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207Challenges and opportunities of nanotechnology in cancer immunotherapy
presentation [30]. Furthermore, this approach boosted both innate (CD80+CD86+DCs)
and adaptive (IFN-γ
+
CD8+T cells) immune responses to eradicate the established tumor
and extend the survival period [30].
PDT combined with adjuvant delivery facilitates amplification of innate immunity by
stimulating type I IFN [31]. In one example, the MOF-based NP was constructed with
tungsten and photosensitizer by coordination bonding. Then, CpG and TLR-9 agonists
were loaded into the NPs to simultaneously implement PDT and deliver CpG into the
endolysosomes [31]. The treatment of the MOF-based NPs with PDT triggered the
emission of tumor-associated antigens and DAMPs, and upregulated the secretion of
IFN-α and IL-6, expanding the population of tumor-infiltrating MHC-II
+
CD80+macrophages and DCs [31]. Additionally, the PDT with an immune checkpoint inhibitor,
PD-L1 antibody, dramatically increased the proportion of tumor-infiltrating CD4
and CD8 + T cells in primary and distant tumors, and also produced IFN-γ, resulting
in superb antitumor immunity [31].
2.3 Photothermal therapy-based ICD
Hyperthermia therapy is a therapy in which heat is administrated into lesion tissues and
has been shown to effective in eradicating the established tumors [1]. A type of hyperthermia therapy is photothermal therapy (PTT), in which temperatures can rise to
40–44°C to exert DNA damage, protein denaturation, and disruption of cell membranes,
leading to cell death [1]. Additionally, febrile heat generation achieved by PTT is capable
of eliciting immune responses by releasing DAMPs including heat shock proteins, strong
immunostimulatory molecules, and recruiting lymphocytes to tumor tissues with elevated temperature [1].
Inorganic NP-based PTT treatments can generate heat locally within tumor sites,
leading to strong ICD induction while compensating for PTT-associated limitations such
as photobleaching, low absorption, and near-infrared (NIR) photothermal conversion
inefficacy [1]. To be exemplified, NIR-based PTT utilizing spiky gold NPs elicited systemic and local antitumor immune responses with enhanced photothermal conversion
effectiveness [32]. The spiky gold NPs were coated with polydopamine to confer both
strong photothermal stability and NIR photothermal efficiency into the system [32].
Also, DOX was loaded into the spiky gold NP systems to perform chemo-PTT in
the tumor [32]. The PTT treatment using the spiky gold NPs locally recruited
tumor-specific CD8
[32]. To synergistically enhance antitumor immunity, the chemo-PTT by DOX-loaded
spiky gold NPs was applied into the tumor, overproducing immunostimulatory molecules, MULT-1 and HSP70, at tumor tissues [32]. It was shown that both the primary
and contralateral tumors were completely ablated whereby the population of
tetramer
+
CD8+T cells and CD107a+NK cells were significantly elevated [32].
+
T lymphocytes into the tumor, thereby retarding tumor growth
+
208 DaeYong Lee et al.
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Furthermore, the combinational therapy possessed the strong capability to abrogate
tumor progression and metastasis in the orthotropic tumor model [32]. In another study
employing gold NPs for PTT, the hybrid of gold NP and phospholipids allowed for ICD
induction into deep tumor tissues, thus potentiating cancer immunotherapy [33] .
Depending on the types of ligands binding to gold NPs and phospholipids, and the molar
ratios of gold NPs to phospholipids, the excitation wavelength of hybrid NP-based systems was determined [33]. The optimal hybrid NPs could be responsive to NIR II ranging from 950 to 1350 nm, thereby facilitating DAMPs release even at deep tumor tissues
[33]. The hybrid gold NPs locally increased the temperature by responding to 1064 nm
laser and stimulated DAMP signals, CRT translocation, and HMGB1 release, even at
deep tumor region (6 mm), thereby activating CD80
+
CD86+DCs into the tumor
and tumor-draining lymph node, and secreting TNF-α, IL-6, and IFN-γ in serum
[33]. The reinforced innate immunity established by NIR II-irradiated PTT recruited
cytotoxic CD4
Tregs (Foxp3
+
and CD8+T cells into the tumor while reducing the proportion of
+
T cell) [33]. Moreover, NIR II PTT treatment with PD-1 antibody pre-
dominantly eliminated tumor proliferation by expanding the proportion of cytotoxic
+
CD8
and CD4+T cells, B cells, and NK cells alongside decreasing that of Tregs [33].
