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Nanoparticle-based therapeutics of inflammatory bowel diseases: a narrative review of the current state and prospects

Yang, Meia; Zhang, Yujiea; Ma, Yanaa; Yan, Xiangjia; Gong, Liuyunb; Zhang, Mingzhena,∗; Zhang, Baojunc,∗

Author Information
doi: 10.1097/JBR.0000000000000078
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Abstract

Introduction

Inflammatory bowel diseases (IBDs) are a group of chronic and relapsing gastrointestinal (GI) diseases characterized by recurrent intestinal mucosal inflammation. Ulcerative colitis (UC) and Crohn disease (CD) are two major forms of IBD.[1] CD may affect the entire GI tract in a non-continuous fashion, but usually occurs in the terminal ileum or perianal region, which causes complications such as strictures, abscesses, and fistulas. Unlike CD, inflammation in UC is usually limited to the colon, extends proximally from the rectum to a varying degree, and frequently involves the periappendiceal region.[2,3] More than 2 million Europeans and 1.5 million North Americans have IBD, and the number of patients in China will reach 1.5 million by 2025. Moreover, the overall cancer rate of UC in China is predicted to reach 3.7%. IBD has become a global burden with accelerating incidence. Although the exact cause of IBD is unknown, previous research indicates a relationship to inappropriate immune responses, environmental factors, and the gut microbiota.[4,5] Indeed, imbalanced immune responses can induce continuous inflammation in the intestinal mucosa.

Due to uncertainties about the etiology of IBD, it currently has no cure. Accordingly, therapeutic strategies aim to attain and maintain remission from inflammatory episodes. Classically prescribed drugs for clinical treatment of IBD include anti-inflammatory drugs 5-aminosalicylates (5-ASAs) and corticosteroids], immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate, and tacrolimus), and biologic anti-tumor necrosis factor (TNF) agents (infliximab, adalimumab, and golimumab). In addition, many newly developed drugs are waiting to be approved for marketing, including a drug that interferes with leukocytes (natalizumab) and several inhibitors of pro-inflammatory cytokines [eg, interleukins 12 and 23 (IL-12 and IL-23)].[6,7] Although these drugs can alleviate inflammation to a certain extent, 30% to 50% of patients have little or no response. In addition, long-term administration increases the likelihood of relapse and multiple adverse effects, thus limiting further clinical applications.[8] Therefore, there is an urgent need to develop new treatment strategies to enhance targeting and reduce side effects.

Theoretically, colon-targeted strategies can enhance drug efficacy and reduce the side effects of systemic administration to some extent. Traditional colon-targeted drug delivery routes comprise parenteral, rectal, and oral routes of administration. Although parenteral and rectal administrations have instant and efficient therapeutic effects, problems with inevitable systemic absorption, inability to accurately reach the diseased area, or patient non-compliance still exist. The most promising mode of administration is oral-targeted colon. Primary strategies of traditional oral colon-targeted drugs include pH-sensitive coating polymers, slowly degrading time-dependent polymers, and approaches based on bacterial enzymes such as pro-drugs and polysaccharides.[9] pH-sensitive drug coating polymers, such as Eudragit® S100, Eudragit® L100, hydroxypropyl methyl cellulose phthalate 50, and cellulose acetate phthalate,[10] are based on a colon-specific pH of 6.1–7.5. However, reduced mucosal bicarbonate secretion, increased mucosal and bacterial lactate production, impaired short chain fatty acids absorption and metabolism, and changes in intestinal transit time and dietary fiber intake may all contribute to a reduced colonic luminal pH in patients with IBD.[11] Changes in colonic pH may impede drug release and absorption, thereby affecting those strategies. Other colon-targeted drugs are coated with a slowly degrading polymer, such as ethylcellulose, based on their long transit time in colon. In healthy individuals, the colonic transit time is about 41.1–62.3 hours; however, a shorter colon length and symptoms such as diarrhea can greatly reduce transit time in patients with IBD to 9.5–39.1 hours.[10] Gut microbiota dysbiosis and altered microbial metabolites in IBD patients lead to dysfunction of mucosal immune responses, defective mucosal barrier function, and immunomodulatory dysfunction, which can further influence colonic transit time and pH.[12] These intestinal microenvironment changes that occur in IBD patients severely reduce the effectiveness of conventional colon-targeted strategies. Moreover, due to the large size of conventional colon-targeted formulations, their ability to penetrate the mucosal barrier and be taken up by cells is further reduced.

