Bioactive Materials 6 (2021) 3358–3382

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Bioactive Materials
journal homepage: www.sciencedirect.com/journal/bioactive-materials

Polysaccharide-based nanomedicines for cancer immunotherapy: A review

Yujun Zeng a, 1, Yufan Xiang a, 1, Ruilong Sheng c, Helena Tomás c, João Rodrigues c,
Zhongwei Gu a, b, Hu Zhang d, Qiyong Gong a, b, Kui Luo a, b, *
a
Huaxi MR Research Center (HMRRC), Department of Radiology, Department of Neurosurgery, Functional and Molecular Imaging Key Laboratory of Sichuan Province,
National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China
b
Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China
c
CQM-Centro de Quimica da Madeira, MMRG, Universidade da Madeira, Campus da Penteada, 9000-390, Funchal, Madeira, Portugal
d
Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA, 91711, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Cancer immunotherapy is an effective antitumor approach through activating immune systems to eradicate
Polysaccharides tumors by immunotherapeutics. However, direct administration of “naked” immunotherapeutic agents (such as
Drug delivery systems nucleic acids, cytokines, adjuvants or antigens without delivery vehicles) often results in: (1) an unsatisfactory
Nanomedicines
efficacy due to suboptimal pharmacokinetics; (2) strong toxic and side effects due to low targeting (or off-target)
Cancer immunotherapy
Anticancer efficacy
efficiency. To overcome these shortcomings, a series of polysaccharide-based nanoparticles have been developed
to carry immunotherapeutics to enhance antitumor immune responses with reduced toxicity and side effects.
Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, as
they could interact with immune system to stimulate an enhanced immune response. Their structures offer
versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high
stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent
advances in polysaccharide-based nanomedicines for cancer immunotherapy and propose new perspectives on
the use of polysaccharide-based immunotherapeutics.

1. Introduction new therapeutic targets [1,8,9] or new strategies [10–12] to improve the
efficacy and reduce the side effect of immunotherapy are becoming
Cancer is one of the major diseases with high prevalence, severe attractive in cancer treatment. However, since tumor immunity is a
symptoms and clinical manifestations, unfavorable treatment responses complex process that is not fully understood yet, this emerging immu­
and poor prognosis, thus early diagnosis and effective treatment of notherapy is facing great challenges such as a low targeting efficacy,
cancer are a hotspot that has attracted great attention. Currently, clin­ which would reduce the therapeutic effect of administrated drugs, and
ically practical and effective treatment methods for cancer are focused intrinsic toxicities of immunotherapeutic drugs, which could cause se­
on surgery, chemotherapy, radiotherapy and immunotherapy, which are vere inflammatory and autoimmune diseases [13–15]. In this context,
known as the four pillars of cancer treatment [1]. Among them, many attempts have been made to improve the efficiency/efficacy of
immunotherapy, using human immune systems to treat cancer, blocks cancer immunotherapy while minimizing its side effects [16,17]. One of
certain immune inhibitory checkpoints or pathways [2,3], promote T the most promising approaches is to apply nanomaterials as carriers for
cells killing ability towards tumor cells (i.e. CAR-T therapy) [4,5] and immunotherapeutic agents.
increase innate immune processes by tumor associated macrophages With the rapid growth of nanobiotechnology, nanomaterials have
(TAMs) and natural killer (NK) cells [6,7] to accomplish targeting im­ become more and more clinically applicable for medical treatment [18,
mune suppression or elimination of tumor cells. Some of these immu­ 19]. These nanomaterials with a size of 10–500 nm are able to increase
notherapy strategies have been adopted in clinical practices and the therapeutic efficacy and reduce the toxicity of therapeutic drugs by
demonstrated to be efficacious for cancer diseases. The emergence of encapsulating or conjugating them to form stabilized nanomedicines

Peer review under responsibility of KeAi Communications Co., Ltd.

* Corresponding author. West China Hospital, Sichuan University, Chengdu, 610041, China.
E-mail address: [email protected] (K. Luo).
1
These authors contributed equally.

https://doi.org/10.1016/j.bioactmat.2021.03.008
Received 13 January 2021; Received in revised form 19 February 2021; Accepted 2 March 2021
Available online 18 March 2021
2452-199X/© 2021 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Y. Zeng et al. Bioactive Materials 6 (2021) 3358–3382

[20,21]. These nanomedicines selectively penetrate into tumor tissues for cancer immunotherapy. Thus this review aims to provide an over­
and achieve controlled, efficient and sustained drug release. All these view of various natural polysaccharide-based immunotherapeutic de­
advantages of nanomaterials earn them a space in the arena of cancer livery nanosystems and their cancer immunotherapy applications. The
diseases treatment [22,23]. Studies [24–26] have also demonstrated types of polysaccharides, their delivery nanosystems for immunothera­
that nanomaterials could encapsulate or conjugate immunotherapeutic peutic agents, mechanisms of immune-activation/suppression at the
antigens, adjuvants, genes or antibodies to act as cancer nanovaccines molecular level, as well as their immunotherapeutic effects are
that could improve the efficacy of cancer immunotherapy (Fig. 1) while described and discussed.
reducing toxicity and side effects of these managed drugs. Among these
applied nanomaterials are polysaccharide-based nanosystems. 2. Cancer immunotherapy and potential role of polysaccharides
Because polysaccharides are biocompatible and biodegradable, thus and their derivatives
relatively safe to be applied in medical practices, polysaccharide-based
nanosystems have attracted significant attention as delivery platforms 2.1. Current status of cancer immunotherapy
for the treatment of various diseases [27,28]. The effectiveness of
polysaccharide-based nanomedicines in improving the antitumor ther­ In response to tumor genesis and growth, living bodies can generate
apeutic efficacy has been demonstrated [29,30]. Polysaccharide-based immune responses to eliminate these tumor cells, this immune stimu­
nanoparticles could bypass adenosine triphosphate (ATP) binding latory effect is usually insufficient to eradicate tumor cells completely,
cassette transporters and are internalized into targeting cells such as and tumor tissues continue to grow and metastasize [67–69]. External
microfold cells or CD44 overexpressing tumor cells [31,32]. Since sys­ immunostimulators and immunomodulators are often required to evoke
temic administration of many antitumor drugs such as cisplatin, pacli­ a strong immune reaction that could effectively suppress or eliminate
taxel, and doxorubicin would result in severe side effects like tumor cells [70–72]. . To achieve cancer immunotherapy, currently
hepatotoxicity, nephrotoxicity, neurotoxicity or hypersensitivity re­ there are three major immunity stimulating and enhancing methods for
actions [33,34], this targeting polysaccharide-based nanosystem could cancer, including immune cell therapy, antibody therapy and cytokine
deliver these antitumor drugs only into selective cells to increase their therapy. Immune cell therapy applies genetically modified immune cells
therapeutic efficacy, and reduce the toxicity and the incidence of side to patients to provoke antitumor responses. Chimeric antigen receptor T
effects. In addition, it has also been reported that some polysaccharides (CAR-T) cell therapy has been successfully commercialized for liquid
could stimulate intrinsic antitumor immune systems themselves cancer, and US Food and Drug Administration (FDA) approved CAR-T
[35–37], thus triggering more studies on polysaccharide-based nano­ therapeutics include Breyanzi (Juno Therapeutics), Kymriah™ (Novar­
medicines for cancer immunotherapy. tis) and Yescarta™ (Kite Pharma). By transducing the CAR gene into T
Regarding to this, functional nanomaterials based on chitosan, hy­ cells through viral vectors, CAR-T cells could specifically recognize
aluronic acid (HA), dextran, alginate and other polysaccharides have tumor cells and initiate a strong immune attack towards them [73].
been explored as potential drug delivery platforms for immunothera­ Provenge (Sipuleucel-T) developed by Dendreon Pharmaceuticals is
peutic agents and a few polysaccharides have been acted as immune another approved cellular product for immune cell therapy, and den­
adjuvants themselves for cancer treatment (Tables 1–3). A few review dritic cells (DCs) instead of T cells are used in this product [74].
articles about polysaccharide-based nanomaterials and their biological Monoclonal antibodies are used as immunotherapeutics for antibody
applications or polysaccharide-derived nanomedicines for cancer ther­ therapy. After formation of B-cell and myeloma-cell complexes with
apy have been published in the past years. Two reviews in 2015 [38,39] unique tumor antigens on myeloma cells, the generated monoclonal
and another two in 2018 [40,41] thoroughly discussed the immuno­ antibodies could specifically target tumor cells, resulting in strong tumor
logical responses of polysaccharides and their potential for immuno­ immune stimulation and modulation. This is achieved through
therapy. Another four reviews in the past 6 years on the other hand antibody-dependent cell-mediated cytotoxicity (ADCC) directly towards
provided an overview of how nanomaterials can be beneficial for cancer tumor cells, or by stimulating the complement system to activate the
immunotherapy [24,42–44]. However, none of these reviews have membrane attack complex. FDA approved therapeutics with this
specifically discussed the role of polysaccharide-based nanomedicines mechanism include Rituximab [75], Alemtuzumab [76], Ofatumumab

Fig. 1. Schematic diagram for the use of

nanoparticles to promote cancer immuno­
therapy. Several modifications and formu­
lation strategies of nanoparticles enable
them to deliver antigens or adjuvants with a
higher delivery efficacy and a lower off-
target effect. These therapeutic agent-
loaded nanoparticles could maturate anti­
gen presenting cells like dendritic cells (DCs)
so as to activate tumor killing T cells. Some
nanocomposites could also directly act on T
cells to promote their tumor killing effect.
Reproduced with permission from Ref. [45].
Copyright 2018 Elsevier.

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Table 1
Polysaccharides in the nano-based cancer immunotherapy and their structure and advantages.
Polysaccharide Type Structure Advantages

Chitosan high biodegradability;

excellent biocompatibility;
great bioactivity;
non-toxicity;
pH-responsiveness;
flexibility in constructing nanosystems with different functions.

Hyaluronic acid good cytocompatibility;

good biodegradability;
non-toxicity;
high binding ability for tumor cell receptors including CD44, LYVE-1, RHAMM.

Dextran great biocompatibility;

excellent biodegradability;
non-toxicity;
alternative for PEGylation.

Alginate good cytocompatibility;

good biodegradability;
mucoadhesiveness;
versatile physicochemical properties for the addition of targeting moieties.

LYVE-1: lymphatic vessel endothelial-1 receptor; RHAMM: receptor for hyaluronic acid -mediated motility.