Similarly, hollow copper sulfide (CuS) NPs possessed the immunoadjuvant property
by releasing DAMPs and also tumor-associated antigens to drive robust antitumor immunity [34]. Hollow CuS NPs were coated with chitosan to be soluble in water and also
incorporated CpG to synergistically unleash innate immunity [34]. NIR laser irradiation
rendered chitosan-coated hollow copper NPs promptly destroyed, thus generating heat
at tumor tissues and releasing CpG to highly recruit and stimulate CD80
mature professional DCs elevated the population of IFN-γ
+
CD8+T cells infiltrated in
+
DCs [34]. The
the tumor, and overproduced IL-2 and IFN-γ in serum, thereby abating primary and
distant tumors [34].
Photosensitizer-loaded NPs also imparted PTT characteristics to enhance antitumor
immunity [35]. For instance, PLGA NPs encapsulating indocyanine green (ICG) and
R838 reinvigorated both innate and adaptive immunity to maximize therapeutic effectiveness [35]. The uptake of the PLGA NPs acted as an in situ vaccine by emitting tumorassociated antigens and DAMPs via laser irradiation, which elevated the population of
+
CD80
CD86+DCs and production of IL-12p70, IL-6, and TNF-α [35]. The mature
DCs migrated into draining lymph nodes, thereby establishing systemic antitumor
immune responses [35]. Furthermore, the NP-based PTT treatment with CTLA-4 significantly eradicated tumors in subcutaneous and orthotropic tumor-bearing mouse
models and tremendously prolonged the survival period, which was associated with
recruitment of tumor-infiltrating CD4 + and CD8 + T cells along with diminishment
of Treg activity [35]. In yet another approach, NPs constructed with α-cyclodextrintethered IR820, PEG and CpG endowed light-responsive immunoadjuvant characteristics into the NP-mediated PTT system [36]. The NP-based PTT treatment and CpG
209Challenges and opportunities of nanotechnology in cancer immunotherapy
delivery considerably escalated the portion of CD40+, CD80+, CD86+, and CCR7
DCs and the production of TNF-α with successful CpG delivery into endolysosomes
[36]. Moreover, the established innate immunity dramatically retarded tumor growth
without side effects, which was attributed to the expansion of cytotoxic CD4
+
CD8
T lymphocytes and secretion of IL-2 and IFN-γ [36].
+
and
3. Vaccination with nanotechnology
Vaccination is a straightforward strategy to build up antitumor immunity by
directly delivering antigens to APCs [37]. The strong benefit of vaccination is to generate
both humoral and cellular immunity with minimizing autoimmunity [37]. In contrast,
limited immunogenicity was featured in cancer vaccination, which was associated with
poor uptake efficacy of antigens to APCs [37]. NP-mediated delivery strategies enable
tumor-associated proteins or antigen-encoding genes to be efficiently delivered into
APCs, thus improving the efficacy of vaccination (Fig. 3). Moreover, NP-mediated vaccination combined with adjuvants maximizes the therapeutic efficacy against tumors in
the absence of adverse effects, thereby achieving the meaningful therapeutic index in
+
Fig. 3 The general strategy of NP-based vaccination for boosting anticancer immunity. Peptide, tumor
cell membranes, or genes are encapsulated with liposomes or polymeric NPs to deliver the cargos to
APCs. The uptake of nanovaccines by DCs promoted DC maturation and antigen presentation, thus
generating tumor-specific cytotoxic T cells to specifically kill the tumor.
210 DaeYong Lee et al.
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preclinical models. In this section, we discuss how to design various NPs allowing for
efficient vaccine delivery and how NPs elicit enhanced antitumor immunity.