The emergence of nanotechnology can overcome these biological barriers to a large extent. First, NPs can deliver drugs in a sustained or controlled way, and be designed to degrade and release their payload in response to different environmental stimuli. Second, the surface of NPs can be chemically modified to enhance targeting of the appropriate intestinal microenvironment. Third, the small size of nanocarriers allows more effective targeting of diseased tissues by accumulation at the inflamed and disrupted epithelium via an enhanced permeability and retention (EPR) effect.[13]

This review summarizes recent progress in nanomedicine for diagnostics and treatment of IBD. We first describe types of nanocarriers, NP-mediated conventional drug therapies, a variety of novel NP-based drug delivery systems (NDDSs), the therapeutic effect of nanozymes, and nanotechnological advances in multimodal imaging of IBD (Fig. 1). Finally, we present challenges associated with the use of nanotechnology and potential developmental directions for future IBD treatments.

Figure 1
Figure 1:
Nanoparticle-based applications in IBD. This summarizes the types of nanocarriers, a variety of novel NDDSs, the therapeutic effect of nanozymes, and nanotechnological advances in multimodal imaging of IBD. IBD=inflammatory bowel disease, NDDSs=NP-based drug delivery systems.

Database search strategy

The authors used the following inclusion criteria: studies that the application of nanoparticle in inflammatory bowel diseases. English language and full-text articles published between January 2015 and October 2020 were included in this non-systematic review. The studied disease models are colitis and Crohn's disease. The authors searched the PubMed database to identify relevant publications. The literature search strategy was conducted as follows: each of two synonymous phrases, that is, (1) nanoparticle, (2) nanotechnology, (3) nanoenzyme, (4) exososome, (5) plant nanoparticle, were combined with each of: (a) inflammatory bowel diseases, (b) colitis, (c) Crohn's disease, (d) imaging, for example, “nanoparticle inflammatory bowel diseases”, viz. (1) + (a); “nanoparticle colitis”, viz. (1) + (b), etc. Twenty queries were obtained. The authors screened the reference list of included studies to identify other potentially useful studies. Firstly, the authors screened the titles and abstracts, then, the full texts for keywords, such as “inflammatory bowel diseases”, “nanoparticle” to find those that were potentially suitable. The data extraction process focused on the information about each study type and coexisting inflammatory bowel diseases. The author also proposed the classification of nanocarriers and some new treatment methods such as nanoparticle-mediated gas therapy and macrophage polarization strategies.

Application of nanomedicine in IBD

Nanocarriers

Nanoparticles (NPs) with sizes ranging from 1 to 100 nm can be divided into inorganic, organic, and newly discovered plant-derived NPs (PDNPs). Inorganic NPs have the advantages of facile preparation, excellent biocompatibility, and wide surface conjugation chemistry[14,15] including carbon nanotubes,[16] semiconducting quantum dots,[17,18] metallic (oxide) NPs,[19–23] magnetic NPs,[24–26] silica NPs,[27–29] Selenium NPs[30] and upconversion NPs.[31,32] In contrast, organic NP carriers, including dendrimer,[33–35] liposome,[36–38] polymeric[39–41] and exosome NPs,[42,43] are mainly based on polymers, proteins, peptides, and lipids.[44] (Table 1) Organic NP carriers are usually derived from natural products like chitosan and dextran, which are biocompatible, biodegradable, and exhibit superior safety profiles. Exosomes are a natural organic nanocarrier for drug and gene delivery whose structure is similar to nanospheres consisting of a lipid bilayer membrane. Exosomes are nanosized membrane vesicles (30–100 nm) secreted from various live cells. Exosomes have many natural advantages, such as their small size, long circulation time, endogenous protein and RNA, avoidance of the lysosomal/endosomal pathway, high stability, and native targeting properties. Accordingly, exosomes have been exploited as drug and gene delivery systems.[43] In addition, recent studies have found that exosome-like NPs can be extracted from some edible plants, such as ginger, grapefruit, carrot, and grape. These PDNPs have displayed significant therapeutic effects on inflammatory diseases and cancer. Indeed, exosomes and PDNPs have been suggested as next-generation therapeutic delivery systems for the treatment of inflammatory diseases, cancer, and other diseases.[45]

