Nanomaterial Journey in the Gut: From Intestinal Mucosal Interaction to Systemic Transport

Abstract

Engineered nanomaterials (NMs) are commonly utilized in food additives, cosmetics, and therapeutic applications due to their advantageous properties. Consequently, humans are frequently exposed to exogenous nanomaterials through oral ingestion, thus...

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Nanoscale
MINIREVIEW
Cite this: DOI: 10.1039/d4nr02480j
Received 16th June 2024,
Accepted 25th September 2024
DOI: 10.1039/d4nr02480j
rsc.li/nanoscale
Nanomaterial journey in the gut: from intestinal
mucosal interaction to systemic transport
Xin Qiao,
a,b,c
Lin Bao,
a,b,c
Guanyu Liu
a,b,c
and Xuejing Cui *
a,b,c
Engineered nanomaterials (NMs) are commonly utilized in food additives, cosmetics, and therapeutic
applications due to their advantageous properties. Consequently, humans are frequently exposed to
exogenous nanomaterials through oral ingestion, thus making the intestinal mucosal system a primary site
for these particles. Understanding the interactions between nanomaterials and the intestinal mucosal
system is crucial for harnessing their therapeutic potential and mitigating potential health risks from unin-
tended exposure. This review aims to elucidate recent advancements in the dual effects of nanomaterials
on the intestinal mucosal system. Upon entering the gut lumen, nanomaterials will interact with diverse
intestinal components, including trillions of gut microbiota, mucus layer, intestinal epithelial cells (IECs),
and the intestinal immune system. Additionally, the systemic fate and transportation of nanomaterials to
distal organs, such as central nervous system, are also highlighted. These interactions result in a distinct
biological effect of nanomaterials on the multilayer structure of intestine, thus displaying complex jour-
neys and outcomes of nanomaterials in the living body. This in-depth exploration of the in vivo destiny
and immunological implications of nanomaterials encountering the intestine has the potential to propel
advancements in oral drug delivery techniques and motivate future investigations in novel toxicology
research.
1. Introduction
Engineered nanomaterials (NMs) have been extensively
employed in a range of consumer products, such as food addi-
tives, cosmetics, and therapeutic agents, owing to their unique
physicochemical properties.
1–3
This increased consumption
has raised concerns about elevated human exposure to NMs
through combustion processes, industrial activities, and
environmental contamination,
4,5
emphasizing the need to
address potential risks associated with their usage. In recent
decades, great endeavors have been made to comprehend the
in vivo side effects of nanomaterials, primarily centered on the
toxic impact on recognized organs including liver, lung, and
kidney.
6
Nonetheless, the potential toxicity of nanomaterials
on the gastrointestinal tract (GIT) has been left behind. Given
the important role of NMs, understanding the interactions
between nanomaterials and the GIT, as well as their under-
lying mechanisms, is essential for both nanosafety and nano-
medicine. This knowledge is critical for mitigating risks and
enhancing the applications of nanomaterials.
The GIT serves as a central site for the exposure of NMs
that are either ingested directly or transported from the respir-
atory tract to the oral cavity before being swallowed.
7
Within
the GIT, NMs will interact with a complex intestinal microenvi-
ronment, especially the mucosal system. While a significant
portion of these NMs are eliminated through fecal excretion,
aided by mucus shedding and intestinal peristalsis, a consider-
able quantity persists, potentially affecting the resident micro-
biota and compromising the mucosal barrier.
8
The sub-
sequent penetration to the lamina propria and interplay with
immune cells can disrupt mucosal immunity, potentially trig-
gering adverse immune responses and exacerbating intestinal
inflammation.
9,10
The unique feature of the intestinal mucosal
immune system is its exposure to a diverse range of antigens,
necessitating the development of sophisticated mechanisms to
defend against pathogenic invasion while maintaining toler-
ance towards commensal bacteria.
11
Multiple studies have
revealed that NMs from vegetables and those endogenously
produced in the body can leverage the distinctive character-
istics of intestinal mucosal immunity to promote mucosal
immune tolerance.
12,13
This dual role underscores the delicate
impact of NMs on mucosal immunity, offering promising
avenues for novel therapies for intestinal inflammatory dis-
orders. However, current research on the intestinal mucosal
a
CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety & CAS
Center for Excellence in Nanoscience, National Center for Nanoscience and
Technology of China, Beijing 100190, China. E-mail: cuixj@nanoctr.cn
b
University of Chinese Academy of Sciences, Beijing 100049, China
c
New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of
Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience,
National Center for Nanoscience and Technology of China, Beijing 100190, China
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effects of NMs is still in its early stage. A comprehensive under-
standing of the underlying immune interactions and mecha-
nisms remains largely unexplored.
This review aims to delineate the multiple interactions
between NMs and the intestinal mucosal system, examining the
implications for gut microbiota, mucus layer, and intestinal epi-
thelial barrier. We also evaluate the beneficial and detrimental
effects of NMs on intestinal immunity. Furthermore, we eluci-
date the subsequent fates of NMs in intestine, differentiating
between the immune responses elicited by degradable versus
non-degradable nanomaterials and mapping the diverse sys-
temic transport pathways these particles may undertake. These
pathways include direct entry into the circulatory system via the
portal vein, lymphatic transport through mesenteric lymph
nodes circumventing hepatic filtration, and neural transport to
the central nervous system, each pathway presenting unique
implications for NMs-mediated effects on human health.
2. Interaction of NMs with intestinal
mucosal system
2.1. The structure of intestinal mucosal system
The intestinal mucosal system is a multilayer structure that
serves as the first line of defense against pathogens and simul-
taneously tolerates harmless microbes and dietary antigens
within the GIT (Fig. 1).
14
In this system, the outermost layer is
the gut microbiota, a diverse array of microbial communities
that exert the functions of immune regulation and nutrient
absorption.