Table 2
Polysaccharide-based nanoparticles as delivery vehicles for cancer immunotherapy.
Polysaccharide Nanomaterial Loaded Agents Therapeutic Effects References
Type

Chitosan polyaniline-glycol-chitosan R848 induce dendritic cell maturation,promote antitumor memory [46]
nanoparticles
chitosan/poly (γ-glutamic acid) interferon-γ induce dendritic cell maturation and macrophage activation [47]
nanoparticles
PEG = MT/PC nanoparticles VEGF-siRNA, PIGF- alter the microenvironment to be anti-tumoral [48]
siRNA
mannose-chitosan-stearic acid ovalbumin and CCR7 induce dendritic cell maturation,increase CD8+ T cell population [49]
nanomicelles pDNA
poly (ethylene glycol)- g-chitosan therapeutic T cells demonstrate a better antitumor efficacy of loaded T cells [50]
hydrogel
Hyaluronic acid HA-gold nanoparticles ovalbumin increase antigen presentation, induce CD8+ T cell proliferation [51]
HA-paclitaxel-marimastat liposomes HA-paclitaxel, alter the tumor microenvironment to suppress tumor growth, metastasis and [52]
marimastat angiogenesis
HA-based hydrogel artificial T cell enhance activation of antitumor CD8+ T cells [53]
stimulating matrix
Dextran pH-sensitive HA-dextran PD-1 antibody, achieve a better therapeutic efficacy of PD-1 antibody [54]
nanoparticles glucose oxidase
spermine modified acetalated nutlin-3a, GM-CSF induce dendritic cell maturation,increase CD8+ T cell population [55]
dextran nanoparticles
dextran-grafted-poly (histidine) BLZ-945 induce M1 macrophages,increase CD8+ T cell population [56]
copolymer micell
porous silicon@acetalated exogenous antigen induce dendritic cell maturation,promote Th-1 cell differentiation [57]
dextran@cancer cell membrane
Alginate mannose-modified alginate ovalbumin increase tumor antigen presentation,induce CD8 T cell proliferation
+
[58]
nanoparticles
Chondroitin chondroitin sulfate-chlorin e6-lipoic docetaxel achieve chemo-sonodynamic combination therapy,induce tumor-associated [59]
sulfate acid nanoplatform antigen release,promote dendritic cell recognition,increase CD8+ T cell
population
Cyclodextrin β-cyclodextrin-based covalent R848 induce M1 macrophages,suppress M2 macrophages [60]
crosslinking nanoparticles

PEG: polyethylene glycol; MT: trimethyl chitosan; PC: citraconic anhydride grafted poly (allylamine hydrochloride); VEGF: vascular endothelial growth factor; PIGF:
placental growth factor; HA: hyaluronic acid; PEI: poly (ethylenimine); GM-CSF: granulocyte-macrophage colony-stimulating factor; PD-L: programmed death ligand.

[77] and Elotuzumab [78]. Another immune modulating mechanism by cells to escape immune elimination. By blocking tumor-related immune
antibodies is to block immune checkpoints. These immune checkpoints checkpoint proteins from binding their receptors or partner proteins,
usually act as error correctors that prevent an overstressed immune immune checkpoint inhibitors could effectively restore the immune
system from harming healthy cells, but could also be utilized by tumor function towards tumor cells and even promote an enhanced immune

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Table 3 immunotherapeutics have a targeting ability, the targeting efficiency is

Polysaccharide-based nanoparticles with intrinsic immunomodulatory effects in usually not quite high enough, leading to a decreased therapeutic effi­
cancer immunotherapy. cacy and increased side effects [95–97].
Polysaccharide Nanomaterial Therapeutic References
Type Effects 2.2. Potential of polysaccharides and their derivatives for immune
Chitosan chitosan/poly (γ-glutamic stimulate M1 [61] modulation
acid) nanoparticles macrophages,
promote dendritic New immunotherapeutics are being developed to achieve a safer and
cell maturation
more effective cancer immunotherapy. Among these immunother­
induce pro-
inflammatory apuetics, polysaccharides-based therapeutics stand out due to their
cytokines, easiness of production, preferable biocompatibility and most impor­
increase tantly, the effectiveness of modulating immune responses [98,99]. It has
antitumor T cell
been discovered that polysaccharides could interact with the immune
population
chitosan conjugated green activate both Th1 [62]
system to change the chemotactic factor and cytokine releasing status,
copper oxide nanoparticles and Th2 cells, maintain the balance between T helper (Th) type 1 and 2 cells, inhibit
induce pro- the expression of matrix metalloproteinase (MMP) and suppress the
inflammatory formation of tumor vessels [100]. Recent studies have also demon­
cytokines,
strated that polysaccharides, especially botanical polysaccharides, could
expand antitumor
T cell population effectively induce the proliferation of macrophages and promote their
Dextran dextran-coated spermine promote dendritic [63] phagocytic function towards foreign materials and tumor cells [101,
functionalized dextran cell maturation, 102]. Polysaccharides and their derivatives that are produced from
nanoparticles stimulate M1
Lepidium meyenii or masson pine pollen could stimulate the release of
macrophage,
induce pro-
pro-inflammatory cytokines/chemokines, reactive oxygen species (ROS)
inflammatory and nitric oxide (NO) from macrophages to result in an enhanced tumor
cytokines immune [103,104]. In addition, it has been reported that poly­
Herbal extract gold-Ganoderma lucidum induce dendritic [64] saccharides from Dendrobium devonianum, Atractylodis macrocephalae
polysaccharide cell maturation,
Koidz and Astragalus could increase the proliferation of B cells and T
nanoparticles increase
antitumor T cells cells, promote their differentiation into plasma cells and effector T cells,
promote and induce their production of lymphocytic antibodies and cytokines to
antitumor create a strong tumor immune reaction [105–107]. Studies also sug­
memory gested that polysaccharides from Rehmannia glutinosa and Pleurotus
Ganoderma lucidum increase [65]
polysaccharide-conjugated radiotherapy
ferulae have the ability to interact with NK cells and DCs to boost innate
bismuth sulfide sensitivity, immune responses and regulate the adaptive responses [108–111]. Most
nanoparticles promote dendritic of these immune stimulating effects from polysaccharides are believed
cell maturation, to be realized through their recognition by receptors on immune cells
induce pro-
like scavenger receptors and toll-like receptors (TLRs), members of the
inflammatory
cytokines pattern recognition receptor (PRR) family [112–114]. Besides, poly­
induce CD8+ T saccharides can also be recognized by mannose receptors and Dctin-1,
cell proliferation one of C-type lectin receptors (CLRs) that cooperate with TLRs in the
Lepidium meyenii Walpers increase M1 [66] initial inflammatory response, and the recognition could induce
derived cationic macrophages
polysaccharide
CD4+/CD8+ T cells-mediated adaptive Th17 and Tc17 immunities
[115]. The recognition of polysaccharides by cell surface receptors may
further trigger immune-enhancing pathways like NF-κB and p38
response. A cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) mitogen-activated protein kinase (MAPK) signaling pathways
blocker, ipilimumab, was the first immune checkpoint inhibitor [116–118], leading to the induction of immune-related gene transcrip­
approved by FDA for the treatment of cancer [79]. Due to safety con­ tion, which results in the activation of immune cells and initiation of
cerns [80], programmed cell death protein 1 (PD-1) and programmed producing pro-inflammatory cytokines.
death-ligand 1 (PD-L1) become the most safe checkpoints for new Although the effectiveness of immune stimulation by poly­
immunotherapeutic drugs. Nivolumab [81], Pembrolizumab [82], Ate­ saccharides has been well-accepted, the relationship between poly­
zolizumab [83], Avelumab [84], Durvalumab [85] and Cemiplimab saccharide structures and their immune stimulation function has not
[86] have been approved by FDA for the inhibition of PD-1 or PD-L1 to been unveiled. Studies have suggested that the conformation, molecular
promote the immunotherapy of cancer. Cytokine therapy utilizes the weight, presence of certain functional groups and branching degree of
immunomodulatory function of cytokines. Cytokines, such as in­ polysaccharides may be correlated with their immune stimulating per­
terferons (IFNs) and interleukins (ILs, especially IL-2, IL-6, IL-12 and formances [38]. It has been indicated that the conformation of poly­
IL-15), are reported to be closely associated with antitumor immune saccharides could affect their interactions towards immune molecules or
responses, thus by administrating these cytokines externally, an cells, thus influencing their immunomodulatory effects [119,120]. Mo­
enhanced antitumor activity could be achieved [87–91]. Currently, lecular weight, as an important structural parameter for structur­
FDA-approved cytokines for cancer immunotherapy include IFN-α [92] e–function relationships, is also believed to significantly affect the
and IL-2 [93]. IFN-γ has also been reported to be effective for cancer immunological response of polysaccharides. For example,
immunotherapy in vitro and in vivo [94], but no commercial IFN-γ drug high-molecular-weight HA polymers have a very different immune
has been approved. response from smaller-molecular-weight HA oligomers [38]. More
Although the concept of cancer immunotherapy has been promoted studies are needed to uncover this structure–function relationship.
for decades and immunotherapeutics have been approved for clinical Furthermore, sulfation, carboxymethylation or phosphorylation of sur­
practice, challenges still remain in this field and improvements are still face groups on polysaccharides and the addition of components like
actively pursued. One of the most important challenging issues is the off- selenium have been reported to enhance or suppress the immune re­
target effect. Despite the fact that most of the approved sponses of polysaccharides [40,121,122]. Sulfation of polysaccharide