Table 1
Table 1:
Summary of classification and characteristics of nanocarriers

The size of NPs contributes to their ability to target areas of inflammation through the EPR effect; however, they are also easily cleared by the reticuloendothelial system (RES). NPs have high surface-to-volume ratios compared with larger particles, which contributes to their ability to adsorb more proteins during circulation in the blood and increases their surface charge. Protein absorption can affect NP stability, promote NP disintegration, and compromise the delivery of cargo to the intended tissue. Moreover, an increased surface charge leads to greater clearance by RES and other filtering organs.[46,47] To develop more effective NDDSs, researchers have designed a multitude of nanocarriers by altering canonical formulations of NPs to optimize their size, zeta potential, composition, shape, and/or surface. In particular, for treatment of IBD, the major challenge for NPs is to arrive at and penetrate the gastrointestinal mucosa to target the underlying inflammatory cells.[48]

Polyethylene glycol (PEG) is the most common surface modification in IBD nanotherapy. Due to its hydrophilic nature, PEG coatings on NPs sterically preclude them from interacting with neighboring NPs and blood components, and shield the surface from aggregation, opsonization, and phagocytosis to prolong circulation time.[49] Other modifications include bioconjugation and biomimetic strategies to camouflage NPs from systemic clearance, and coating of NPs with self-recognizing peptides or proteins (eg, cell membranes extracted from erythrocytes or leukocytes) to promote self-recognition of the NP construct.[50,51]Table 1 summarizes nanocarriers used for IBD in recent years.

NP-mediated conventional medicine for the treatment of IBD

Table 2 summarizes conventional IBD drugs, including aminosalicylates, corticosteroids, immunomodulators, and biologics, used for NP-mediated delivery to the colon. NPs loaded with traditional IBD drugs are designed into an intelligent targeted drug delivery mode based on the pathophysiological changes of IBD intestinal tissue, and NP-mediated delivery of conventional IBD drugs to the colon has shown greater therapeutic impact compared with conventional delivery in animal models. To a certain extent, these NDDSs can overcome physiological barriers to achieve better therapeutic effects. Although the traditional oral medicines facilitate the self-medication, improved patient compliance, and avoid the pain and possible contamination caused by intravenous injection, the medicines need to overcome many physiological obstacles before reaching targeted colon site. For example, gastrointestinal differences in pH, various enzymes and mucous layer that blocks drug absorption. The designed NDDSs can use nanoparticles that are stable in the pH environment of the gastrointestinal tract to protect drugs from degradation by enzymes, and modification of the NP surface enables the NPs to penetrate the mucus barrier.[52] Conventional intravenous administration provides high systemic bioavailability but inevitably increases the possibility of severe drug side effects. With the aid of NDDSs, drugs could circulate in the blood for a longer time and release their cargo to the sites of disease locally, which reduces the drug dosage and minimizes harmful side effects.[53]