15,16
The mucus layer, produced by goblet cells,
acts as the initial barrier to intestinal antigens, microorgan-
isms, and other substances, capturing the invading foreign
materials and aiding in their clearance.
17
The intestinal epi-
thelial cells (IECs) lie beneath the mucus layer, comprising the
second tier of the mucosal barrier. This epithelial stratum is
composed of various cell types, each with distinct functions.
These include: (1) absorptive epithelial cells, which facilitate
the uptake of nutrients; (2) goblet cells, pivotal in the pro-
duction of mucus; (3) Paneth cells, known for their secretion
of antimicrobial peptides; (4) tuft cells, which are sensitive to
the presence of parasites; (5) enteroendocrine cells, respon-
sible for the secretion of hormones; (6) M cells, specialized for
antigen sampling and presentation. This intricate arrange-
ment of cell types underscores the complexity and multifunc-
tionality of the intestinal epithelium, which is essential for
maintaining the mucosal barrier’s integrity and conducting
immune surveillance.
18
The lamina propria, situated beneath
the epithelial layer, forms the third tier of the mucosal
immune system, often referred to as the immune barrier.
19
This layer is rich in immune cells, including dendritic cells
Fig. 1 The structure of small intestinal mucosal immune system.
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(DCs), macrophages, B cells, T cells, and plasma cells, which
are instrumental in mounting a robust immune response to
pathogens and promoting immunological tolerance. Within
the epithelium and lamina propria, Peyer’s patches are strate-
gically positioned and integral to the gut-associated lymphoid
tissue (GALT), which are teeming with immune cells such as B
cells in germinal centers, T cells, DCs, and macrophages, con-
tribute to initiating the mucosal immune response.
20
Beyond
the lamina propria, the mucosal system includes scattered
lymphoid follicles throughout the intestine, which are vital for
localized immune surveillance and reaction.
21
Of note, the
intestine is connected to the mesentery (a new organ identified
in the year of 2016) that offers structural support.
22
Within the
mesentery lie mesenteric lymph nodes, which function as a
conduit for lymphatic drainage from the intestinal mucosa to
the systemic immune system.
23
These lymph nodes are crucial
for initiating and regulating immune responses, acting as
filters that identify and process pathogens and antigens from
the intestine.
24
The complex interplay of cells and structures is
designed to ensure a balanced immune response, protecting
the host from infections while avoiding overreactions to
benign environmental elements.
2.2 The interaction of NMs with gut microbiota and luminal
contents
Upon entering the gut lumen, nanomaterials interact with the
vast population of gut microbiota, potentially influencing its
composition, diversity, and functionality, these changes can
subsequently impact the host’s metabolic processes and
immune responses.
25,26
For instance, numerous studies have
demonstrated that NMs possess antibacterial properties
through various mechanisms, such as membrane disruption,
27
interference with the electron transport chain,
28
catalytic bac-
tericidal activity,
29
inhibition of bacterial division,
30
toxicity
from metal ions,
31
and bacterial entrapment mediated by
aggregation.
32
To be noticed, the antibacterial properties of
NMs can disrupt the normal structure of gut microbiota.
33
Our
recent finding indicate that following a short-term (14-day)
administration, both silver NMs and silver nanowires sup-
pressed the proliferation of Gram-negative bacteria.
34
This
inhibitory effect may be attributed to the presence of hydro-
philic lipopolysaccharide (LPS) on the surface of Gram-nega-
tive bacteria, thus facilitating the adsorption of silver nano-
materials.
34
As a result, the α-diversity of the gut microbiota
gradually changed.
34,35
Apart from the antibacterial properties,
certain bacteria can in turn utilize the NMs as available carbon
source to change the structure of gut microbiota. For example,
we have shown that butyrate-producing bacteria can ferment
carbon NMs as a carbon source, which shift the overall bac-
terial compositions.
36
Interestingly, a recent study found that
fullerol NMs could be degraded by gut microbiota, exhibiting a
similar ability as inulin to promote short-chain fatty acid
(SCFA) production.
37
Additionally, NMs can modulate reactive
oxygen species (ROS) levels in the intestine, impacting the
composition of the intestinal microbiota. Wang et al. devised a
carbon nanoparticle suspension injection to counteract radi-
ation-induced ROS within the gut microenvironment, thereby
preserving the equilibrium of the gut microbiota.
38
They also
suggested that these nanoparticles attenuated harm to the
intestinal mechanical barrier, consequently impeding patho-
genic bacteria from reaching epithelial cells and dominating
the microbiota through unbridled proliferation.
38
In summary,
despite progress in elucidating the mechanisms through
which NMs influence the gut microbiota, the fundamental
principles governing these interactions are still incipient and
necessitate further exploration.
Alterations in the gut microbiota induced by NMs can sig-
nificantly impact gastrointestinal and overall health. The
Firmicutes to Bacteroidetes (F/B) ratio is commonly associated
with intestinal health, and deviations in this ratio have been
linked to obesity.
39
For example, Chen et al. demonstrated that
exposure of mice to silver NMs at a dose of 2.5 mg kg
−1
for 7
days led to a decreased F/B ratio and subsequent weight loss.
40
Similarly, Li et al. revealed that TiO
2
NMs can reduce the popu-
lation of Bifidobacterium, leading to the degradation of the
mucus layer.
41
Moreover, TiO
2
NMs have been found to dimin-
ish beneficial probiotics like Bifidobacterium and Lactobacillus,
potentially contributing to weight loss and inflammation.
42
Currently, most studies have been focused on the effects of
nanomaterials on the intestine.