3.1 Peptide vaccine
Peptide-based cancer vaccines have been intensively investigated due to their safety profile and ease of manufacturing [38]. Despite their prominent advantages, the immunogenicity generated by peptide vaccination remains disappointing, resulting from
inefficient antigen and adjuvant delivery to APCs and draining lymph nodes [38].To
overcome the hurdles of unsatisfactory antitumor immunity, NP-based delivery systems
have been extensively harnessed to obtain the meaningful therapeutic index in preclinical
models by ameliorating the delivery efficacy (Fig. 3) [38]. Also, adjuvant molecules have
been included in NPs to elicit an enhanced antitumor immune response [38]. For one
example, the phospholipid-based nanodiscs incorporating tumor-associated antigens
and CpG successfully delivered antigens and CpG to APCs, and accelerated the drainage
of activated APCs into lymph nodes, thus eliciting tumor-specific antitumor immune
responses [38]. The antigens and CpGs were tethered to the phospholipid-based nanodisc
with disulfide linkage to enable cytosolic delivery [38]. The uptake of peptide vaccine
and CpG by DCs predominantly promoted antigen presentation on DCs surface for
up to 50 h, and the activated DCs triggered the drainage into lymph nodes, thus expanding antigen-specific CD8
metastasis [38]. Moreover, the vaccination with immune checkpoint inhibitors,
CTLA-4, and PD-1 antibodies, eradicated the inoculated tumor and also increased
the survival rate and period by eliciting robust and long-lived T cell immunity [38].
As another example using TLR agonist, peptide-TLR-7/8 agonist conjugate vaccine
self-assembled into an NP and amplified CD8
[39]. The peptide-TLR-7/8 agonist conjugate was constructed with several functional
moieties in this order; charge-modifying group, minimal epiotope degradable linker,
and R838 [39]. This structure facilitated uniformed NP formation and an increase in
loading efficiency of neoantigen, thus recruiting and activating DCs, thereby expanding
tumor-specific and IFN-γ
Similar to using TLR agonist, various NPs stimulating cGAS-STING pathway also elevated the potency of cancer immunotherapy [40,41]. In such an example, polymersome
NPs with cGAMP and neoantigen efficiently induced antigen-specific antitumor
responses by activating the type I IFN pathway [40]. pH- and GSH-responsive
polymersomes escaped from endolysosmes and then were deconstructed to release the
encapsulated cargos in the cytosol of DCs, thus upregulating the costimulatory markers,
CD40 and CD86, MHC-II, and also promoting antigen presentation [40]. Strengthening
innate immunity by the polymersome-based vaccination not only suppressed tumor proliferation but also increased survival, which was associated with the expansion of
+
T cells to suppress not only tumor growth but also lung
+
T cell immunity to tumor antigens
+
CD8+T cells infiltrated into the tumor for up to 35 days [39].
antigen-specific CD8+T cells [40]. As another example, a STING-activating NP generated tumor-specific T cell immunity by stimulating STING pathway by themselves
[41]. Various polymer libraries were synthesized to find the optimal candidate that can
elicit robust antigen-specific Th1 and Th2 responses [41]. Then, the STING-activating
NPs were constructed with the optimal polymer, PC7A, and ovalbumin [41]. Mechanistically, the NPs allowed for cytosolic delivery of tumor antigens to APCs in draining
lymph nodes, thus promoting DCs maturation and antigen presentation and also
upregulating type I IFN signaling pathway [41]. Moreover, the STING NPs inhibited
tumor growth and prolonged survival in tumor-bearing mice by generating robust
and systemic tumor-specific T cell immunity [41]. To reveal the mechanistic behavior
of antitumor immunity, IFNα/βR
and cGAS
tumor-specific CD8
/
mice were used in this study [41]. The specific killing was achieved by
+
T cells in STING
/
, MyD88
gt/gt
/-
TRIF
, and cGAS
/
, MAVS
/
mouse groups, demonstrating
/
STING
gt/gt
that the NPs generated antitumor immunity is dependent on activating the cGASSTING pathway [41].