Table 2 - Overview of applications combining nanotechnology with conventional medicine for treatment of inflammatory bowel disease
Medications Drug names Nanoparticles Size IBD model Reference
Aminosalicylates 5-aminosalicylates Liposome 0.5–1.5 μm DSS Kesisoglou et al[54]
PCL 200–350 nm TNBS Pertuit et al[55]
Silica 140 nm TNBS Moulari et al[27]
SiO2 90 nm DSS Tang et al[29]
PLGA 200–300 nm In vitro Davoudi et al[56]
ZnO 30 nm DSS Li et al[22]
HSA 190 nm DSS Iwao et al[57]
Sodium alginate/inulin nanohydrogels 100–180 nm In vitro Bahadori et al[58]
Chitosan-coated ginger-derived nanocarriers 93.5 nm In vitro Markam and Bajpai[59]
Corticosteroids Budesonide PLGA/Eudragit 260-–290 nm TNBS Makhlof et al[60]
Lipid 200 nm DSS Beloqui et al[65]
PLGA/Eudragit® S100 240 nm DSS, TNBS and oxazolone Ali et al[61]
PLGA 200 nm Oxazolone Ali et al[63]
HA 177-–293 nm In vitro Vafaei et al[66]
Carboxymethyl inulin (CMI) 210 nm DSS Sun et al[67]
Dexamethasone Ascorbyl palmitate hydrogel Not mentioned Knockout mice Zhang et al[68]
PLGA 162 nm DSS Lee et al[64]
Solid lipid 72.9 nm DSS Dianzani et al[36]
Immunomodulators Cyclosporine A PLGA 158 nm DSS Melero et al[40]
Lipid 107–205 nm DSS Guada et al[37]
Tacrolimus PEG-bPLA copolymer with cationic lipids 110 nm DSS Wang et al[62]
Biologics TNF-α siRNA Cationic polymer p(CBA-bPEI) 211–275 nm DSS Xiao et al[69]
PLA-PEG 609 nm DSS Laroui et al[71]
Calcium phosphate/PLGA 152 nm DSS Frede et al[70]
Ginger-derived lipid vehicles 232.7 nm In vivo Zhang et al[73]
Infliximab PEGylated polyesterurethane (PU-PEG) 200–287 nm In vitro Pabari et al[74]
5-ASAs = 5-aminosalicylates, bPEI = branched polyethylenimine, CBA = cystamine bisacrylamide, DSS = dextran sulfate sodium, HA = hyaluronic acid, HSA = human serum albumin, IBD = inflammatory bowel disease, PCL = poly(ε-aprolactone), PEG = polyethylene glycol, PLA = polylactic acid, PLGA = poly(lactic-co-glycolic acid), siRNA = Small interfering RNA, TNF-α = tumor necrosis factor α.

Because 5-ASAs are rapidly absorbed in the small intestine, the amount of drug that reaches the colon is usually minimal; however, use of an NDDS can effectively solve this problem. Organic nanocarriers, including liposome,[54] polymers,[55,56] proteins,[57] nanohydrogels,[58] have been employed for 5-ASA nanodelivery. Among them, polymer nanocarriers are the most widely used. These polymers have high drug-loading rates and good biocompatibility, and can be deposited at the site of inflammation. 5-ASA/polymer NPs were shown to more efficiently reduce inflammation at much lower doses than free 5-ASA, thus offering an alternative for the dosing of IBD drugs to avoid medication-related side effects. Moreover, encapsulating 5-ASA in polymers can greatly reduce its absorption by the small intestine to slow down drug release in the intestinal environment, which significantly mitigated colitis in mice.[55,56] Inorganic NPs have also demonstrated many advantages for drug loading. For example, silica NPs have the advantages of adjustable size, easy preparation, and non-toxicity, and are thus favored by numerous researchers. Compared with a high dosage of free 5-aminosalicylic acid (5-ASA), 5-ASA-SiO2 NPs could efficiently reduce levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and myeloperoxidase at a 32-times-lower drug dosage in a dextran sulfate sodium (DSS)-induced UC mouse model.[29] Recently, researchers have developed new varieties of NPs that not only exert anti-inflammatory effects themselves, but also play a role in loading and delivery of drugs. Li et al[22] utilized ZnO nanoparticles (ZnONPs) combined with 5-ASA to treat DSS-induced colitis in mice. ZnONPs treatment alone could reduce oxidative stress, attenuate inflammatory responses, and, importantly, restored the balance of intestinal flora in DSS-induced colitis mice, which may be attributed to the release of Zn2+ from ZnONPs. Combination therapy with ZnONPs and 5-ASA enhanced the antiulcer activity of 5-ASA in DSS-induced colitis model mice. Therefore, ZnONPs can act as an adjunct therapy for IBD. Markam et al[59] used electrostatic attraction to generate chitosan-bound ginger-derived nanocarriers exhibiting excellent drug-loading capacity and anti-inflammatory properties, as ginger itself is an anti-inflammatory agent. Therefore, such combinations have enormous potential applications in NDDS.