10,34,38,43,44
However, limited
research has been conducted on the effects of the intestinal
components on the NMs, especially on the biodegradable
ones. Of note, several pieces of evidence indicate that the
NMs, such as those made from engineered carbon-based
materials and polylactic acid polymers, are capable of degrad-
ing through enzymatic activity and microbial interactions in
the GIT.
36,45
Our recent study has demonstrated that gut
microbiota can decompose single-walled carbon nanotubes
(SWCNTs) and graphene oxides (GO) nanosheets into smaller
fragments, which are further metabolized into organic buty-
rate through microbial fermentation.
36
This degradation
process appears to be particularly prevalent among graphene-
based nanoparticles, likely attributable to the ample oxidation
and defect sites in SWCNTs and GO. These sites provide reac-
tive targets for bacterial action through their dangling bonds
and surface groups such as carboxyl, hydroxyl, and epoxy.
Additionally, some butyrate-producing bacterial genera such as
Roseburia and Odoribacter, along with members of the
Ruminococcaceae family, utilize these degradation products to
synthesize organic butyrate via the central pyruvate metabolic
pathway. This finding highlights the potential for gut micro-
biota to metabolize NMs as carbon sources, altering the micro-
biome. Moreover, increased butyrate production through
microbial fermentation can inhibit stem cell proliferation,
enhance the intestinal barrier, regulate immune responses in
the gut, and provide energy substrates for colonocytes.
46
In
contrast to the engineered nanoparticles, an interesting study
has shown that biodegradable polylactic acid (PLA) microplas-
tics can be enzymatically cleaved into oligomers by commer-
cial lipases, and these oligomers then self-assemble into nano-
plastic particles through hydrophobic interactions.
45
The
accumulation of these oligomers and resulting nanoplastic led
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to acute inflammatory reactions in the intestine of mice.
45
Particularly, smaller nanoplastics (∼50 nm) produced during
digestion showed a tendency to penetrate the GIT and spread
throughout the body via the bloodstream, thus posing systemic
risks.
47
The breakdown of degradable NMs into smaller fragments
or precursor forms leads to distinct patterns of distribution,
cellular uptake, elimination, and immune reactions compared
to non-degradable counterparts. For instance, the degradation
of microplastics into nanoplastics altered their biological dis-
tribution, with smaller dimensions correlating with a broader
dissemination scope.
48,49
Typically, the degradation of NMs
speeds up their elimination, with NMs or their degradation by-
products smaller than 5.5 nanometers being quickly excreted
through the renal system.
50
In contrast, particles larger than 6
nanometers are mainly eliminated through the hepatobiliary
pathway.
50
Although this degradation process may reduce the
risk of accumulation, it introduces new complexities to the
interaction between gut microbiota and host metabolism,
potentially impacting gut health and disease development.
Notably, certain types of NMs previously considered non-bio-
degradable, such as gold, silicon dioxide, and iron oxide NMs,
have been found to undergo structural changes or degradation
in the body.
51
Therefore, a comprehensive understanding of
the reciprocal influences between these degradable particles
and the intestinal environment is crucial for fully assessing
their long-term effects on human health.
2.3. Interaction of NMs with mucus
Mucus secreted by epithelial goblet cells forms a vital defen-
sive barrier that traps invading exogenous substances, prevent-
ing their deeper penetration into intestinal tissues (Fig. 2). In
the small intestine, a thin layer of mucus aids in nutrient
absorption and digestion.
52
In contrast, the colonic mucus
consists of an inner compact layer and an outer fluidic layer.
This stratification, approximately 50 μm in murine models and
200 μm in human from the epithelial surface, allows endogen-
ous proteases to convert the inner layer to the outer layer,
creating a distinct boundary.
53
The formation of this mucus
barrier primarily involves mucoprotein polymerization
through disulfide linkages, forming a molecular sieve-like
network.
54
The outer colonic mucus layer contains larger
pores, enabling the passage of particles up to 0.5 μm, includ-
ing bacteria.
52
In addition to the size, various intrinsic pro-
perties of NMs including shape, surface charge, chemical com-
position, hydrophilicity, and ligand density, can also influence
their permeability within mucus.
33
In general, NMs can interact with mucin in various ways to
alter their physicochemical properties. For example, Ag NMs
have been found to stimulate goblet cells in rats, leading to
increased mucin production and changes in mucin compo-
sition characterized by elevated salivary mucin levels and
decreased thiomucin content.
55
Furthermore, gut microbiota
are important contributors to mucin production,
54
The pres-
ence of bacteria, including probiotic strains like Lactobacillus
rhamnosus and opportunistic pathogens like Gram-negative
Escherichia coli, can stimulate mucus production.
56
Nonetheless, the simultaneous exposure to titanium dioxide
NMs (TiO
2
NMs) and E. coli does not impact mucus secretion,
whereas co-exposure with TiO
2
NMs and L. rhamnosus mark-
edly diminishes mucus production. These findings suggest
that NMs not only directly influence the mucus layer but also
potentially modulate its thickness and composition through
the interactions with bacterial populations.
Fig. 2 The schematic diagram illustrates the structure of the intestinal mucus layer and the varying permeability of nanomaterials across this
barrier. The density of the mucus network typically increases from inner to outer layers, enabling it to selectively filter nanomaterials with different
sizes. (A) In the small intestine, the mucus layer is loose, non-attached, can be readily removed, forming a discontinuous layer. (B) The large intestine
presents two distinct mucus layers: a compact inner layer firmly attached to the epithelial cells and a more relaxed outer layer with looser connec-
tions to the inner layer. Created with BioRender.com.
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The interaction between intestinal mucin and NMs signifi-
cantly dictates the trajectory of nanoparticles in the body,
beyond their impact on mucosal mucin. For instance, intesti-
nal mucin facilitates the aggregation of NMs, leading to
increased endocytosis, decreased transcytosis, and enhanced
retrograde transport pathways.