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was reported to enhance the phagocytosis activity of macrophages and [145]. Due to its versatility to form nanosystems with different func­
induce the release of pro-inflammatory cytokines [123]. This has been tions, along with its excellent biocompatibility, non-toxicity and
confirmed by in vitro and in vivo experiments [124,125]. Phosphoryla­ mucoadhesiveness for enhancing drug absorption and bioavailability,
tion of polysaccharide surface groups is believed to enhance the prolif­ chitosan is usually considered to be one of the most widely used poly­
eration of lymphocytes, induce the maturation of B cells and increase the saccharides in the nanomedicine field [146–148]. The generated
ability of their antigen presentation and cytokines secretion, thus chitosan-based nanomedicines usually have high biodegradability,
effectively regulating the systemic immune function [126]. The addition excellent biocompatibility, bioactivity and polycationicity [149–151],
of selenium could promote lymphocyte proliferation, induce or promote thus they are effective nanocarriers for drug delivery applications
lymphocytes to produce interferon, IL-2 and other soluble immune [152–154]. As will be presented next, only recently, there are several
factors, which is supported by the study of Qin et al. [127]. However, the studies attempting to use chitosan-based nanomaterials to deliver
influence of carboxymethylation of polysaccharides on immunomodu­ immunotherapeutic agents for cancer treatment.
lation is quite dependent on the structure of the original poly­
saccharides. Studies have demonstrated that carboxymethylation of 3.1. Chitosan-based nanosystems to deliver adjuvants
herbal polysaccharides from Astragalus mongholicus or the seeds of
Plantago asiatica L. could effectively enhance the immune activity of One of the most promising immunotherapeutic agents, which have
immune cells such as DCs [109,128], while carboxymethylation of been developed and also approved for clinical trials, are molecular ad­
herbal polysaccharides from Ganoderma atrum [129] or Dendrobium juvants [155]. They enhance the efficiency of antigen delivery and
candidum [40] had not enhanced the immune activity or had an induce their recognition by antigen presenting cells (APC). By increasing
immunosuppressive effect. Therefore, structure modifications of poly­ immunogenicity, adjuvants could stimulate the anti-tumor immunity
saccharides need to be rationally designed for favorable immunomod­ and decrease the immune evasion of tumor cells. It has been reported
ulatory effects. that a few adjuvants could induce the expression of CD80 and CD86 on
When polysaccharides are applied as a drug delivery platform, the the surface of DCs, which are the markers of DC maturation. These
loaded immunotherapeutics should be aligned with the structure of their maturated DCs would increase their production of pro-inflammatory
delivery platforms. For example, it was reported that positively-charged cytokines that could boost downstream antitumor immune responses
particles for gene delivery have higher transfection efficiencies [156,157]. However, some adjuvants exhibit intrinsic immunogenicity
compared with neutral or negatively-charged delivery vectors [130]. thus they could be degraded before they achieve the modulatory effects
Therefore, chitosan, with a positive-charge property, has been applied to towards DCs. Some adjuvants could systemically modulate the immune
deliver nucleic acids for cancer immunotherapy more often than other environment besides the maturation of DC, which would cause severe
polysaccharides like HA or dextran or alginate, which are negatively side effects [158,159]. How to effectively and selectively deliver adju­
charged. The surface charge of polysaccharide-based nanomaterials vants into DCs is crucial for adjuvant-based cancer immunotherapy. In
should be considered when they are used to load polypeptide-based or this regard, Chen et al. [46] developed nanomedicines with hydrophilic
protein-based antigens with different charges [131,132]. In addition, glycol-chitosan (GCS) as the backbone and conjugated hydrophobic
hydrophilicity or hydrophobicity of polysaccharides nanomaterials also polyaniline (PANI) with GCS to address the above challenge. These
plays a significant role in effectively loading and releasing immuno­ PANI-GCS nanomaterials were utilized as a biocompatible and water
therapeutics [133,134]. By taking the above factors and commercial soluble nanocarrier for successful delivery of resiquimod (R848), a
availability into consideration, chitosan, hyaluronic acid, dextran and TLR-7/8 agonist which has already been approved by FDA as an
alginate are the most widely applied polysaccharides in the immuno­ immunomodulatory agent for cancer clinical trials [160]. The
therapy. The structures of these polysaccharides are shown in Table 1 PANI-GCS-R848 nanomedicines were found to promote their maturation
and their application as delivery vectors in cancer immunotherapy is selectivity towards DCs (Fig. 2a). The PANI moiety attached to the GCS
summarized in Table 2. Although chitosan, hyaluronic acid, dextran and backbone had excellent light absorption and great photothermal effect,
alginate without any modification are generally believed to have low/no while hydrophobic interaction and π-π stacking of PANI/R848 could
immunogenicity, their derivatives are often reported to demonstrate enhance the loading efficiency of R848. These maturated DCs would
excellent immunomodulatory effects with enhanced immune responses secrete several pro-inflammatory cytokines such as IL-6 and tumor ne­
[40,135–138] as shown in Table 3. Thus, these polysaccharides have crosis factor (TNF)-α, which are actively involved in the immunity
been widely employed to incorporate immunotherapeutic agents to mediation and modulation of anti-tumor effects [161], in a considerable
prepare novel nanomedicines for cancer immunotherapy. Most of these amount and for a prolonged time. A long-lasting memory of systemic
polysaccharides-based nanomedicines could act as antitumor vaccines. anti-tumor responses was also observed from their experiments. These
They are distributed in lymph nodes after subcutaneous injection and R848-loaded chitosan-based nanomedicines could be further systemat­
target tumor-associated immune cells to achieve synergetic and ically examined as in situ vaccines for cancer treatment. Another TLR-9
enhanced cancer immunotherapy [41,139,140]. Some agonist CpG oligonucleotide has also drawn attention recently due to its
polysaccharides-based nanomedicines, especially HA-based nano­ excellent capability of maturating DCs [162,163].
medicines with their binding ability towards CD44-expressing cells, Nevertheless, the majority of oligonucleotides was reported to be
could also target the tumor microenvironment to make tumor cells more degraded by deoxyribonuclease (DNase) and excreted by the kidney
vulnerable to immune responses [141,142]. rapidly after administration through injection subcutaneously, which
significantly reduced their circulating time and the therapeutic dose,
3. Chitosan-based nanomedicines thus limiting their therapeutic applications [165,166]. To overcome this
issue, chlorin e6 (Ce6)-doped-azobenzene-glycol chitosan (GC)-PEG-­
Chitosan is a positively-charged natural polysaccharide that is modified mesoporous silica nanoparticles (CAGE) were introduced to
derived from deacetylation of chitin, which is abundantly found in fungi deliver CpG oligonucleotides (Fig. 2b) [164]. These CAGE nanoparticles
cell walls and anthropods shells [143,144]. Chitosan is acid-soluble due were hypoxia-responsive and could protect the loaded oligonucleotide
to the amino groups of it possess an excellent protonation ability at a low from biodegradation or renal clearance, thus improving the intracellular
pH environment, which could lead to preferred “pH-responsive man­ uptake efficacy as well as the targeting efficiency of adjuvants and
ners” in acidic subcellular organelles such as endosomes and lysosomes. photosensitizers to DCs. Since the delivered agents could induce the
It had been reported that chitosan and their oligomers could interact generation of immunogenic debris, promote the maturation of DCs, help
with negatively-charged agents such as tripolyphosphate (TPP) to form a exposure of tumor-associated antigens of tumor cells and enhance the
series of nanosystems with various particle sizes and zeta potentials antigen presenting effect of DCs, an increased intracellular uptake and

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Fig. 2. Preparation of chitosan-based nanomedicines (a: R848@NPs; b: GC-CAGE complex) and their therapeutic application on cancer immunotherapy. The use of
these chitosan-based nanosystems to carry immunotherapeutic agents could significant inhibit the tumor growth (c) thus beneficial for both primary and metastatic
tumor treatment (d). Reproduced with permission from Refs. [46,164]. Copyright 2019 Elsevier and 2018 American Chemical Society, respectively.

targeting efficiency would result in a higher DC maturation rate and a 3.2. Chitosan-based nanosystems to deliver cytokines
greater antigen presenting efficiency, reduce the incidence of tumor
evasion and promote a stronger immune response towards tumor cells. Another promising type of agents that are involved in immuno­
In addition to protective and targeting delivery of the loaded adjuvants, therapy of cancer is cytokines. Cytokines could direct proliferation,
these chitosan-based nanomedicines could perform synergistically with activation and differentiation of the downstream immune cells and
photodynamic therapy to achieve multi-modality therapy of cancer. The induce them to express and secrete substances demonstrating tumor
PANI-GCS-R848 nanomedicines were reported to induce inhibition of suppression or killing effects [167,168]. Chitosan-based nanoparticles
tumor cell growth due to photo-generated hyperthermia and the have been explored for delivery of certain cytokines to achieve a better
immunoregulative effect from R848 [46], which enhanced the efficacy outcome of immunotherapy. Previous studies had demonstrated chito­
of these chitosan-based nanomedicines for cancer treatment. san/poly (γ-glutamic acid) nanosystems and applied them to deliver
therapeutic agents such as hormones and chemokines [169–171], and
evaluated the maturation efficacy of their intrinsic macrophages and
DCs [172]. Recently these chitosan/poly (γ-glutamic acid) nanosystems

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had been further evaluated as a drug delivering platform to achieve More importantly, they noticed that these siRNA-loaded nanomedicines
targeting delivery of IFN-γ to DCs and macrophages [47]. They have could promote differentiation of T cells towards Th1 and suppress their
discovered that these IFN-γ-loaded chitosan/poly (γ-glutamic acid) differentiation towards regulatory T cells (Tregs). Since Th1 is one of
nanoparticles (IFN-γ-Ch/γ-PGA NPs) could increase the expression of main anti-tumor functioning T lymphocytes and the induction of Tregs is
CD40, CD83 and CD86 of DCs and human leukocyte antigen-DR one of the mechanisms for immunosuppression and immune evasion of
(HLA-DR), and the secretion of pro-inflammatory cytokines such as tumor cells [183–185], these siRNA-loaded PEG-chitosan-lactate nano­
IL-6, IL-12/IL-23 (p40) and TNF-α [173]. Administration of these medicines could effectively stimulate anti-tumor immune responses
IFN-γ-Ch/γ-PGA NPs resulted in promotion of maturation and activation selectively at the tumor sites without systemic injection of A2AR an­
of DCs. They also had a high internalization efficiency towards macro­ tagonists that may cause unwanted side effects through induction of Th1
phages, thus they activated certain monocyte-macrophage lineages and and suppression of Tregs. As the induction of antitumor immune re­
increased the release of pro-inflammatory cytokines so as to enhance the sponses requires activation or inhibition of different receptors or
immune stimulatory effect [174,175]. These Ch/γ-PGA NPs could not signaling pathways, administration of multi-type nucleic acids targeting
only protect the cytokines from degradation and retain their bio­ at different pathways may have the potential to further enhance the
functions, but also deliver therapeutic agents towards targeting macro­ efficacy of cancer immunotherapy [186,187]. However, how to achieve
phages and DCs so as to increase the therapeutic efficacy and decrease co-delivery of different nucleic acids to targeting sites and simulta­
their side effects, which provided a new and effective way to promote neously maintain their inherent bioactivity, is still a great challenge.
cytokine-based cancer immunotherapy. While Ch/γ-PGA NPs worked Recently, chitosan-based nanomaterials have been used to address this
well for delivery of IFN-γ, another study applied chitosan-modified se­ challenge. A novel nanomaterial composing of polyethylene glycol and
lenium nanoparticles to successfully deliver TNF–α, another critical mannose-modified trimethyl chitosan (PEG = MT) and citraconic an­
pro-inflammatory cytokine that could induce and activate downstream hydride grafted poly (allylamine hydrochloride) (PC) was synthesized
effectors for antitumor responses [176]. According to in vitro and in vivo for co-delivery of both vascular endothelial growth factor (VEGF) siRNA
results, these nanoparticles could achieve stable and sustained release of (siVEGF) and placental growth factor (PIGF) siRNA (siPIGF) [48]. These
the loaded TNF-α derived polypeptides (P16) so that they could effec­ serum stable and “smart” pH-sensitive nanomedicines could accumulate
tively suppress proliferation of several types of tumor cells, while in tumor tissues and effectively target tumor-associated macrophages
demonstrated no toxic effect against normal non-tumorigenic epithelial and breast cancer cells without damages to other normal cells. Two
cells. Since P16 was previously reported to exhibit a limited therapeutic released siRNAs would synergize in effectively silencing certain genes,
efficacy due to its high renal clearance and hepatic metabolic rate [177], thus inhibiting proliferation of cancer cells and also changing the
this nanoparticle-based delivery could prolong the circulating time of microenvironment of tumor tissues from pro-oncogenic to anti-tumoral.
P16 and thus yielded a higher efficacy to affect the p38 MAPK/JNK It is worth noting that, by co-delivery of two siRNAs using this nano­
signaling pathway, the G0/G1 cell cycle arrest, and the material, distant metastasis of the original tumor cells to lungs has also
caspase-dependent apoptosis pathway so as to suppress proliferation been significantly inhibited. Chitosan-based nanomaterials were also
and also induce apoptosis of tumor cells. It has been suggested that prepared to achieve co-delivery of not only nucleic acids, but a mixture
combination of multiple types of cytokines could achieve a synergistic of nucleic acids and therapeutic agents. For example, chitosan oligomers
immune effect, resulting in a better antitumor efficacy [168]. were mixed with TNF-α or CD40L plasmids to form DNA-loaded nano­
Chitosan-based nanosystems could be employed to deliver other types of complexes [188]. Mammary carcinoma 4T1 cells were in vitro trans­
cytokines or co-deliver multiple types of cytokines to enhance cancer fected with these chitosan-based nanomedicines and these transfected
immunotherapy. 4T1 cells could effectively induce the maturation of DCs and signifi­
cantly increase the amount of pro-inflammatory cytokines secreted by
3.3. Chitosan-based nanosystems to deliver nucleic acids DCs. This immune process would further stimulate the proliferation of T
cells, enhance the production of IFN-γ while suppressing the release of
Apart from the delivery of the above discussed immunotherapeutic IL-4 of these T cells, thus playing a more active role in the tumor immune
agents, chitosan-based nanomaterials are also explored to deliver response.
nucleic acid (gene) for modulating immune responses for eradicating All the above studies indicated that the use of chitosan-based
cancer. The immune responsive nucleic acid (DNA or RNA) could nanocomplexes could protect the integrity and increase the therapeu­
modify DCs or T cells genetically so that these genetically modified tic efficacy of the loaded plasmids, while exhibiting low/no toxicity to
immune cells could enhance their responses to tumor antigens normal cells. Since chitosan-based nanomaterials could also achieve
[178–180]. targeting endocytosis to avoid the recognition of P-glycoproteins [189],
In a recent study, chitosan-coated selenium nanoparticles were pre­ using this nanomaterial to deliver therapeutic agents may also help the
pared and conjugated with a folic acid-targeting moiety to deliver suppression of drug resistance. In addition to co-delivering cytokines
Photinus pyralis firefly luciferase (Fluc) mRNA [181]. These nano­ and plasmids, these chitosan-based nanoparticles were applied to
particles could efficiently bind and stabilize mRNA, protect them from deliver CD40, inducible co-stimulator ligand (ICOSL), and EGFP-N1
degradation from RNase and selectively deliver them into cancer cells. mRNA to DCs to enhance the antitumor effects of these immune cells
More importantly, these nanomedicines possessed low cytotoxicity to [190]. These mRNA-loaded chitosan nanocomplexes could induce a
normal cells but displayed much higher cytotoxicity to colorectal car­ higher expression of CD40, ICOSL, CD86, and MHC-II on the surface of
cinoma (Caco-2) and colon carcinoma (HT-29) cancer cells, which DCs, thus assisting in their maturation. The maturated DCs could pro­
significantly reduced the incidence of side effects, promoting a safer and mote the secretion of pro-inflammatory cytokines, which would further
effective way to deliver nucleic acids for cancer immunotherapy. promote the proliferation of T cells and induction of Th1 differentiation
However, the experimental data from these chitosan-coated nano­ that could strengthen the anti-tumor immunity [191]. These
medicines were obtained at the cellular level and further evaluation of chitosan-based nanoparticles have demonstrated a high efficacy to
their in vivo delivery efficacy is still needed. Ali et al. [182] prepared deliver not only DNA or RNA, but also other different therapeutic agents
PEG-chitosan-lactate nanoparticles to load therapeutic siRNAs. In vitro to achieve synergistic effects between them and promote combinational
experiments demonstrated that these siRNA-loaded nanomedicines were therapy towards cancer treatment.
low toxic, stable in serum and could achieve controllable release of the
loaded siRNA within 60 h. Cellular and animal studies showed that these
PEG-chitosan-lactate nanomedicines could selectively target T cells at
the tumor site, enhanced T cell proliferation and reduced apoptosis.