Interestingly several NPs were formed without encapsulating materials to simplify the
formulation can be capable of electing strong immunogenicity [42]. For example, in one
study only antigens and adjuvants were exploited to self-assemble into an NP using disulfide bridges [42] . Oligolysine segments were labeled to both ends of the neoepitope and
TLR agonist, respectively, and then both the monomers were condensed by forming
disulfide bonds [42]. This approach highly increased not only the uptake efficacy of
DCs but also lymph node targeting in comparison to nonconjugated antigen or adjuvant
[42]. The DCs pulsing with the NPs accelerated rapid deconstruction of them by cleaving
the redox-responsive linkers and then releasing antigens and adjuvants in the cytosol, thus
upregulating the expression of CD40 and CD80, and accelerating proliferating CD8
T cells in vitro [42]. When applied in vivo, the NP-based vaccine significantly allowed
for an upsurge in cytotoxic T cell immune responses, IFN-γ
specific CD62L
CD44+T cells (effector T cells), thereby leading to tumor regression
+
CD8+T cells, antigen-
and extension of the survival period [42]. Another study utilizing nanovaccine without
condensing materials, formed the nanovaccine by cross-linking ovalbumin and thiolated
CpG with disulfide networks [43]. The use of encapsulating agents caused extremely low
loading efficacy of antigen and adjuvant molecules, bringing about limited potency of
cancer immunotherapy [43]. These minimalist NPs considerably upregulated the expression of CD40, CD80, CD83, CD86, and MHC-II compared with unparticulated ovalbumin and CpG treatment, which was associated with the higher uptake efficacy [43].
Additionally, the minimalist NP formation increased the amount and retention of CpG
and ovalbumin accumulated into draining lymph nodes for up to 168 and 96 h, respectively [43]. The in vivo study showed that the minimalist NPs strengthened both innate
and adaptive immunity by activating DCs and proliferating cytotoxic CD4
antigen-specific CD8
+
T cells infiltrated into the tumor [43].
+
T cells and
211Challenges and opportunities of nanotechnology in cancer immunotherapy
,
+
212 DaeYong Lee et al.
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In situ NP formation in serum conditions has also simplified the NP formulation while
showing improved therapeutic effects [44]. Albumin-binding vaccine or adjuvant forming NPs accelerated the delivery of associated payloads into lymph nodes, thus achieving enhanced antitumor immunity [44]. The antigen or adjuvant was modified with
maleimide functionalized Evans blue derivatives that enable the molecular docking to
albumin, simply self-assembling into an NP [44]. The albumin-binding vaccine rendered
antigens and adjuvants to accumulate considerably in draining lymph nodes, which elevated the uptake efficacy of antigens and CpG by resident DCs [44]. The vaccine delivery
into lymph nodes significantly increased the population of antigen-specific CD8
+
IFN-γ
TNF-α+CD8+ T cells, and CD44+CD62LCD8+T cells, thereby signifi-
+
T cells,
cantly suppressing tumor progression [44]. Moreover, the albumin-binding vaccine
combined with PD-1 antibody dramatically reduced the tumor proliferation and also
suppressed lung metastasis, which was associated with a tremendous increase in
antigen-specific CD8
+
T cells and CD44+CD62LT cells [44].
Virus-like particles have been exploited to unleash innate immunity by delivering
peptide-based antigens and self-adjuvantizing viruses to APCs [45]. In one example,
nanoparticles derived from the cowpea mosaic virus suppressed metastatic cancer by
in situ vaccination [45]. Cowpea mosaic virus self-assembled into 30-nm icosahedral
structures containing small and large protein units [45]. The exposure of virus-like
NPs in DCs produced proinflammatory cytokines, IL-1β, TNF-α, MIP1-α, IL-6, and
IL-12p40 as the virus-like NPs are inherently immunogenic [45]. The in vivo treatment
of the virus-like NPs dramatically increased the population of monocytic and granulocytic myeloid-derived suppressor cells MDSCs, tumor-infiltrating neutrophils,
and activated neutrophils, and also highly produced proinflammatory cytokines and
chemokines, thus enabling recruitment of cytotoxic NK cells or T cells into B16F10
tumor [45]. Moreover, lung metastasis generated by metastatic cancers was highly
repressed by downregulating the expression of tyrosinase-related protein 1 mRNA
[45]. The systemic and robust antitumor immunity was established by activation of both
innate and adaptive immunity as demonstrated by IL12
and NOD/SCIDlL2R-γ
/
mice [45]. Additionally, virus-like NP-based vaccination
/
,IFN-γ
/
, Ly6G-depleting,
was also effective in different tumor models, such as colon, breast, and ovarian
cancers [45].