57
Furthermore, mucus-adherent
NMs, characterized by poor permeability and features such as
positive surface charge or hydrophobic characteristics, strongly
adhere to the mucus layer through electrostatic and hydro-
phobic interactions, resulting in their entrapment.
58
These
trapped particles are generally eliminated from the mucosal
tissue along with the shedding of the outer mucus layer, a
process that can occur within seconds to several hours based
on their specific locations.
59
This elimination is facilitated by
peristaltic movements and culminates in their excretion via
fecal matter.
60
Conversely, smaller NMs
61
or those with tai-
lored surface modifications, such as neutral or slightly nega-
tive surface charge,
62,63
hydrophilicity,
62,64
rod-like shape,
65,66
and moderate rigidity,
67,68
may penetrate this barrier and
reach deeper underlying tissues.
2.4. Interaction of NMs with intestinal epithelial cells
The intestinal epithelial barrier comprises a monolayer of cel-
lular structures that serve not only as a physical barrier but
also play a crucial role in immune protection and mediating
interactions between microbial entities and immune cells.
Within the intercellular spaces of adjacent epithelial cells lie
essential components such as occludins and claudins, which
are indispensable components in the formation of tight junc-
tions.
69
These structures cooperate with each other to prevent
the translocation of bacteria and pathogen-associated mole-
cular patterns (PAMPs) larger than 0.6–1.2 nm in diameter
from breaching the intercellular space into the lamina
propria.
70
A recent study has demonstrated the effects of nano-
materials on the epithelial layer, revealing their potential to
induce epithelial cell death and compromise epithelial barrier
integrity.
33
The intracellular accumulation of NMs leads to
increased production of ROS, a key factor in NM-induced cyto-
toxicity.
71
NMs exposure elevates ROS levels, causing DNA
damage, mitochondrial dysfunction, increased intracellular
calcium levels, cellular structure impairment, and activation of
inflammatory signaling pathways such as NF-κB and MAPK.
72
This oxidative stress particularly affects the intestinal epithelial
barrier, resulting in cell death through apoptosis, necrosis,
and pyroptosis, as well as the release of pro-inflammatory
mediators (e.g., mtDNA, ATP, IL-1β, TNF-α) from compromised
cells and organelles.
73
However, it is important to note that
not all nanomaterials have detrimental effects on epithelial
cells. For example, our research has shown that carbon nano-
tubes can enhance intestinal organoid growth by modulating
the viscoelastic properties of the extracellular matrix and intra-
cellular energy metabolic processes.
74
In contrast to the direct effect of NMs on IECs, NMs might
indirectly impact the IECs through influencing gut microbial
metabolism that are essential for intestinal homeostasis.
34
To
be noticed, SCFAs, especially butyrate, are important metabolic
products of gut microbiota in the colon produced mainly
through dietary fiber fermentation, which is vital for support-
ing intestinal epithelial cells and maintaining colonic
stability.
75,76
The intestinal epithelial cells at the crypt surface
utilize butyrate as a primary energy source through
β-oxidation, depleting local oxygen levels from nearby blood
vessels.
14
This process creates a gradient of butyrate and
oxygen along the crypt axis, establishing an anaerobic, buty-
rate-rich environment at the luminal surface while maintain-
ing an oxygenated environment at the crypt base to protect
stem cells from the inhibitory effects of butyrate on cell pro-
liferation.
14
Furthermore, our research indicates that gut
microbiota can convert inorganic carbon NMs into organic
butyrate, potentially disrupting epithelial homeostasis and
impacting intestinal stem cell function.
36
Moreover, SCFAs,
particularly butyrate, play a crucial role in regulating tight
junction proteins through various signaling pathways, includ-
ing stabilization of hypoxia-inducible factor-1 (HIF-1) and inhi-
bition of histone deacetylases (HDACs). These findings imply
that carbon NMs could potentially compromise the integrity of
the intestinal epithelial barrier by altering the interactions
with gut microbiota. Additionally, a recent study has shown
that the reduction in bacterial populations caused by micro-
plastics and nanoplastics predominantly impacts beneficial
microorganisms, which are known to enhance tight junction
functionality.
77
This indicates that alterations in the gut micro-
biome induced by these particles substantially contribute to
the indirect toxicological effects that lead to the deterioration
of intestinal barrier functions.
77
2.5. Translocation mechanisms of NMs across IEC
The primary function of the intestinal epithelial barrier is to
segregate the luminal contents of the intestine from the host,
thereby protecting against foreign substances.
78
NMs can
translocate the epithelial barrier through various pathways
(Fig. 3). Initially, NMs can traverse the epithelium and
undergo secretion on the opposite side via transcytosis, with
transport through M cells being particularly efficient.
79
Alternatively, NMs may potentially traverse the epithelial layer
by utilizing gaps in the tight junctions of IECs through a para-
cellular pathway. However, given that tight junctions, consist-
ing of transmembrane integral proteins, typically have a span
of only 0.3 to 1 nm, the likelihood of NMs passing through
this route is minimal.
80
Therefore, the use of permeation
enhancers is often necessary to augment the permeability of
these junctions, thereby facilitating the passive transportation
of NMs. Substances such as EDTA, chitosan, sodium caprate,
bile salts, and specific synthetic peptides have demonstrated
efficacy in transiently widening these junctions to enable
passive transport.
81
Despite these interventions, studies indi-
cate that even with permeation enhancers, the enlargement of
tight junctions seldom surpasses 20 nm, leading to unresolved
debates regarding the feasibility of transporting larger NMs via
the paracellular route.
82
Interestingly, small NMs such as
quantum dots and nanotubes with diameters of just several
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nanometers can pass directly through gaps in the cellular
membrane phospholipid bilayer, facilitating passive diffusion
across epithelial cells.