Corticosteroids and immunomodulators have also been demonstrated as effective for treating IBD. However, long-term use of these drugs is limited by global immunosuppression and other numerous systemic side effects. In recent years, polymeric NPs,[60–64] lipid,[36,37,65] and some natural-derived nanocarriers,[66–68] have mainly been used for delivery of these drugs into inflamed intestinal tissues, which improves local bioavailability and the drug toxicity profile. Both Makhlof et al[60] and Ali et al[61] used budesonide (BUD)-loaded poly(lactic-co-glycolic acid) (PLGA) polymers coated with pH-sensitive Eudragit® S100 (∼240 nm) to treat IBD. Presence of the polymer coating increased NP stability in the stomach and elicited better therapeutic efficacy on IBD symptoms. In addition, an oral redox-sensitive BUD nanocarrier based on an amphiphilic inulin polymer with 4-aminothiophenol grafted onto carboxymethyl inulin (CMI) was developed.[67] In the intestine, BUD can be quickly released in the presence of glutathione (GSH). 4-Aminothiophenol-CMI NPs exhibited a superior therapeutic effect compared with a suspension of BUD in an IBD model. Tacrolimus, an immunosuppressant agent, has also been included in different nanocarrier systems. Tacrolimus-loaded cationic lipid-assisted nanoparticles were synthesized from poly (ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA) and 1,2-dioleoyl-3-trimethylammonium-propanechloride. In vitro and in vivo studies demonstrated the stability and accumulation of these NPs in the colon, leading to attenuation of DSS-induced colitis.[62]

As a pro-inflammatory factor, TNF-α plays an important role in the development of IBD. To this end, TNF-α small interfering RNA (siRNA) technology has been widely employed for IBD. Varieties of polymeric NPs, such as cationic polymer,[69] PLGA,[70] poly(lactide) poly(ethylene glycol) (PLA-PEG),[71] and chitosan NPs,[72] have been explored for their ability to deliver TNF-α siRNA for the treatment of IBD. Zhang et al[73] developed a novel siRNA delivery system using ginger-derived lipid vehicles. In vivo studies showed that siRNA-CD98/ginger-derived lipid vehicles could effectively and specifically target colon tissues, resulting in reduced expression of CD98. Infliximab, that is, the antibodie of anti-TNF-α, are easily degraded in the harsh milieu of the gastrointestinal tract. Pabari et al[74] used a novel polymer nanomaterial polyesterurethane (PU) as nanocarrier of infliximab, and significantly increases the ability of cellular interaction and uptake compared with other polymer NPs. This result demonstrated the potential of PU and PU-PEG NPs for drug delivery to treat gastrointestinal inflammation.

In summary, the nanocarriers described above can effectively deliver IBD drugs to the colon, thus avoiding some of the disadvantages of traditional drug delivery and providing good therapeutic prospects for IBD patients.