3.2 Tumor cell membrane vaccines
Tumor cell membranes include various tumor-associated antigens that can act as a potential personalized antigen for a vaccine [46]. For this reason, NPs incorporating the components of tumor cell membranes have been intensively developed to simply prepare the
personalized vaccine by isolating various antigens from tumor cells (Fig. 3) [46]. Furthermore, tumor cell membrane NPs provide improved vaccine efficacy in the absence of
cytotoxicity [46]. For example, PEGylated tumor cell membrane NPs ameliorated serum
stability and possessed the capability of lymph node targeting to prolong the systemic circulation and increase immunogenicity [46]. Tumor cell membrane components were
isolated by multiple free thaw lysis cycles, tethered with PEG, and anchored with
cholesterol-CpG into the phospholipids to form PEGylated tumor cell membrane
NPs via extrusion (130 nm) [46]. The NPs accelerated the lymph node draining and
were preferentially taken up by B cells, DCs, and macrophage residents in the lymph
nodes, thus activating antigen-specific CD8
+
T cells to retard tumor growth [46]. Moreover, the NPs administration with PD-1 antibody remarkably expanded the population
of antigen-specific CD8
+
T cells and also extended survival periods without adverse
effects to other organs [46].
The hybrid of tumor cell membranes and polymeric NPs also showed multi-antigenic
antitumor immunity [47]. For instance, CpG-loaded PLGA NPs coated with tumor cell
membranes provided a new strategy of personalized vaccination with increased efficacy
[47]. The NP assembly significantly increased the uptake efficacy of CpG in DCs, mac-
rophages, B cells, granulocytes, and T cells, thus sensitizing the release of IL-12p40 and
IL-6 even at low doses compared with naked CpG treatment [47]. The enhanced uptake
of the NPs allowed DCs activated by upregulating the expression of CD40, CD80,
CD86, and MHC-II on their surface, thereby proliferating tetramer
+
CD8+T cells to
abate tumor growth [47]. Moreover, the combo treatment with CTLA-4 and PD-1 antibodies remarkably suppressed tumor growth and also increased survival [47].
To increase pharmacokinetics in vivo, a hybrid of two different cell membranes was
shown to prolong systemic circulation and increase the probability of inducing lymphatic
drainage without undesirable immune toxicity [48]. In one such study, the hybrid NPs
were formed using red blood cell membranes and tumor cell lysates to increase immunogenicity with high biocompatibility [48]. Increasing the ratio of red blood cell membranes to tumor cell lysate in the hybrid NPs allowed the NPs to be trafficked into the
spleen where various immune cells are dense, thus promoting DCs by higher expression
of CD40, CD80, CD86, and MHC-II [48]. The spleen targeting characteristic of the
hybrid NPs also stimulated NK cells, CD4 + T cells, CD8
+
T cells, and CD19
B cells and triggered the secretion of IFN-α, IL-6, IFN-γ, IL-12p70, and TNF-α
[48]. To maximize the T cell immune responses, the hybrid treatment of the NPs with
PD-1 antibody eliminated the established tumor by expanding the population of tumorinfiltrating T lymphocytes [48]. Another hybrid NP approach, fused cell membranes
derived from DCs and cancer cells imparted therapeutic effects by mimicking tumor cells
and APCs [49]. The hybrid NP activated T cells, CD80
+
CD86+DCs, secretion of TNF-
α, and IL-6, which was attributed to cytokine-cytokine receptor interaction, inflammatory responses, and chemokine signaling [49]. The hybrid NPs induced lymph node
targeting and was retained into lymph nodes for up to 36 h, which activated CD8
T cells and overproduced IFN-γ and IL-6 in vivo [49].
213Challenges and opportunities of nanotechnology in cancer immunotherapy
+
+
214 DaeYong Lee et al.
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To endow APC targeting ability in NP systems, mannose moieties enabling C-type
lectin targeting were conjugated onto cancer membrane-coated NPs [50]. R837-loaded
PLGA NPs as a core material was coated with cancer cell membranes and mannosetagged PEG-phospholipids for specific targeting to DCs [50]. The mannose moiety
on the NPs induced the preferential uptake by DCs via receptor-mediated internalization, and also increased the expression of CD80 and CD86 on DCs and the secretion of
IL-12p40 and TNF-α [50]. Moreover, the active DC targeting elevated the amount of
NPs accumulating into lymph nodes compared with the NPs without mannose, which
activated T cell activation in tumor and secreted IFN-γ, thereby suppressing tumor
proliferation [50].