83,84
Persorption is a mechanism where
solid particles up to 130 μm pass into the lamina propria by
mechanical kneading at the epithelial gap of the GIT villus tip,
particularly at desquamation zones, before entering the circu-
latory system.
85
This phenomenon is attributed to the cellular
turnover at these sites, resulting in transient openings that
permit particle translocation.
86
Furthermore, receptor-
mediated endocytosis allows for NMs internalization through
interactions with specific receptors and cell surface molecules,
with NMs endocytosis categorized into macropinocytosis, cla-
thrin-mediated, caveolae-mediated, and other receptor-
mediated endocytosis. Caveolin-mediated endocytosis predo-
minantly facilitates the uptake of NMs ranging from 20 to
100 nm, whereas clathrin-mediated endocytosis mainly
handles the uptake of submicron particles between 100 and
350 nm.
87
Macropinocytosis is especially vital for internalizing
larger NMs, as it allows for the formation of large vesicles
from 0.2 to 5 μm.
88
Engineered NMs, designed with specific
bioactive compounds such as vitamins, oligopeptides, fatty
acids, and antibody fragments, leverage receptor-mediated
endocytosis for the targeted delivery of active pharmaceutical
agents.
89
The key receptors targeted in this process include the
folate receptor,
90
transferrin receptor,
91
vitamin B12 recep-
tor,
92
and neonatal Fc receptor.
93
M cells, along with goblet cells among the various types of
IECs, are of great importance to promote intestinal tolerance
and initiate mucosal immune responses.
94,95
These cells
sample luminal contents indiscriminately and facilitate the
transport of intact antigens to underlying DCs for antigen pro-
cessing and presentation. Located in the follicle-associated
epithelium (FAE) covering Peyer’s patches, M cells are charac-
terized by unique morphology, including short, folded apical
invaginations and a significant basolateral pocket that allows
close interaction with antigen-presenting cells (APCs) or
lymphocytes.
96,97
This special structure enables M cells to
capture particulate matter through receptor-dependent path-
ways, involving cytoskeletal proteins such as glycoprotein 2,
β1-integrin, prion protein PrP, dectin-1, claudin-4, and
CD155.
14
After antigen uptake, M cells efficiently deliver them
to neighboring immune cells through processes like transcyto-
Fig. 3 NMs traverse the intestinal epithelial barrier via multiple pathways. (A) M cell-mediated transcytosis in Peyer’s patches; (B) enterocyte-
mediated transcytosis; (C) paracellular transport facilitated by the disruption of intercellular tight junctions; (D) passive diffusion across the lipid
bilayer of epithelial cells; and (E) persorption during the process of epithelial desquamation. (F) Additionally, NMs are internalized by IECs through
various endocytic mechanisms such as macropinocytosis, clathrin-mediated endocytosis, caveolae-mediated endocytosis, and receptor-mediated
endocytosis, culminating in transcellular egress via exocytosis, thereby facilitating the transport across the epithelial barrier. Created with BioRender.
com.
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sis, phagocytosis, or the release of microvesicles.
98
Despite
constituting only about 5% of FAE cells and 1% of the total
absorptive surface area of IECs in humans,
99,100
M cells face
challenges in transporting significant amounts of nano-
particles.
101
Studies in rodents suggest that villous cells are
primarily responsible for absorbing 2 μm polystyrene particles,
accounting for 93% of absorption, while FAE is associated
with a minimal 4%.
102
This evidence indicates that IECs rather
than M cells are the main players in NM translocation.
103–105
Furthermore, goblet cells are implicated in enhancing the
transport of luminal antigens to DCs beneath the
epithelium.
106,107
However, research on goblet cell-mediated
NM transport is limited, highlighting a significant gap in our
understanding of mucosal NM delivery mechanisms.
3. The mucosal immune effects of
NMs on intestine
3.1. The innate immune effects of NMs
Upon breaching the mucus layer and entering the epithelial
layer and lamina propria, NMs are known to elicit innate
immune responses. In 1996, Powell et al. identified conglom-
erations of TiO
2
NMs within M cells and adjacent macro-
phages in the GALT of intestinal biopsy specimens from indi-
viduals with inflammatory bowel disease (IBD).
108
Similarly, a
variety of NMs such as TiO
2
, ZnO, SiO
2
,Fe
3
O
4
, aluminosili-
cates, and Ag have been observed to accumulate on the cell
surface and within the cytoplasm of IECs, M cells, Peyer’s
patches, and macrophages in the GI tract.
108–112
The intracellu-
lar accumulation of these particles is widely known to catalyze
the overproduction of ROS like superoxide (O
2
•−
), hydroxyl rad-
icals (OH
•
), and hydrogen peroxide (H
2
O
2
), which are recog-
nized as primary contributors to cytotoxicity.
113–116
In
addition, the surface chemistry of NMs can also contribute to
ROS formation.
113,117
For example, the prooxidant functional
groups on the surfaces of NMs, such as surface-bound radicals
found on quartz particles like SiO
•
and SiO
2
•
, plays a crucial
role in ROS generation.
113,118,119
Notably, ZnO NMs have
shown to induce more pronounced ROS levels compared to
SiO
2
, likely due to their heightened chemical reactivity.
113,115
Furthermore, the intrusion of NMs into mitochondria can
stimulate the endogenous generation of ROS by disrupting the
electron transport chain, leading to structural impairment,
activation of NADPH-like enzyme systems, and mitochondrial
membrane depolarization.
115
This oxidative stress sub-
sequently prompts the release of pro-inflammatory mediators
through key signaling pathways such as Nuclear Factor-κB (NF-
κB), mitogen-activated protein kinase (MAPK), and phosphoi-
nositide 3-kinase (PI3K).
120
The innate immune system employs various pattern reco-
gnition receptors (PRRs) such as Toll-like receptors (TLRs) and
NOD-like receptors (NLRs) to recognize PAMPs and damage-
associated molecular patterns (DAMPs).