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3.4. Chitosan-based nanosystems to deliver other types of cervical cancer [208], and breast cancer [209]. However, in vivo and
immunotherapeutic agents clinical trials are highly demanded to confirm these immune enhancing
effects towards cancer treatment. In addition to delivery of therapeutic
In addition to adjuvants, cytokines, and nucleic acids, there are other drugs, chitosan-based polymers have also the potential to deliver living
types of therapeutic drugs that could achieve the immunomodulatory cells to achieve immunotherapy of cancer. Tsao et al. [50]designed poly
effect for cancer treatment. Generally, cancer cells express a higher (ethylene glycol)-g-chitosan hydrogel to carry therapeutic T cells. They
amount of tumor-associated antigens than normal cells, and some of found that the chitosan-based hydrogels were compatible with T cells
these antigens are exclusively identified on tumor cells: tumor-specific and could retain their anti-tumor function. After loading T cells in the
antigens or neo-antigens [192,193]. But these antigens on tumor cells chitosan-based hydrogel, these T cells displayed a better therapeutic
are usually not directly recognized by the immune system due to im­ efficacy compared with controlled groups. It might be caused by the fact
mune evasion of tumor cells [194], thus delivery of exogenous that these hydrogels could provide an optimal pore size to enable better
tumor-associated antigens into cancer cells is a feasible approach for invasion of T cells [210]. This study provides a new way of delivering T
anti-tumor immune stimulation. However, administration of these cells for immunotherapy of cancer but this method is still in need of
“naked” antigens alone would result in their premature degradation in further studies, for example, to unmasking the mechanism of action for
the body fluid before they reach tumor sites. Concerns also arise that better efficacy.
non-targeting administration of these antigens would cause undesirable
systemic inflammatory reactions. Thus protective and selectively tar­ 3.5. The immunomodulatory effect of chitosan-based nanosystems
geting delivery platforms are needed to promote antigen-based cancer
immunotherapy [195,196]. Windberg et al. [197] applied poly­ Apart from delivery of immunotherapeutic agents, previous studies
peptide/Chit2DC (chitosan-deoxycholate) micelles to deliver an exoge­ have demonstrated that chitosan-based nanosystems without thera­
nous MAGE-3 polypeptide antigen, which is a CD4+ and CD8+ T cell peutic drugs could also have immunomodulatory properties. It has been
epitope. In the animal model study, they demonstrated that these reported that chitosan-based nanosystems could significantly increase
nanoscale vaccines could induce the immune response towards MAGE-3 the secretion of IFN-γ by Th1 cells and stimulate the cell-mediated im­
expressing tumor cells by increasing differentiation of cytotoxic T munity. Compared to chitosan oligosaccharides, the chitosan nano­
lymphocyte (CTL) against MAGE-3 antigens, which would inhibit the particles showed an enhanced immunomodulatory effect (1.2–1.5-fold),
growth of tumor cells and promote apoptosis in tumor tissues. Another indicating the immunomodulatory effect could be tuned by aggregation
mannose-chitosan-stearic acid nanomicelles have also been developed of nanoparticles [211]. Wardani et al. [212] also applied chitosan
to deliver ovalbumin and CCR7 pDNA [49]. After these cargos-loaded nanoparticles to animal models and concluded that these nanoparticles
nanomaterials were applied to the tumor-bearing mice, they could could effectively stimulate immune responses and have a therapeutic
effectively promote the maturation of DCs and also induce the migration potential for immunotherapy.
of these immune cells to lymph nodes to generate an enhanced antigen A further study [61] examined the detailed tumor immunity induced
presenting process. A significant increase in the population of antitumor by chitosan-based nanosystems and it was found that they could stim­
cytotoxic CD8+ T cells had been witnessed. Both novel chitosan-based ulate macrophages towards a pro-inflammatory profile, expressing less
nanomaterials have achieved safe and effective delivery of exogenous CD163 molecules and producing more secretory IL-12 p40 and TNF-α. In
antigens, and demonstrated the feasibility of applying tumor-associated addition, they discovered that these chitosan-based nanoparticles could
antigens in cancer immunotherapy. It is worth noting that a patent [198] stimulate DCs, increase their expression of co-stimulatory molecules and
has already been applied in which chitosan nanoparticles were utilized HLA-DR, promote the secretion of pro-inflammatory cytokines that
to deliver antigens. Their patent document demonstrated that the could stimulate antitumor effectors, and induced differentiation and
chitosan-antigen complex nanoparticles possessed superior immune activation of CD4+ and CD8+ T cells so as to modulate the whole tumor
response-stimulating effects and could be used in therapeutic immune response. Their in vivo study also confirmed these immuno­
vaccination. modulatory results evidenced by inhibited growth of tumors and coun­
Rajaei et al. studied the immunoregulatory effect of arteether teracted invasion of cancer cells. A more recent study [62] also achieved
delivered by folic acid-chitosan-Fe3O4 composite nanoparticles [199]. a similar immunostimulatory effect by application of chitosan-coated
These arteether-loaded chitosan-based nanomedicines were applied to copper oxide nanoparticles. In both in vitro study on breast cancer
4T1 cell lines and breast cancer-bearing mice and significant augmen­ cells (MCF-7) and cervical cancer cells (HeLa) and in vivo study on breast
tation in the production of cytokines IFN-γ and IL-4 was demonstrated. cancer (4 T1 cells induced) bearing mice, a great therapeutic efficacy of
Since IFN-γ and IL-4 could induce and activate downstream antitumor this nanomaterial has been demonstrated as it activated both Th1 and
effectors, the growth of 4T1 tumor cells was greatly inhibited and the Th2 cells, increased the production of pro-inflammatory cytokines and
tumor volume in the breast cancer-bearing mice was significantly expanded the CD4+ T cell population. Furthermore, a chitosan-based
shrunk. This experiment indicated that the folic acid-chitosan-Fe3O4 biopolymer, N-dihydrogalactochitosan, could synergize with photody­
nanocomposite might be another promising arteether delivery platform namic therapy or cryoablation therapy to result in better antitumor ef­
for cancer immunotherapy. Another promising immunotherapeutic ficacy. This synergetic effect of N-dihydrogalactochitosan was further
agent that could be used in cancer treatment is curcumin. It has been confirmed by its ability of direct tumor killing and prominent immune
reported that curcumin could affect several cell signaling pathways that modulation [213]. More recently, another chitosan micelle has been
are involved in tumorigenesis and cancer metastasis and has the po­ synthesized as antigen-capturing adjuvants that could achieve an
tential of converting Tregs into Th1 cells to avoid immune evasion of enhanced cancer immunity. It has been discovered that this
tumor cells and induce tumor killing responses [200–204], while the chitosan-based nanomedicine could effective target at tumor-draining
mechanism for the conversion is still unknown. One study has been lymph nodes and induce strong CD4+ and CD8+ T cell antitumor re­
conducted to use chitosan-based mesoporous silica nanoparticles [205] sponses [115,214]. Based on previous positive findings, Moran et al.
to deliver curcumin to promote the immunotherapeutic efficiency [215] published a review to systemically examine the immunomodula­
against cancer. Their in vitro results showed that these chitosan-based tory properties of chitosan polymers. In their review, they concluded
nanomedicines could effectively deliver curcumin and achieve stable that chitosan-based materials could activate both cGAS-STING DNA
and sustained controllable release of it in the U87MG glioblastoma sensing pathway and NLRP3 inflammasomes so as to induce differenti­
tumor cells. Other studies also indicated that chitosan-based nano­ ation and activation of Th1 cells and suggested they could be applied as
systems could effectively deliver curcumin to tumor tissues thus increase a promising vaccine adjuvant for cancer immunotherapy.
their treatment efficacy in pancreatic cancer [206], colon cancer [207], Overall, chitosan-based nanomaterials have great potential to use in