3.3 Gene vaccine
Gene-based vaccines have been emerging as a promising technology to elicit effective
and long-lasting immunogenicity against tumors [51]. However, gene vaccinations, in
general, have shown poor immunogenicity driven by unsuccessful delivery of genes
to target organelles. For successful gene vaccination, the gene of interest must be protected from enzymatic attacks and safely delivered to the target sites [52]. To address the
limitation of gene-based vaccination, gene delivery systems condense gene molecules
with cationic materials, such as liposomes, dendrimer, polysaccharide, and synthetic
polycations [52].
DNA vaccinations that can produce multiple antigens require gene translocation into
the nucleus a process referred to as transfection [52]. DNA vaccine delivery has been reliant on viral or nonviral delivery systems and/or electroporation for efficient intracellular
delivery [52]. However, each strategy possessed obvious drawbacks such as safety issues
and low transfection effectiveness thus causing difficulty in clinical translation [52]. The
major failure of DNA vaccination is that DNA molecules are often too large to be delivered in the cytosol based on the type of delivery systems employed. Recently, local
administration techniques facilitated more efficient DNA delivery to APCs, thus improving the transfection efficacy [53]. One such technique is a microneedle-assisted delivery
that effectively elicits immunogenicity via local administration into the dermis where
APCs are highly dense [53]. Microneedle-assisted DNA delivery with pH-responsive
copolymers elevated the uptake efficiency of the DNA vaccine [53]. The layer-by-layer
coating strategy using pH-responsive copolymers was first reported in 2013 and showed
improved DNA vaccination efficacy without adverse effects [53]. The layer-by-layer
coating on microneedle with DNA and two different polymers allowed for DNA loading
on microneedle and in situ release of DNA molecules encapsulated with the polymers
[53]. Moreover, in situ polyplexes through the local administration considerably
increased the uptake efficacy of DNA by APCs, thus eventually expanding
antigen-specific CD8
+
T cells [53]. Although this report did not exhibit the DNA
vaccine-mediated cancer immunotherapy, this approach possessed the strong capability
to amplify both innate and adaptive immunity [53]. Similarly, plasmid DNAs encoding
ovalbumin were loaded on microneedle via layer-by-layer coating method using dual
charged copolymers for enhanced cancer immunotherapy [54]. When the microneedle
was applied to the skin, the loading materials and payloads were rapidly dissolved in the
body fluid, and then in situ DNA-loaded polyplexes were formed in the dermis, thus
increasing the uptake efficacy of DNA vaccine by resident DCs [54]. The DC maturation
and antigen presentation on DCs achieved antibody-dependent cell-mediated cytotoxicity and antigen-specific CD8
+
T cells to kill cancer cells [54].
mRNA vaccines has been shown to have strong benefits for cancer immunotherapy.
First, mRNA did not cause potential danger of injections and insertional mutagenesis
[55]. Additionally, mRNA is easily degraded by RNase, and the in vivo pharmacokinetic
can be controlled by various delivery methods [55]. Second, in vivo delivery of condensed
mRNAs into a nanovehicle, triggers rapid uptake and expression of antigens in APCs
[55]. Last, RNA vaccines are easy to manufacture even on a bulk scale with low cost
[55]. RNA vaccination can be facilitated by condensing RNA molecules with cationic
materials to safely deliver the cargo and block the enzymatic attacks [55]. There are several nanotechnology methods that have been shown to harness RNA vaccinations to
induced improved immunogenicity [55].