121
The interactions
between NMs interaction and macrophages, along with the
ensuing cellular immune responses, are complicated, invol-
ving various pathways that lead to inflammasome activation
through PRRs. This activation process generally involves the
identification of NMs as exogenous entities, the perturbation
of cellular equilibrium, and the release of danger signals (e.g.,
mitochondrial DNA
122
and ATP
123
), facilitated by both direct
and indirect NMs interactions with cellular components.
These interactions can cause disturbances in ion levels, desta-
bilization of lysosomes, and ROS production.
124
Among
inflammasomes, the NOD-, LRR-, and pyrin domain-contain-
ing protein 3 (NLRP3) inflammasome is particularly notable
for its responsiveness to a diverse array of stimuli, including
silica and aluminum crystals, asbestos, and diverse
NMs.
125–128
In an acute colitis mouse model induced by
dextran sodium sulfate (DSS), oral administration of TiO
2
NMs
was found to induce the formation of the NLRP3 inflamma-
some.
9
This led to the release of pro-inflammatory cytokines
such as interleukin (IL)-1βand IL-18, exacerbating intestinal
inflammation. Interestingly, TiO
2
NMs did not provoke the
same colitis pathology in NLRP3 knockout mice, underscoring
the critical role of the NLRP3 inflammasome in mediating
intestinal inflammation. A similar study demonstrated that
oral administration of small SiO
2
NMs also worsens DSS-
induced colitis by activating the apoptosis-associated speck-
like protein containing a CARD (ASC)-mediated inflammasome
in immune cells of the colonic lamina propria.
10
This potential
influence on innate immunity by NMs may thus lead to macro-
scopic mucosal immune effects and clinical symptoms associ-
ated with inflammation. A recent study has demonstrated that
administering Ag NMs orally to mice significantly increased
levels of IL-1β, IL-6, and TNF-α, leading to classic symptoms of
ulcerative colitis including elevated disease activity index and
decreased colon length.
40
Furthermore, exposure to SWCNTs
has been shown to cause substantial intestinal damage,
marked by increased histological lesion scores, heightened
intestinal permeability, and elevated secretion of proinflam-
matory cytokines.
129
Further investigations have revealed that
the administration of 150 mg kg
−1
of nano-MoS
2
resulted in
mucosal hemorrhage, villus shortening in the small intestine,
and edema in the intestinal wall of the large intestine, along-
side a notable increase in TNF-αgene expression.
130
A question arises as to whether nanoparticles are directly
recognized by innate immune cells or if proteins and other
biomolecules adsorbed on the surface of NMs act as “NM-
associated molecular patterns”(NAMPs), triggering an
immune response.
131
The concept of NAMPs was introduced
by Gallo and Gallucci in 2013, based on the evidence of
immune cell detection of NMs.
132
However, recent studies
suggest that the diverse signal responses of the NLRP3 inflam-
masome are more appropriately activated in response to
“homeostasis-altering molecular processes”(HAMPs) rather
than specific molecular patterns.
133
Nonetheless, in the case
of NMs such as SiO
2
NMs and carbon nanotubes, a distinct
identification mechanism involving NAMPs has been
observed. In 2017, Nakayama et al. revealed that SiO
2
NMs pri-
marily interact with the class B scavenger receptor (SR-B1),
identifying it as the main receptor for silica.
134
This interaction
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is specific to SR-B1 and both amorphous and crystalline silica,
with no corresponding recognition observed for TiO
2
NMs, latex
NMs, or monosodium urate crystals. Subsequently, they demon-
strated that the extracellular domain of murine T cell mucin
immunoglobulin 4 (Tim4) contains a specific cluster of aromatic
residues that facilitate binding to multi-walled carbon nanotubes
(MWCNTs).
135
Similarly, they found that sialic acid binding
immunoglobulin-like lectin-14 (Siglec-14), highly expressed on
human macrophages, binds to carbon nanotubes (CNTs),
thereby initiating pro-inflammatory signaling.
136
In particular,
they observed that Tim4 engages with polystyrene (PS) micro-
plastics through aromatic–aromatic interactions, thus facilitating
the macrophage uptake of these microplastics.
137
Despite these
interactions, PS microplastics do not induce the release of
inflammatory cytokines from macrophages.
In addition to the immune recognition, NMs have been
found to contribute to the modulation of macrophage acti-
vation, differentiation, and polarization. An example for this
phenomenon was that TiO
2
NMs instigate an aberrant acti-
vation of macrophages, as manifested by the amplified pro-
inflammatory M1 phenotype coupled with TLR4-mediated sup-
pression of innate immune.
138
Furthermore, TiO
2
NMs have
been implicated in inducing significant mitochondrial dys-
function and attenuating macrophage phagocytic ability,
showing increased mitochondrial ROS levels, diminished ATP
synthesis, and reduced metabolic activity within the tricar-
boxylic acid (TCA) cycle.
139
Notably, NMs in the GIT also
exhibit an adjuvant effect by enhancing the immune response
to biomolecules adsorbed on their surfaces.
112
The interaction
between macrophages and antigens or toxins attached to par-
ticles leads to increased T-cell proliferation compared to
soluble forms.
140
Moreover, studies have shown that TiO
2
NMs
induce increased inflammatory response of primary human
mononuclear phagocytes to endotoxin lipopolysaccharides
(LPS), which is enhanced in cell culture media containing
calcium that promotes the binding of biomolecules to intesti-
nal proteins and calcium precipitates.
141,142
These findings
exhibit the intricate interplay between NMs, cellular immune
responses, and the local microenvironment.
3.2. The immune tolerance mediated by NMs
The intricate interplay between endogenous NMs and immune
tolerance in the GIT is essential for maintaining intestinal
health.