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the immunotherapy of cancer. These nanomaterials could not only act as cells and macrophages could be activated and maturated to present
a nano-platform to carry immunotherapeutic agents to tumor tissues tumor killing properties and to produce pro-inflammatory cytokines
effectively and selectively so as to enhance anti-tumor immune re­ [226,227], immunotherapeutic drugs themselves are exogenous anti­
sponses, but also display immunomodulatory effects as immune adju­ genic agents that could be recognized and eliminated by immune sys­
vants themselves to induce tumor-killing immune responses. Despite tems before they reach tumor cells. That is partially the reason why
positive outcomes of their in vitro and in vivo studies, clinical trials are managing these immunotherapeutic agents alone usually results in a
required to examine in vivo safety and effectiveness of these chitosan- limited efficacy and often leads to unfavorable side effects [228–230].
based nanomaterials as potential immuno-therapeutics towards cancer HA, on the other hand, is a polysaccharide that demonstrates an
treatment. anti-inflammatory and anti-immunogenic function. It has been reported
that HA could provide an immunoprotective and immunomodulatory
4. Hyaluronic acid-based nanomedicines effect towards conjugated/encapsulated agents and protect them from
elimination by the immune system [137,231,232]. Although this
HA is negatively charged natural polysaccharides and they have been anti-inflammatory effect of HA may seem to be contradictory to the
widely used in the biological and medicinal field. It has a linear structure principles of immunotherapy, this effect results in a decrease in the
with repeated units of N-acetyl-D-glucosamine and D-glucuronic acid di- incidence of premature degradation of loaded drugs and a reduction in
saccharide bound via beta-linkages [216]. The hydroxyl, carboxylic and undesired immune responses. Since HA could selectively target CD44,
N-acetyl groups of HA allow further structural manipulation via chem­ LYVE-1 and RHAMM receptors that are usually overexpressed by tumor
ical reaction, which opens a door for broad applications of this material cells, HA-assisted delivery of exogenous immunotherapeutic drugs
[217]. Similar to chitosan, HA is a natural biomaterial that could be would increase their accumulation inside tumor tissues and selectively
found in many living organisms. HA is one of the main components of stimulate immune responses in the tumor microenvironment. Likewise,
the extracellular matrix, which are synthesized and secreted by inter­ HA could directly target some immune cells through CD44 targe­
stitial cells such as fibroblasts [218]. While low-molecular-weight HA ting/binding [233]. HA, often as a subset to bind to CD44 on T cells
oligomers resulting from degradation by hyaluronidase was reported to (mouse), could inducibly stimulate PMA/ionomycin, CD3 antibodies
be immunostimulatory [214,219], HA polymers with a high molecular and specific antigens [234]. HA could also bind to CD4+ CD25+ T reg­
weight have been demonstrated to possess great cytocompatibility and ulatory cells (human and mouse) and stimulate CD3+/− CD28 activation
biodegradability, low toxicity and no immunogenicity. Thus many [235]. These processes would result in an increased efficacy of loaded
studies have been conducted to develop HA-based medicines for immunotherapeutic drugs and decreased incidence of side effects
biomedical applications [220,221]. Many cancer cells overexpress (Fig. 3).
CD44, lymphatic vessel endothelial (LYVE)-1 receptors and receptor for
HA-mediated motility (RHAMM), which are HA-binding receptors [141,
4.2. Hyaluronic acid-based nanosystems to deliver tumor-associated
222], hence one approach to utilizing HA is to apply HA-based nano­
antigens
materials as drug delivery carriers to selectively target tumor cells
[223–225]. Recently, the HA nanosystem-based targeting drug delivery
Using HA-based nanosystems to deliver tumor-associated antigens to
system has been developed for cancer immunotherapy.
enhance the immunity towards tumor cells is one of the most promising
applications of HA-based nanoparticles for cancer immunotherapy. The
4.1. Hyaluronic acid to induce immunoprotection use of HA-based nanomaterials was reported to extend the release pro­
file of administrated immunomodulatory agents, thus effectively
Although immunotherapy of cancer diseases requires stimulation of enhancing their therapeutic efficacy [237]. Although several
patients’ immune responses so that certain immune cells such as DCs, T tumor-associated antigens [238,239] are helpful in cancer

Fig. 3. Hyaluronic acid-coated nanomedicines could selectively target at CD44+ cells, effectively deliver loaded drugs into the cytoplasm and promote the activation
of antigen presenting cells. Reproduced with permission from Ref. [236]. Copyright 2019 American Chemical Society.

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immunotherapy, ovalbumin (OVA) is the most widely used one due to its tissues [246]. Using this method, these PEI-HAase nanomaterials could
bioavailability and therapeutic efficacy [240,241]. However, similar to successfully deliver both OVA and CpG to induce a better efficacy of
other soluble antigens, administrating OVA alone usually does not result immunotherapy. This method sacrifices the targeting ability of HA but
in a satisfactory therapeutic effect. This is mostly caused by its intrinsic utilizes the penetrating ability of HAase to achieve enhanced intracel­
immunogenicity and an insufficient dose delivered into immune cells. lular uptake and a sufficient amount of therapeutic agents in tumor site.
Thus it is important to develop delivery platforms to aid in in vivo de­ This concept has also been applied in another study [247]. However,
livery of these tumor-associated antigens [242]. Recently, a novel further examinations are required to elucidate which method, HA or
multifunctional micellar platform, consisting of self-assembled poly­ HAase-assisted delivery, could achieve a better immunotherapeutic
ethylenimine (PEI), vitamin E succinate (VES), HA and PEGylated HA efficacy.
(mPEG-g-HA), was introduced to load OVA to form immunotherapeutic Besides HA (ase)-PEI nanosystems, nanosystems made from HA, OVA
nano-micelles (OVA@mPEG-g-HA/VES-g-PEI) [243] (Fig. 4). It has been and gold (Au) particles have also been applied for immunotherapy [51]
discovered that HA in these micelles could decrease the cytotoxicity of (Fig. 5). It has been reported that after triggering with laser irradiation,
the attached PEI by neutralizing its positive charge and also assist in the these nanomaterials could achieve a similar immune stimulation process
targeting delivery of the nanomedicines into HA receptor-overexpressed to enhance the tumor immunity. During this process, near infrared (NIR)
tumor cells. This HA receptor-targeted delivery would further increase laser irradiation could trigger not only the rupture of endosomes and
cellular uptake of the micelles into tumor cells. Once this endocytosis lysosomes, but also the production of ROS which could enhance the
process is completed, hyaluronidases would degrade the HA shell of the proteasome activity and boost the antigen presenting process [248].
micelles so as to expose the inner OVA-loaded PEI structures. This Moreover, these loaded OVA and NIR irradiation generated ROS could
process could also benefit for the endosome/lysosome-mediated OVA promote the enhancement in CD8+ T cells-mediated anti-tumor immune
release and then promote antigen presentation. These responses, endowing this HA-Au nanomaterial as an excellent platform
OVA@mPEG-g-HA/VES-g-PEI-treated tumor cells could express MHC-I candidate to boost antitumor immunity, but ensure the targeting de­
peptide epitope OVA257–264 on their surfaces so that DCs could recog­ livery of antigens with negligible toxicity. Alternatively, pH-sensitive
nize and then trigger differentiation and activation of antigen-specific HA derivative-modified liposomes have been developed to achieve tar­
CD8+ T cells to achieve the tumor killing responses [243]. geted delivery of exogenous antigens to DCs [236]. These
However, although these HA-based micelles could promote the anti- antigen-loaded nanomaterials could increase the production of
tumor immunity, this immune stimulatory effect does not last longer, anti-tumor cytokines by Th1 cells and induce strong anti-tumor re­
and the long-term immune enhancement is still relatively weak [244, sponses, leading to effective tumor growth inhibition in the
245]. Thus future modification of these micelles is needed to extend the tumor-bearing mice.
stimulatory time. Interestingly, another PEI-derived nanoparticles have Although above studies have explored the use of HA-based nano­
also been adopted to deliver therapeutic agents. Instead of HA, these systems to deliver sole antigens, a recent study [249] attempted to
nanoparticles were combined with HAase to break down extracellular employ levodopa and poly (ε-caprolactone-co-lactide)ester-functional­
HA so as to increase the permeability of these nanoparticles to tumor ized HA hydrogels to co-deliver both OVA and granulocyte–macrophage

Fig. 4. Synthesis of OVA-loaded mPEG-g-HA/VES-g-PEI micelle (a) its therapeutic efficacy on cancer immunotherapy. This antigen loaded HA-based nanomedicine
could targetedly deliver OVA into the tumor cells and induce an enhanced cytotoxic T lymphocyte (CTL)-mediated immune response (b). This HA-based nano­
medicine could effectively induce the maturation of DCs (c) and increase the expression of tumor-associated antigens to activate CTLs (d), thus killing tumor cells (e).
*p < 0.01 compared with the OVA group in (c) and (d); *p < 0.01 compared with all other groups in (e). Reproduced with permission from Ref. [243], Copyright
2019 Elsevier.

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Fig. 5. Synthesis of HA-OVA-AuNPs complexes (a) and its therapeutic efficacy on cancer immunotherapy. This HA-based nanoparticle could be used as nanovaccine
and effectively enhance both MHC-I and MHC-II antigen presentation process (b), thus demonstrating a comprehensive anti-tumor immune promoting ability to
significantly inhibit the tumor growth (c). **p < 0.01; ***p < 0.001. Reproduced with permission from Ref. [51]. Copyright 2018 WILEY-VCH Verlag GmbH &
Co. KGaA.

