
T cell engineering [
presenting cells (aAPCs) have T cell-stimulating molecules conjugated to their surface and therefore mimic APCs [44].
Numerous other cutting-edge techniques, such as CRISPERmediated drug delivery [
adapt to their environment and release drugs in a controlled manner, molecularly imprinted polymers (MIPs) [
[
18], and biomaterials that respond to physical stimuli [29], are
currently being investigated and could be very useful in the future
of drug delivery. Regardless of the advancements in how drugs are
delivered to the immune system, challenges and worries still need to
be addressed. The variations between species must also be considered because they have a substantial impact on different delivery
techniques.
52]. In addition to
27] and are found to stimulate TLRs
in significant IFN-γ release on incubation
57]. A DNA nanoparticle platform was
55]. Further, synthetic artificial antigen-
66], biomaterials that can automatically
68], microfluidics
27 Conclusions
Immunotherapy is revolutionizing the approach to disease treatment and has experienced significant advancements over the past
five years. This progress is highlighted by the clinical approval of
several products, including monoclonal antibodies (mAbs) and
adoptive cell transfer therapies. Notably, immunotherapy is
emerging as one of the most effective strategies for combating
cancer.
Most immunomodulators
often constrained by factors such as large size, poor stability, limited
penetration across physiological barriers, and rapid clearance by the
are biological drugs, but their use is
456 Santanu Pal et al.
reticuloendothelial system. To enhance immunotherapy, high doses
and repeated intravenous injections of these biological drugs are
frequently required, raising safety concerns and significantly reducing patient compliance. Engineering biomaterials for drug delivery
presents a promising approach to improving the delivery of biologics to targeted sites. Numerous drug delivery systems (DDSs) have
shown remarkable immunotherapy efficacy in preclinical stud
ies for
various inflammatory diseases. However, the clinical approval of
DDS-mediated immunotherapy is extremely limited due to potential toxicity, uncertain in vivo behavior, modest scalability,
and
inconvenient dosing routes. The selection of an appropriate DDS
is crucial for successful translation. DDSs with excellent safety
profiles and promising industrial potential are considered optimal
for immunotherapy. These include liposomes or liposome-like
nan
oparticles, degradable polymeric carriers such as PLGA nanoparticles or microspheres, albumin-based nanopar ticles, and cell
carriers like red blood cells. Additionally, the choice of dosing
route is essential for translation, with well-accepted delivery
pathways such as oral, buccal, transdermal, nasal, inhalation, and subcutaneous routes being preferred.
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