143
In particular, amorphous magnesium-substituted
calcium phosphate (AMCP) NMs, formed in the gut from
secreted calcium and phosphate ions, participate in the regu-
lation of immune responses. These NMs facilitate the capture
of soluble macromolecules such as proteins and bacterial pep-
tidoglycan, facilitating their transport across the epithelial
barrier to APCs located in Peyer’s patches (Fig. 4).
12
This
process not only shields protein antigens from enzymatic
degradation en route but also modulates the intestinal
immune equilibrium by promoting immune tolerance.
12
Of
note, the simultaneous co-transportation of peptidoglycan
alongside AMCP NMs is vital, as it influences the APCs pheno-
type by upregulating PD-L1, an immunosuppressive molecule
that increases during inflammation to mitigate tissue
damage.
144
The complex interplay emphasizes the vital role of
AMCP NMs in coordinating the intestinal immune response,
elucidating a fundamental strategy by which the body pre-
serves tolerance to external antigens while combating patho-
genic challenges.
Thus far, investigations have also illuminated the contribu-
tory role of NMs present in edible plants towards the regu-
lation of intestinal immune balance. For instance, Zhang et al.
demonstrated that sulforaphane (SFN), delivered by nano-
Fig. 4 NMs exhibit double-edged effects on the mucosal immune system. Accidentally exposed NMs may precipitate intestinal inflammation,
whereas endogenous and specific food-derived NMs can foster immune tolerance. This paradoxical characteristic underscores the necessity to miti-
gate nanotoxicity while simultaneously offering insights for the conceptualization of nanomedicine strategies.
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particles derived from broccoli (BDNs), effectively alleviated
mouse colitis by promoting tolerogenic DCs through AMP-acti-
vated protein kinase (AMPK) activation.
13
They revealed that
BDN treatment not only reduced the levels of TNF-α, IL-17A,
and IFN-γ, which were elevated by DSS, but also enhanced the
expression of IL-10. Furthermore, BDN administration pre-
vented weight loss associated with DSS, reduced inflammatory
infiltrates in the mucosa, preserved a higher number of
colonic goblet cells, and significantly mitigated colonic short-
ening compared to mice that received only DSS. This study
highlights the importance of nanoparticle-mediated SFN deliv-
ery to DCs in the lamina propria, compared to the free form of
SFN, which lacks DC-targeting specificity.
145
In addition to
broccoli, numerous edible plants, including grapes, grape-
fruits, ginger, and tomatoes, are sources of NMs.
146
Analogous
to BDNs SFN, NMs from these dietary sources may harbor
molecules with similar functions, capable of fostering intesti-
nal immune tolerance. Various edible plants such as grapes,
grapefruits, ginger, and tomatoes also contain nanoparticles
that may possess similar immune-modulating properties as
BDNs SFN, potentially promoting intestinal immune tolerance.
Therefore, nanoparticles in edible plants play a significant role
in maintaining intestinal immune homeostasis.
Leveraging the concept of NMs shielding antigens to
promote immune tolerance, various immunotherapeutic strat-
egies have been proposed.
145
The GIT plays a crucial role in
immune responses by distinguishing harmless dietary anti-
gens from harmful pathogens, maintaining a delicate balance
between immune tolerance and activation.
147
NMs, with their
unique physicochemical properties, have emerged as effective
tools for modulating this balance. By delivering antigens,
immune regulatory signals, or therapeutic agents to the GALT,
NMs promote the generation of regulatory T cells (Tregs) and
facilitate local or systemic immune tolerance.
12,148,149
This
novel approach overcomes the limitations of traditional immu-
notherapy, offering a precise method to modulate the immune
system. The application of NMs to induce intestinal immune
tolerance represents a promising advancement in the manage-
ment of inflammatory bowel disease (IBD), food allergies, and
other gastrointestinal immune disorders. However, further
research is warranted to elucidate the intricate interactions
and long-term impacts of NMs within the human body to
ensure the safety and efficacy of clinical interventions.
4. Systemic fate of NMs in the
intestine
Following translocation across the epithelial barrier, non-
degradable particles typically undergo two primary pathways
Fig. 5 The schematic diagram depicts the route of NMs following oral administration through the intestine. Lymphatic transport occurs through
two main mechanisms: passage through M cells in Peyer’s patches and conveyance of chylomicrons via central chyle ducts. NMs first enter collect-
ing ducts, undergo filtration at mesenteric lymph nodes, and are ultimately directed to the thoracic duct through the cisterna chyli. Subsequently,
they enter the systemic circulation via the subclavian vein. The enterocytes, enteric nerves, and connected peripheral nerves, mediate the transloca-
tion of NMs from the gut to the central nervous system. Created with BioRender.com.
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including lymphatic transport and circulation transport via the
portal vein.
150
For instance, Volkheimer et al. investigated the
behaviors of non-degradable microparticles, using polyvinyl
chloride (PVC) particles ranging from 5 to 110 μmasa
model.
150
Initially, these PVC particles traverse the intestinal
wall, entering the chyle in lymph vessels below, thereby facili-
tating lymphatic transport. Alternatively, these particles can
translocate through the portal vein circulation, as evidenced by
elevated particle levels in blood from mesenteric veins after
PVC particle ingestion. Actually, the effective lymphatic trans-
port is supported by chylomicrons (dietary lipids encapsulated
into NMs by intestinal epithelial cells) and M cells in Peyer’s
patches, predominantly through lacteals (Fig. 5).
151,152
Within
the villus core connective tissue, one to two longitudinal lym-
phatic capillaries, referred to as the central lacteal, originate at
the villus apex, descend through the mucosal muscle layer into
the submucosa, and give rise to a lymphatic plexus. The lym-
phatic journey of NMs involves passage through pre-collecting
lymphatics, collecting lymphatics, lymphatic trunks, and
ducts, culminating in arrival at the thoracic duct via mesen-
teric lymph nodes and the lacteal pool (Fig. 5).