colony-stimulating factor (GM-CSF). The stable release of the loaded memory T cells to secret antitumor IFN-γ when encountered with spe­
drugs from the hydrogels suppressed the growth of tumor cells. It is cific antigens. Importantly, this inexpensive HA nanoparticle-based de­
worth noting that subcutaneous injection was utilized as the adminis­ livery system could enhance the bioavailability of CpG ODNs and reduce
tration route, which could effectively avoid potential side effects due to the risk of side effects caused by positively-charged cationic lipids,
systemic drug administration. The HA-based nanomaterials were also which made these adjuvant-loaded nanomedicines safer and more
employed to deliver antigens in a needle-free administration route. affordable for cancer immunotherapy. In addition to delivering CpG
Bussio et al. [250] found that OVA-loaded HA nanovaccines could be ODN with Poly I: C, in another recent study [258], HA-based nano­
absorbed through skin thus no needles were involved in this process to particles were employed to load CpG along with another therapeutic
avoid risks of injuries and infections. However, more studies are needed hypoxia inducible factor: signaling inhibitor Acriflavine (ACF)
to confirm the in vivo therapeutic efficacy of the HA-based nanovaccines [259–261]. In this study, HA coated metal–organic framework-based
through this needle-free approach. nanoparticles were synthesized through H2TCPP and zirconium ions
as a delivery platform (PCN-ACF-CpG@HA). Due to the binding ability
of HA, these PCN-ACF-CpG@HA could selectively target cancer cells
4.3. Hyaluronic acid-based nanosystems to deliver other
which usually overexpress CD44 receptors. The synergistic therapeutic
immunotherapeutic agents
effect of the loaded CpG and ACF has been demonstrated by inducing
significant antitumor immune responses and inhibiting growth and
Besides tumor-associated antigens, HA-based nanosystems have also
metastasis of tumor mass. This opens a new avenue to using HA-based
been employed for delivering other types of therapeutic agents to pro­
nanomedicines for cancer immunotherapy at a low cost.
mote immunotherapy of cancer diseases.
Although chemotherapy and immunotherapy are two different
CpG oligodeoxynucleotide (CpG ODN) and polyinosinic-
methods for cancer treatment, different types of therapeutic agents with
polycytidylic acid (Poly I: C) are both members of pathogen-associated
distinct antitumor mechanisms could be combined to achieve a greater
molecule pattern (PAMP) families that could be recognized by TLR-9
tumor inhibition efficacy. Nevertheless, co-delivery of different types of
and -3. The former is usually found in bacteria and the latter is a syn­
therapeutic agents together and maintenance of their own biofunctions
thetic analogue of double-stranded RNAs from viral-infected mamma­
remains a challenge. Lv et al. [52] used HA-based nanoparticles to
lian cells [251–254]. The combination of these two substances was
deliver both chemotherapeutic and immunotherapeutic agents to ach­
reported to demonstrate synergistic effects to stimulate T cell responses
ieve a combinational therapy. They used a HA-paclitaxel (HA-PTX)
and thus were explored as promising immune adjuvants for immuno­
prodrug and marimastat (MATT)-loaded thermosensitive liposomes
therapeutic vaccines [255,256]. Despite their effectiveness, this com­
(MATT-LTSLs) to from self-assembled nanoparticles and applied them to
bination would result in severe side effects. Using phosphorothioate to
the treatment of breast cancer. The results showed that these
modify the phosphodiester backbone could be one possible solution, but
CD44-targeting nanomedicines could selectively deliver the loaded
this solution would inevitably increase the cost for this therapy. Liu et al.
drugs (HA-PTX and MATT) into the tumor microenvironment, inhibit
[257] developed HA-modified cationic lipid-poly (lactic-co-glycolic
the matrix metalloproteinase (MMP) and expression of TGFes and TNC,
acid) (PLGA) hybrid nanoparticles to deliver both Poly I:C and natural
and suppress tumor growth, metastasis and angiogenesis. This provides
phosphodiester CpG ODNs. They discovered that these adjuvant-loaded
another effective way to promote the nanomaterial-based combination
nanomedicines could significantly induce the maturation of DCs and
cancer therapy. Camptothecin (CPT) is a chemotherapy drug that sup­
increase the population of antitumor CD4+IFN-γ+, CD8+IFN-γ+ and
presses the activity of DNA enzyme topoisomerase I in tumor cells so as
CD8+CD107a+ T cells, while inhibiting the development of immuno­
to achieve remarkable inhibition effect against tumor cells [262,263].
suppressive myeloid-derived suppressors cells. Furthermore, they found
Sun et al. [264] found that CPT-conjugated HA nanomedicines could
these adjuvant-loaded nanomedicines could increase the population of
have synergistic effects to increase the immunotherapeutic efficacy.
memory CD4+ and cytotoxic T cells and shorten the intervals of these

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Although 4T1 tumor cells usually express a low level of PD-L1 and they understanding of tumor immunity and the emergence of new thera­
do not have great response to the anti-PD-L1 therapy, these peutic concepts and new immunotherapeutic drugs, more applications
CPT-conjugated HA nanomedicines could sensitize the tumor microen­ of HA-based nanomedicines for cancer immunotherapy will be further
vironment so as to enhance the immune checkpoint blockade therapy. discovered and evaluated.
The effect of improving the sensitivity of the tumor microenvironment to
immunotherapeutic drugs by a chemotherapeutic agent was also 5. Dextran-based nanomedicines
confirmed from previous combinational therapeutic studies [265–267].
It is believed that the incorporation of chemotherapeutic agents could Dextran is a polysaccharide with an α-1,6-glycosidic bonding chain.
enhance the proliferation of long-term and effective tumor anti­ It is water-soluble with great biocompatibility and biodegradability and
gen–specific T lymphocytes, thus achieving a synergic antitumor effi­ has low toxicity and non-immunogenicity. Modifications of dextran
cacy from chemotherapy and immunotherapy [268,269]. However, the through the hydroxyl groups in the backbone chain would allow in­
detailed mechanisms remain to be discovered. teractions with selective receptors and other therapeutic ligands or
Herbal extracts such as curcumin and baicalin are another type of agents, and remain their biocompatibility, which makes it another
potential immunotherapeutic agents, which had been delivered by using excellent candidate for nano-delivery of therapeutic drugs to achieve
HA-derived nanoparticles delivery platforms to achieve effective cancer efficient treatment of diseases [282–285]. Furthermore, it has been
chemotherapy [270–273]. Recently, the HA-based nanoparticles were indicated that dextran could be utilized as an alternative for PEGylation
employed to deliver herbal extracts so as to promote cancer immuno­ to prevent interactions of nanomedicines with opsonin [147,286]. Due
therapy. Wang et al. [274] developed quercetin-dithiodipropionic to these advantages of dextran, it is widely used for the formation of
acid-oligomeric hyaluronic acid-mannose-ferulic acid (Que-S-S-oHA- nanomedicines. Recently, a number of dextran-based nanomedicines
Man-FA, QHMF) to form dandelion-like nanomicelles for delivering both have been developed for cancer immunotherapy.
curcumin and baicalin into tumor tissues. They demonstrated that these
drug-loaded nanomicelles could easily penetrate through vascular bar­ 5.1. Dextran-based nanosystems to deliver immunotherapeutic agents
riers and enter tumor tissues. Further examinations revealed that these
drug-loaded nanomicelles could reprogram the tumor-associated mac­ Wang et al. [54] developed a microneedle patch to deliver anti-PD-1
rophages from a pro-tumor M2 phenotype into a tumor-killing M1 antibody into tumor tissues to achieve immunomodulation (Fig. 6). In
phenotype, thus exhibiting a higher tumor growth inhibition effect their study, the microneedle patch consisted of biocompatible HA and
compared with free curcumin and baicalin. Moreover, increasing pH-sensitive, anti-PD-1 and glucose oxidase-loaded dextran nano­
secretion of cytokines TNF-α and IL-6 indicated that baicalin could be particles. The drug-loaded nanoformulations were applied to the treat­
employed as an adjuvant to enhance the immunomodulatory efficacy. ment of melanoma in model mice. The microneedle patch could
Recently, hyaluronate-polylactide (HA-PLA) nanoparticles have also effectively deliver PD-1 antibodies into the tumor microenvironment
been applied to encapsulate curcumin [275]. Instead of promoting and achieve sustained release of them. They discovered that the thera­
antitumor immunity, these drug-loaded nanomedicines could repro­ peutic efficacy of this delivering strategy was greater than that of
gram macrophages from a M1 phenotype to a M2 phenotype so as to administrating free anti-PD-1 antibodies. This microneedle
reduce the production of pro-inflammatory cytokines and suppress the patch-assisted immunotherapy enhancement technology has already
inflammation response. Although some studies stated that curcumin been filed as a patent by this research group [287]. Another immuno­
could promote inflammatory immune responses towards cancer [276, therapeutic agent (type B CpG DNAs) has been conjugated to dextran
277], curcumin has also been widely used in the treatment of autoim­ polymers and the formulated nanomedicines were applied to
mune diseases which rely on the inflammatory immune inhibition effect tumor-bearing mice [288] (Fig. 7a). These dextran-CpG conjugates were
of curcumin [278–280]. Thus the therapeutic mechanism of action of discovered to significantly enhance the antigen presenting process and
these curcumin-loaded HA-based nanomedicines for tumor immune increase the population of CD8+ T cells to achieve improved tumor
responses still remains controversial. killing immune responses. Yuba et al. [289] suggested that dextran and
Besides the above-mentioned therapeutic agents, a US patent docu­ its derivatives could be added to construct pH-sensitive liposomes that
ment [281] reported HA-based layer-by-layer nanoparticles to load cy­ could increase the safety and efficacy of the delivered antigens. More
tokines for the treatment of cancer. The proposed nanosystems were recently, Shin et al. [290] introduced a carboxymethyl dextran
composed of a liposomal core, a bilayer poly (L-arginine) coating and an (CMD)-based polymeric conjugate to deliver exogenous antigens
HA and poly (L-glutamic acid) polymer coating. These nanoparticles (Fig. 7b). Ovalbumin (OVA) was loaded into this polymeric conjugate
were applied to encapsulate and deliver cytokines such as IL-12 and with CMD as the backbone. This drug-loaded nanomaterial was applied
found that this cytokine-loaded nanomedicine formulation could to tumor-bearing mice. Compared with free OVA, this CMD-OVA con­
significantly increase the secretion of antitumor IFN-γ by splenocytes, jugate could target tumor tissues and accumulate there with a prolonged
and the tumor growth of both MC38 tumor-bearing and HM1 retention period, effectively promoting the antigen presentation process
tumor-bearing mice had been effectively suppressed. However, although and stimulating greater anti-tumor immune responses. In addition to
cytokines have been greatly appreciated in cancer immunotherapy these immunotherapy strategies, a few studies on dextran-based nano­
[168], the strategy of using HA-containing nanoparticles to deliver cy­ systems have been attempted to deliver therapeutic agents to achieve
tokines to enhance the immunotherapy efficacy directly is still at the reprogramming of tumor-associated macrophages. In a recent study
early stage. Recently HA-based hydrogels were developed to deliver conducted by Wang et al. [56], they synthesized a novel
artificial T cell stimulating matrix, which is not cytokines but a mixture erythrocyte-cancer cell hybrid membrane camouflaged pH-responsive
of substances (ECM, Anti-CD28, MHC, etc) crucial for T cell activation. dextran-grafted-poly (histidine) copolymer micelle to deliver BLZ-945,
Antitumor immune responses stimulation was achieved [53]. Further a CSF-1R inhibitor specific for tumor-associated macrophages. Their
investigations are needed to evaluate the efficacy and clinical applica­ preclinical results showed that this nanomedicine could effectively
bility of this immunotherapy method. reprogram the tumor microenvironment with increased M1 macro­
Overall, HA-based nanosystems, with their selective targeting ability phages and elevated CD8+ T cells, thus resulting in inhibition of tumor
to tumor cell receptors and their immunoprotective effects to protect the growth. Besides, dextran-based nanomaterials have M2-TAMs targeting
conjugated/enveloped therapeutic agents, provide a simple and effec­ ability. Huang et al. developed a dextran-based tumor-targeting nucleic
tive way to deliver exogenous drugs with minimal side and toxic effects, acid delivery system derived from a tumor
which makes them a very promising candidate for delivery of immu­ microenvironment-responsive carrier and a TAMs-specific receptor
notherapeutic agents towards cancer immunotherapy. With a deep [291]. All these recent studies demonstrated dextran-based

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Fig. 6. The structure of anti-PD-1therapeutics loaded dextran-based nanoneedle patch MN-Gox-aPD1 (a: Schematic diagram; b: SEM image) and its therapeutic
efficacy on cancer immunotherapy. This nanoneedle patch could effectively inhibit the growth of tumor tissues and reduce the tumor size, resulting in a decreased
tumor signal in bioluminescence imaging in vivo (c, d). *p < 0.05. Reproduced with permission from Ref. [54]. Copyright 2016 American Chemical Society.