A sugar moiety derived from the microbial wall is recognized by APCs as a pathogen,
which enables selective targeting to DCs [56]. Thus a recent study, mRNA-loaded layerby-layer NPs were formed with imine bridges between amines from PEI and aldehydes
from mannan (200 nm in hydrodynamic diameter) [56]. The sugar-imprinted mRNAloaded NPs efficiently drained to lymph nodes and escalated the proportion of CD86
DCs over a long term (up to 80 h) compared with the non mRNA containing sugarimprinted silica NPs due to the inherent accelerated lymph node draining [56]. The
uptake of sugar imprinted mRNA-loaded NPs by DCs activated the expression of
CD40 and CD86, and also produced TNF-α, IL-12p40, and IL-6 with minimal cytotoxicity [56]. The activation of DCs significantly expanded the population of CD4
T cells and antigen-specific CD8+T cells and also recruited NK cells into the tumor,
thus leading to the retardation of tumor growth [56]. Similarly, liposome-based RNA
vaccination orchestrated both innate and adaptive immunity by not only stimulating type
I IFN pathway but also achieving systemic targeting of DCs [57]. By varying the ratio of
different phospholipids with mRNA, the optimal liposome-based NPs (200 to 300 nm in
diameter) was formed to deliver mRNA to DCs that are resident in the spleen [57]. The
mRNA delivery to the spleen improved the uptake efficacy of mRNA in macrophages
and DCS but not in NK, B, and T cells. The clearance of RNA-based liposome NPs
within 1 h from circulating blood occurred secondary to the role the spleen plays in
removing blood-borne pathogens, which was the driving rationale for spleen targeting
[57]. The RNA-loaded liposome NPs stimulated the TLR7-mediated type I IFN
215Challenges and opportunities of nanotechnology in cancer immunotherapy
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216 DaeYong Lee et al.
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signaling pathway, resulting in the proliferation of APCs, effector cells, NK cells, B cells,
T cells, and also activating antigen-specific CD8
+
T cells [57]. The establishment of systemic antitumor immunity by RNA delivery not only abolished tumor growth even after
tumor inoculation but also suppressed the tumor growth and metastasis of aggressive
tumors [57]. Moreover, the clinical trial of RNA-loaded liposome NPs produced
dose-dependent increases of IFN-α, T cell priming, and recruited antigen-specific
T cells into the tumor [57].
The hybrid of liposome and polycation for RNA delivery strongly condensed
mRNAs into the core of the NPs and also attained the successful RNA delivery to
DCs for enhanced vaccine efficacy in cancer immunotherapy [58]. mRNA and CpG
molecules were packed with poly(β-aminoester) followed by phospholipids to form
mRNA-loaded lipopolyplexes [58]. The uptake of mRNA-loaded lipopolyplexes by
DCs secreted IFN-β, IL-6, TNF-α, and IL-12, and highly expressed costimulatory
makers CD40, CD86, and MHC-II to promote DC maturation and antigen presentation
[58]. Activating innate immunity recruited cytotoxic CD4+ and CD8+ T cells, thus
preventing tumor growth and metastasis [58].
The delivery of mRNA vaccine with heterocyclic lipids maximized antitumor
immunity by STING-mediated immune cell activation [59]. A library of the lipids
was developed using a one-step three-component reaction to find the optimal lipids
and formulation that could successfully deliver mRNA and stimulate the STING pathway [59]. Top-performing mRNA-loaded liposomes showed improved drainage into
lymph nodes, increased the population of antigen-specific CD8
+
T cells infiltrated into
the tumor, thus activating the regression of the tumor [59]. A second library of the lipids
was screened to evaluate for robust stimulation of antigen-specific T cells and humoral
responses [59]. The mRNA-loaded liposome constructed with heterocyclic aminecontaining lipids remarkably increased the secretion of IFN-γ, the population of IFNγ + CD4+ T cells, and IFN-γ + CD8 + T cells to induce specific tumor killing, and also
boosted antibody production compared to linear amine-containing lipids [59]. Moreover, the mRNA-loaded liposome including heterocyclic amines highly expressed
CD40, CD86, and MHC-II, and also secreted CXCL10 compared to those with linear
amines, which was attributed to STING activation by the binding of the lipid with the
heterocyclic amine to STING, as demonstrated by using Sting/ mouse model [59].
4. Activation of innate immunity
Reinforcing innate immunity is essential for inducing tumor-specific adaptive
immunity in cancer immunotherapy.[60]However, immunosuppressive signaling also activate innate immune cells such that they cannot recognize tumor cells and o shift their phenotype to a proinflammatory mode, thus adversely affecting T cell priming [60].To
awaken innate immunity, immunostimulatory molecules or immunosuppressive inhibitors
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