79
Consequently, these substances evade first-pass metabolism in
the liver.
153,154
Apart from the blood and lymphatic vessels, our recent
report has unveiled a novel pathway for the transportation of
orally administered NMs to the central nervous system via peri-
pheral nerves, specifically demonstrating the direct transpor-
tation of Ag NMs in the GI tract to the brain and spinal cord
through the vagus and spinal nerves, bypassing the traditional
blood circulation route.
155
This transport mechanism is prob-
ably facilitated by the selective uptake of Ag NMs by neurons,
due to their argyrophilic properties.
156
It is well established
that a complex and dynamic interplay exists between the
nervous system and the immune system. The nervous system
regulates immune functions by directly innervating lymphoid
organs and releasing neurotransmitters that modulate
immune cell activities.
157
Conversely, immune cells can influ-
ence neuronal function through the secretion of cytokines.
158
Hence, the discovery of this novel neural pathway for NMs
transportation from gut presents a significant opportunity to
modulate neural immunity. It provides innovative approaches
for delivering therapeutic agents directly to the central nervous
system, potentially impacting immune responses associated
with neurological disorders.
5. Conclusions and perspectives
The intersection of nanotechnology and intestinal health has
sparked interdisciplinary research into NMs and their impact
on the gut.
33
This review explores the complex journey of NMs
in the intestinal environment, including: (1) interactions with
enzymes and microbes in the gut lumen, which can affect the
microbiome and overall intestinal health; (2) passage through
the intestinal mucus layer, where NMs may be eliminated or
penetrate deeper; (3) interaction with intestinal epithelial cells
and potential translocation across the epithelial barrier; (4)
involvement with the mucosal immune system, leading to acti-
vation of innate immune responses or induction of immune
tolerance, thus influencing mucosal immunity; and (5) trans-
portation to distant organs through circulatory, lymphatic, or
neural pathways.
It is essential to recognize that the interaction between
NMs and the gut environment is inherently bidirectional.
Enzymes and microorganisms within the gut lumen can cata-
lyze the degradation of biodegradable NMs, altering their
physical and chemical properties. Concurrently, the NMs and
their degradation products can significantly influence the
structure and function of these initiating microbial commu-
nities, with the potential to induce extensive systemic physio-
logical changes. After these initial interactions, NMs progress
to the intestinal mucus layer, which serves as a critical selec-
tive barrier. Depending on their altered physicochemical pro-
perties, NMs may be either retained and eliminated or pene-
trate deeper, reaching the epithelial cells beneath. This pivotal
interaction with the intestinal epithelium not only determines
the potential for NMs to translocate across the epithelial
barrier but also significantly impacts intestinal health.
Understanding these initial stages of NM interactions within
the gut is crucial for setting the stage for their subsequent
engagement with the mucosal immune system and systemic
transport, thereby influencing broader physiological effects.
This comprehensive view underscores the importance of con-
sidering both the local level interactions and the broader sys-
temic implications when studying the impact of NMs on intes-
tinal health.
The dual functionality of NMs concerning mucosal immu-
nity has been a focal point of this review. While some studies
have begun to explore the activation of innate immune
responses and the promotion of mucosal tolerance by
NMs,
9,12,13
a comprehensive understanding of the underlying
mechanisms remains elusive. The current literature primarily
observes the impact of NMs on macrophages and DCs, particu-
larly in the context of inflammation. However, there is a
notable gap in our knowledge regarding the direct effects of
NMs on macrophage polarization and the molecular mecha-
nisms. Future researches are warranted to delve deeper into
the specificity of immune activation by NMs, identifying the
targeted immune cell types (e.g., macrophages, DCs, T cells)
and elucidating the modulation of activation or suppression
pathways within these cells. In addition, unraveling the precise
mechanisms of NM interaction with cell surface receptors and
the subsequent intracellular signaling pathways is critical for
advancing our understanding of NMs’impact on mucosal
immunity.
The convenience and high patient compliance associated
with oral drug delivery have garnered significant interest in the
transport of NMs across the intestinal epithelium. Although
we have outlined three primary pathways for the systemic cir-
culation of orally administered NMs, a thorough analysis of
the transport mechanisms, especially through mesenteric
routes, is still lacking. The processes by which NMs transition
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from the intestinal lumen to systemic circulation and the influ-
ence of their physicochemical properties on this translocation
are areas that require further investigation. Additionally, the
variability in research findings, attributed to differences in
experimental models and individual variances, underscores
the complexity of NMs and the need for a more nuanced
understanding of their transport dynamics.
In conclusion, the field of nano-intestine research has
made substantial strides in enhancing our knowledge of NMs’
biosafety, offering valuable insights that promote human
health and societal advancement. Despite the significant pro-
gress, there is an ongoing need for research to address the
gaps identified in this review. Understanding the specificity of
immune activation by NMs, the detailed mechanisms of their
interaction with the mucosal immune system, and the path-
ways facilitating their passage through the intestinal epi-
thelium are essential for harnessing their therapeutic potential
while mitigating potential health risks.
Data availability
No primary research results, software or code have been
included and no new data were generated or analysed as part
of this review.
Conflicts of interest
The authors declare that they have no competing interests.
Acknowledgements
This work was supported by the National Key Research and
Development Program of China (2022YFC2409701,
2021YFA1200900), the National Natural Science Foundation of
China (32271460, 22388101), the Youth Innovation Promotion
Association of Chinese Academy of Sciences (2023042), Beijing
Nova Program (20240484663), and the New Cornerstone
Science Foundation (NCI202318). All figures were retrieved
from https://app.biorender.com.
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