nanomaterials as an excellent candidate for targeting delivery of various demonstrated the intrinsic immune stimulating properties of dextran-
immunotherapeutic agents with low apparent toxicity. On the basis of based nanosystems. Fontana et al. designed porous silicon@acetalated
these positive results, further studies could be conducted to optimize the dextran@cancer cell membrane (TOPSi@AcDEX@CCM) nanovaccines
structure of these dextran-based nanomaterials for delivering different for immunotherapy of cancer [57]. In their study, thermally-oxidized
therapeutic agents to achieve a combinational therapy with better out­ porous silicon was coated by acetalated dextran polymers and the
comes. In this context, Bauleth-Ramos et al. [55] used nanostructure was co-extruded with cancer cell membrane particles to
spermine-modified acetalated dextran nanosystems for co-delivery of form core-shell-structured nanovaccines. These nanovaccines could
cis-imidazoline nutlin-3a, a chemotherapeutic agent, and cytokine significantly increase the expression of CD80 and CD86 on antigen
GM-CSF, an immunotherapeutic agent. These dextran-based nano­ presenting cells and induce T cells activation on both KG1 and BDCM
medicines could release the loaded cargos in a pH-dependent manner cells, which could result in a greater immunostimulation efficacy. In
and also help in promoting endosomal/lysosomal escape of the deliv­ addition, the authors noticed that these nanovaccines could induce the
ered drugs. Their in vitro study revealed that these nanomedicines could polarization of T cells towards Th1 cells to secret a greater amount of
selectively target wild-type p53 cancer cells and exhibit killing effects on anti-tumor IFN-γ and IL-2 as well. Furthermore, this nanovaccine system
them, but displayed no toxicity to immune cells. These nanomedicines could also be used to deliver exogenous antigens such as Trp2 to further
could also maturate DCs by increasing the expression of CD83 and CD86 improve the immunotherapeutic efficacy [57]. Moreover, Bamberger
on their surfaces, which would enhance their antigen presenting abili­ and their colleagues [63] developed a linear low molecular-weight
ties, induce proliferation and activation of the down-stream immune dextran attached with spermine-modified acetalated dextran nano­
cells like cytotoxic CD8+ T cells, promote the secretion of IL-1β and particles. These surface-modified dextran nanosystems could selectively
reduce the expression of IL-10. Based on these findings, acetalated target DCs and trigger the activating signaling pathways of DCs, which
dextran nanoparticles-loaded injectable alginate cryogel was also could significantly stimulate activation of these antigen presenting cells.
introduced as an in situ cancer vaccine [292]. This peritumoral inject­ A similar immunostimulatory effect was also found for B cells and
able cancer vaccine was reported to demonstrate cytotoxicity towards macrophages [63,293,294]. However, in this study, it was also indicated
tumor cells and induce immunogenic cell death, which potentially that these dextran-based nanoparticles would induce cytotoxic effects
decreased cancer recurrence. on immune cells, which is the main drawback of applying them for
cancer immunotherapy. Further studies are needed to reduce the cyto­
toxicity of these dextran-based nanosystems to immune cells and
5.2. The immunostimulatory effects of dextran-based nanosystems discover more clinical applications for cancer immunotherapy.

In addition to their drug delivering ability, previous studies also

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Fig. 7. Synthesis of type B CpG DNAs conjugated dextran-based nanoparticles (a) and carboxymethyl dextran-ovalbumin (b) and their therapeutic efficacy on cancer
immunotherapy. Through improving the reorganization of tumor associated antigens by antigen presenting cells (c), these dextran-based nanomedicines could
effectively enhance anti-tumor immunity thus resulting in the decreased tumor sizes (d). **p < 0.01. Reproduced with permission from Refs. [288,290]. Copyright
2017 American Chemical Society and 2018 BMC Open Access, respectively.

6. Alginate-based nanomedicines response without any noticeable cytotoxicity.

In addition to targeting macrophage, alginate-based nanomedicines
Alginate is a linear polysaccharide that serves as one of the main could interact with DCs. Zhang et al. [58] conjugated OVA to
components of marine brown algae cell walls. Due to the chemical alginate-based aldehyde (ALG-CHO) through a pH-sensitive Schiff base
structure and physicochemical properties of alginate, it is biocompat­ bond and then assembled the conjugate with mannose (MAN) modified
ible, biodegradable and bioadhesive to mucosal surfaces [295,296]. alginate (MAN-ALG) to form MAN-ALG/ALG = OVA nanoparticles
Furthermore, the structure of alginate is versatile for modifications, and (Fig. 8). These ovalbumin-conjugated nanomedicines were demon­
this could allow the incorporation of specific targeting and functional strated to enhance uptake of these nanomedicines and promote the
moieties onto alginate to improve the mechanical strength, gelation, and cytosolic release of these OVA antigens in DCs. They could induce
cell affinity of alginate-based nanomedicines [297,298]. Thus maturation of DCs, proliferation and activation of cytotoxic CD8+ T
alginate-based materials have been widely studied for their biomedical cells, and increase the production of anti-tumor cytokines. Bencherif
applications. Recent studies have utilized alginate to prepare functional et al. [304] synthesized alginate-derived cryogel sponge vaccines to
nanomaterials and applied them to immune treatment of cancer encapsulate GM-CSF and CpG ODN and achieved a similar efficacy of DC
diseases. stimulation and population increase. This efficacy of the
Since alginate has been widely reported to interact with macro­ alginate-derived cryogel vaccine to enhance cancer immunotherapy was
phages to exhibit the immunomodulatory effect [299–301], many also confirmed by a recent study [305]. However, due to the very few
studies have first evaluated the feasibility of using alginate-based studies being published related to this type of polysaccharide-based
nanomaterials to achieve macrophages-targeting delivery. Since mac­ nanomaterial, the clinical applicability of it for delivering other thera­
rophages are one of the major types of antigen presenting cells, peutic agents to enhance the immunotherapy efficacy is to be confirmed
tumor-associated antigens were often used in this delivery process. Zhu and validated.
et al. [302] loaded alginate nanoparticles with ovalbumin323–339 peptide
and evaluated their therapeutic efficacy against the B16-OVA cancer 7. Other polysaccharide-based nanomedicines
model in the mice. They found that these OVA peptide-loaded alginate
nanomedicines could be uptaken effectively by macrophages and pro­ Polysaccharides are a big family of sugar-based natural polymers
mote activation of macrophages to demonstrate their anti-tumor func­ with a large variety of members. Besides the aforementioned poly­
tion. By activating tumor-associated macrophages, these nanomedicines saccharides, other types of polysaccharide-based nanomaterials have
could also increase the production of IL-8, IL-1β, G-CSF, TNF and IFN-γ, been explored in cancer immunotherapy. Some examples are discussed
which are all cytokines inducing or presenting tumor cell killing effects. below and more conformation and in vivo studies are expected.
Another ε-polylysine-sodium alginate self-assembled nanoparticles have Pullulan is a polysaccharide produced by the Aureobasidium pullulans
been applied to deliver exogenous antigens into macrophages [303]. fungus and popularized as a food and oral hygiene additive. It has long
These alginate-based nanosystems could effectively deliver antigens into been recognized for its great water solubility, biocompatibility and
macrophages and achieve sustained release of these antigens to boost biodegradability, and no obvious toxicity, immunogenicity or mutage­
the antigen presenting process and the down-stream adaptive immune nicity has been noted [306–308]. Due to these properties, it has been

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Fig. 8. Preparation of MAN-ALG (a) and ALG = OVA (b). ALG/ALG = OVA nanoparticles could significantly inhibit tumor cell proliferation by displaying a lower
tumor volume (c) and a smaller tumor weight (d). **p < 0.01. Reproduced with permission from Ref. [58], Copyright 2017 Elsevier.

explored in nano-scale drug delivery systems. Kyogoku et al. [309] these chondroitin sulfate derivative-modified liposomes could selec­
discovered that cholesteryl-pullulan-melanoma antigen gene-A4 nano­ tively deliver tumor-associated OVA antigens into DCs and increase the
gels were effective in promoting tumor immune responses and they have production of anti-tumor cytokines (Fig. 9). Their in vivo study also
entered a phase I + II clinical trial as a vaccine for cancer treatment. demonstrated a significant tumor growth inhibition effect of the
However, frequent administration of this vaccine may result in some OVA-chondroitin liposomes on growth and metastasis of tumors in the
undesirable changes in the anti-tumor immunity. Miura et al. [310] mice. Liu et al. also synthesized a chondroitin sulfate-based lipoic acid
designed cholesterol-bearing pullulan (CHP) self-assembly nanogels to nanoplatform that was triple-responsive to redox, enzyme and ultra­
deliver OVA antigens. It has been discovered that this nanogel could sound [59]. By conjugating Ce6 and loading docetaxel, this nano­
selectively deliver OVA into the lymphatic system to be recognized by conjugate could not only achieve a combinational therapy of
APCs. The anionic charge of the nanogel contributed to the enhanced sonodynamic therapy and chemotherapy, but also recruit cytotoxic
interactivity of the loaded OVA with APCs, which induced strong lymphocytes into tumor tissues, resulting in an enhanced antitumor
adaptive immune responses towards tumor cells with enhanced activa­ immune response. During the sonodynamic therapeutic process with
tion of the Th1 immune pathway and the increased population of CD8+ this nanomedicine, ROS were generated in the tumor tissues. These ROS
T cells. A previous study indicated that pullulan-based nanosystems would activate innate and adaptive immune responses, promote the
could exhibit high affinity towards asialoglycoprotein receptors on he­ antigen release from tumor cells that DCs could recognize to induce and
patocytes [311], and they could be a promising targeting delivery activate CD8+ T cells [59].
platform for hepatocellular carcinoma. More studies on directly β-cyclodextrin (CD), a low molecular-weight polysaccharide, has
applying pullulan-based nanomedicines for hepatocellular carcinoma been also reported to be applied in the immunotherapeutic drug delivery
treatment are still demanded. [316,317]. It has seven glucopyranose units with a polar and hydro­
Chondroitin sulfate is another polysaccharide that could be used in philic external surface and a relatively nonpolar and hydrophobic in­
the drug delivery system. It has been reported that modified chondroitin ternal surface, and this structure feature has been considered for
sulfate could exhibit low hydrophilicity to protect the loaded drugs since delivery of immunotherapeutic agents. In a recent study, β-cyclodextrin
the structure of chondroitin sulfate is similar to that of HA [312–314]. was covalently reacted with lysine to form crosslinked CD nanoparticles
Okubo et al. [315]developed chondroitin sulfate-based pH-responsive (CDNPs) [60]. These nanoparticles were able to load R848 and deliver it
liposomes to deliver OVA antigens for tumor therapy. They found that to tumor tissues. These drug-loaded CDNPs could selectively target

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Fig. 9. Synthesis of chondroitin sulfate derivatives that could modify liposomes (a) and bioreaction of chondroitin sulfate derivatives-modified liposomes for
stimulation of cancer immunity in subcutaneous tissue (b) and tumor tissue (c). Reproduced with permission from Ref. [315], Copyright 2019 American Chemi­
cal Society.

tumor-associated macrophages and induce alteration of macrophages immunotherapy has been studied. Xia et al. [326] utilized
from a pro-tumor M2 phenotype into an anti-tumor M1 phenotype, low-molecular-weight heparin to coat dendrimer-based core-shell
resulting in suppression of tumor growth and protection of animals nanocomposites to deliver CpG ODNs for cancer
against tumor recurrence. Furthermore, it has also been discovered that chemo-immunotherapy. According to their study, this
these R848 loaded-cyclodextrin nanomedicines along with anti-PD-1 nanomaterials-based combination therapy could effectively enhance the
agents could demonstrate synergistic effects to achieve an enhanced maturation of DCs and increase the population of cytotoxic CD8+ T cells.
immunotherapeutic efficacy [60]. The coating of low-molecular-weight heparin would prevent the
Pectin is a dietary component in plant-based foods such as fruits and epithelial-mesenchymal-like transition of tumor cells and suppress their
vegetables. It serves as one main component of plant cell walls from inhibition effect by damaging the arrangement of their actin cytoskel­
where it can be extracted. Modified pectin materials are reported to etons, thus presenting as a promising candidate for chemo- and immu­
possess excellent biological properties which have been applied in the notherapy of cancer diseases. Another study applied a similar core-shell
treatment of cancer [318,319]. Hira et al. [320]synthesized pectin-guar nanostructure with gambogic acid, heparin and CpG ODN to treat he­
gum-zinc oxide nanocomposites that could be used in cancer immuno­ patocellular carcinoma [327]. It has been reported that these nano­
therapy. In their study, these nanocomposites were shown to induce medicines could effectively increase the population of cytotoxic T cells,
activation of tumor cell killing processes and improve the tumor cell induce differentiation of Th1 cells and promote Th1-based antitumor
killing capacities of peripheral blood lymphocytes. It increased the immune responses, which contribute to cancer immunotherapy.
production of anti-tumor cytokines IFN-h, IL-2 and TNF-α which further With their excellent biocompatibility and targeting ability, inulin
led to the killing of tumor cells and inhibition of tumor growth. A deep and their derivatives have also been studied as a nanoplatform to deliver
understanding of pectin-based nanomaterials and their immunotherapy therapeutic agents to target certain cells or tissues [328–330]. Although
applications will pave the way for clinical trials. the application of inulin-based nanomaterials to cancer immunotherapy
Another polysaccharide heparin has a long history of uses in clinical is still at a very early stage, inulin acetate-based polymers have been
practice [321–323]. Its anticoagulation, anti-platelet aggregation and reported to deliver exogenous antigens into DCs effectively [331]. These
anti-thrombus functions make them versatile for a variety of clinical OVA-loaded inulin acetate-based polymers could be selectively recog­
conditions [324,325]. Recently, application of heparin in cancer nized by DCs through TLR4 and induce the maturation of these cells. In

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vivo experiments demonstrated that these nanomedicines could signifi­ nanoparticles to achieve radiotherapeutic applications [65]. Through
cantly increase the titers of serum antibodies such as IgG1 and IgG2a and this conjugation, these nanoparticles could not only increase the sensi­
the amount of cytokines like IL-4 and IL-10 to present strong immune tivity of radiotherapy, but also prominently promote activation and
responses towards tumor cells. By managing these OVA-loaded inulin maturation of DCs and increase the population of CD8+ T cells, which
acetate polymers, inhibition of metastasis of melanoma cells to lungs has further led to increased secretion of pro-inflammatory cytokines to
been witnessed in the experimented animals [331]. The targeting ability enhance antitumor immune responses. These GLP-Bi inhibited the
to DCs and biosafety of these inulin-based nanosystems make them safe tumor growth simultaneously and suppressed metastasis [65]. In a more
and effective carriers to deliver immunotherapeutic agents. recent study [332] galactoxyloglucan extracted from Tamarindus indica
Herbal extraction polysaccharide is another substance which has seeds was utilized to improve the stability and pH tolerance of copper
recently been applied in cancer immunotherapy (Fig. 10). Zhang et al. nanoparticles. According to this study, these
[64] used polysaccharide extracts from a natural herb (Ganoderma galactoxyloglucan-processed nanomedicines could significantly induce
lucidum) and gold to form gold-Ganoderma lucidum polysaccharide antitumor immune responses so as to reduce the tumor burden. Their
(GLP-Au) nanoparticles. Through their in vitro experiments, these excellent biodegradability, biocompatibility and immune stimulatory
GLP-Au nanoparticles could effectively promote the maturation of DCs effect warrant further investigations of their applications in cancer
and increase the transcription of anti-tumor cytokines. These nano­ immunotherapy. Astragalus membranaceus extracted polysaccharide is
systems also induced differentiation and activation of CD4+ and CD8+ T another herbal polysaccharide to be synthesized as nanomedicines for
cells. In vivo studies revealed that GLP-Au nanoparticles could signifi­ cancer immunotherapy [333]. These herbal nanomedicines induced the
cantly suppress tumor growth and its pulmonary metastasis. A signifi­ radiation-induced abscopal effect and promoted the systemic anti-tumor
cant increase in the number of CD4+/CD44+ memory T cells towards immunity. Anti-tumor immune memory has also been enhanced so that
tumor immunity has been also witnessed. These Ganoderma lucidum not only primary tumor growth has been inhibited, but growth of sec­
polysaccharide has also been used to conjugate bismuth sulfide (GLP-Bi) ondary tumor remote to primary lesions was also suppressed. These

Fig. 10. Synthesis of GLP-Bi nanoparticles (a) and GLP-Au nanoparticles (b). GLP-based nanoparticles could effectively inhibit tumor growth (c) through the
interaction with immune cells (d). Reproduced with permission from Refs. [64,65]. Copyright 2018 Elsevier and 2019 American Chemical Society, respectively.

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natural herb-based nanomedicines may be feasible for both radio­ anti-angiogenic and immunosuppressive to 20 kDa to be angiogenic,
therapy and immunotherapy against cancers. More recently, cationic immune-stimulatory and inflammatory. The immunotherapeutic effect
polysaccharide derived from Lepidium meyenii Walpers has also been of HA-based NPs with different molecular weights should be investi­
proven effective for tumor immunotherapy. This herb-extract nano­ gated in clinical trials [214]. Furthermore, clinical trials for cancer
medicine could re-educate tumor associated macrophages to M1 immunotherapy have their own unique considerations, and clinical trial
phenotype, which alter the immunosuppressive tumor microenviron­ designs should be tuned for these polysaccharide-based nanomedicines.
ment into strong antitumor immune-activated, leading to the effective For example, due to safety concerns of immunotherapeutics, the clas­
tumor growth inhibition [66]. Nevertheless, since many herbal extracts sical phase I 3 + 3 dose escalation may not be appropriate for continuous
were reported to display short-term or long-term toxicities, whether assessment of the relationship between their efficacy and toxicity.
these herbal polysaccharide-based nanomaterials would generate tox­ However, an adaptive and seamless phase I/II combined trial with
icities to normal tissues, especially in the long-term, is still in need of multiple cohorts and continuous assessment of their efficacy and toxicity
long-term assessments. is recommended [336]. Furthermore, patient selection, clinical mea­
surements, administration protocols, endpoint determination and anal­
8. Conclusion and future perspectives ysis methods should be adjusted and harmonized in order to obtain safe,
effective and regulatory body-acceptable clinical trial results
In summary, this review discussed recent progress of polysaccharide- [336–339]. The issues mentioned above may inspire future inves­
based nanomaterials and their applications in cancer immunotherapy. tigations/explorations on the development and improvement of
These natural or modified nanomaterials, with their excellent physico­ polysaccharide-based nanomaterials, and these immunotherapeutic
chemical and biological properties, could be used as nano-carrier plat­ drug formulations would become mature for clinical cancer treatment.
forms to deliver immunotherapeutic agents such as adjuvants,
cytokines, nucleic acids, and exogenous tumor-associated antigens. The Declaration of competing interest
polysaccharide nanomaterial-based drug delivery method could help to
achieve targeting delivery of immunotherapeutic agents to immune cell The authors declare no conflicts of interest.
subtypes and effectively improve the therapeutic efficacy of the loaded
agents. Some of these polysaccharide-based nanomaterials could even Acknowledgement
play a role as an immunomodulatory agent in addition to enhancing the
immunotherapeutic efficacy. This work was supported by the National Natural Science Foundation
Despite these encouraging outcomes of polysaccharide-based nano­ of China (51873120, 51673127, 81621003), National Science and
materials for immunotherapy, a few key challenges of these Technology Major Project of China (2017ZX09304023), Ruilong Sheng,
polysaccharide-based nanomaterials need to be overcome, such as Helena Tomás and João Rodrigues appreciate the support from
rational modification of polysaccharides, quantitative control of their Fundação para a Ciência e a Tecnologia (Base Fund UIDB/00674/2020,
molecular weight and the degree of modification, and incorporation of CQM, Portuguese Government Funds) and ARDITI-Agência Regional
multi-stimuli-responsive moieties to achieve smart and programmable para o Desenvolvimento da Investigação Tecnologia e Inovação through
immunotherapeutic effects. Especially, some essential aspects of the project M1420-01-0145-FEDER-000005-Centro de Química da
polysaccharide-based nanomaterials in immunotherapy are waiting to Madeira-CQM+ (Madeira 14–20 Program) and ARDITI-2017-ISG-003.
be investigated in future studies, including: 1) mechanistical studies of
polysaccharide-based immunotherapeutics towards “precision” immu­ Abbreviations
nomedicines. For efficient immune cell-activation and tumor targeting,
the mechanisms of polysaccharide-based nanoformulations and their ACF Acriflavine
immune-response properties need to be systematically elucidated, such APC Antigen presenting cell
as quantitative activation of immune cells (e.g. DCs, T cells, B cells and ATP Adenosine triphosphate
macrophages), intracellular localization of these nanoformulations and Caco-2 Colorectal carcinoma
intercellular localization of these immune-substances, especially, CAR-T cell Chimeric antigen receptor T cell
related up/down-regulation of immune-responsive genes, proteins/en­ Ce6 Chlorin e6
zymes; 2) Polysaccharide-based combinational cancer immunotherapy. CMD Carboxymethyl dextran
Since tumorigenesis mechanisms differ individually, a single therapeutic CpG ODN Oligodeoxynucleotide
agent may not be able to trigger enough immune responses to achieve CPT Cptothecin
satisfactory outcomes for cancer treatment. Therapy by combining CTL Cytotoxic T lymphocyte
multiple immunotherapeutic agents, namely combinational immuno­ DC Dendritic cell
therapy, is becoming an important strategy for tumor/cancer treatment. DNase Deoxyribonuclease
Some aforementioned studies have attempted to apply polysaccharide- FDA Food and Drug Administration
based nanomaterials to deliver two different types of therapeutic Fluc Luciferase
agents for combinational therapy, but up to now, the number of related GCS Glycol-chitosan
studies is very scarce. Moreover, how different immunotherapeutics are GM-CSF Granulocyte–macrophage colony-stimulating factor
combined rationally, quantitatively, compatibly and synergistically into HA Hyaluronic acid
one nanosystem to achieve high-performance combinational immuno­ HLA-DR Human leukocyte antigen-DR
therapy remains a great challenge; 3) Clinical trials of the HMGA High mobility group protein A
polysaccharide-based nanotheraputics from animal-models to human ICOSL Inducible co-stimulator ligand
beings. Although several studies stated that their polysaccharide-based IFN Interferon
nanomaterials have demonstrated a satisfactory efficacy without IL Interleukin
obvious toxicities, there are still concerns on whether these nano­ LPH Lipid-protamine-hyaluronic acid
medicines could be administrated safely and effectively in the human LYVE Lymphatic vessel endothelial
body [334,335] since most of these experiments were conducted only in MAN Mannose
animal models while still in the absence of clinical trial data in the MAPK Mitogen-activated protein kinase
human body. A recent study has shown that naturally-derived HA had a MATT Marimastat
wide range of molecular weights, ranging from a size of 104 kDa to be MMP Matrix metalloproteinase

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