Novel colon-targeted NDDS for IBD

As a result of advances in nanotechnology in recent years, a variety of colon-targeted NDDSs have been designed, mainly relying on the physiological and pathological environment of the intestine in IBD. Such factors include the pH environment of the GI track, overproduction of redox substances in response to inflammation, overexpression of specific enzymes and receptors, and changes in the gut microbiota (Fig. 2). Based on these factors, single or multiple-stimuli colon-targeted NDDSs can be designed to achieve more precise drug release, which minimizes the side effects of drugs in healthy tissue and achieves the therapeutic effect with the lowest dose of medicine. In the following sections, we outline the pathophysiological characteristics of colitis and summarize several novel strategies to achieve colon-targeted drug delivery.

Figure 2
Figure 2:
Different Colon-targeted drug delivery system strategies. (A) NP targeting of inflamed intestinal tissues is mediated by size. (B) NP targeting of inflamed intestinal tissues is based on the specific pH of the intestine. (C) NP targeting of inflamed intestinal tissues is mediated by enzymes or redox responsive. (D) NP targeting of inflamed intestinal tissues is mediated by microbiota. (E) NP can be targeted to intestinal tissues through active targeted modification. (F) NP derived from plants or exosomes can be used to target intestinal tissues. DC=dendritic cells, NPs=nanoparticles, ROS=reactive oxygen species.

Size-dependent NDDS

For precise targeting of tumors, the size of NPs is very important because it directly affects their pharmacokinetics, as they mainly enter tumor tissue through the EPR effect. Larger NPs tend to have higher retention in tumor tissue, but smaller NPs have better penetration ability.[75] In the pathological process of colitis, various inflammatory cells are activated to secrete a variety of inflammatory mediators, such as histamine, bradykinin, leukotriene and serotonin, which increase permeability of the endothelial barrier. Therefore, entry of NPs into inflamed colonic tissue mainly depends on the EPR effect and uptake by inflammatory cells.[76] Therefore, designing NPs of the correct size is very important for the treatment of colitis.

To explore the role of NP size in treatment of colitis, a nanosystem based on an SS-cleavable and pH-activated lipid-like material was designed to produce particles with sizes ranging from 50 to 180 nm. Utilizing the redox- and pH-responsiveness of the nanosystem, three different-sized NPs were generated: LNDsmall (54 nm), LNDmiddle (113 nm), and LNDlarge (183 nm). Particles mainly accumulated in inflamed colon tissue of DSS-induced colitis model mice, but were seldom observed in healthy mice. Compared with LNDsmall and LNDlarge, LNDmiddle exhibited the highest accumulation in the region of colitis.[77] However, no additional data was provided to indicate the most suitable size of NPs. In summary, the effect of NP size is an important consideration when designing NDDSs for IBD or other inflammatory diseases.

Stimulus-responsive NDDS

pH-responsive

In the healthy GI tract, luminal pH in the proximal small bowel ranges from 5.5–7.0, gradually rises to 6.5–7.5 in the distal ileum, thereafter decreases in the caecum to 5.5–7.5, and finally rises in the left colon and rectum to 6.1–7.5. However, changes in diet, mucosal bicarbonate and lactate production, bacterial fermentation of carbohydrates, and mucosal absorption of short chain fatty acids can lead to abnormal luminal pH in IBD patients. Some data from UC patients suggest substantially reduced pH values in the right colon, while the limited results available for Crohn disease have been contradictory.[11] Regardless, many researchers have used pH change in colon to design drug-delivery systems that allow for specific release of drugs in the colon.

As described above for conventional IBD drug-delivery systems, the most common strategies involve coating of NPs with pH-responsive polymers, such as chitosan, Eudragit® S-100, Eudragit® L100, and poly(acrylic acid) (PAA). Integration of a pH-sensitive polymer as a nanocarrier provides protection that allows drug transport to the lower region of the GI track. Importantly, this strategy effectively increases drug concentrations in the colon and reduces drug-related side effects. For example, to evaluate the therapeutic efficacy of glycyrrhizic acid and curcumin (CUR), Beloqui and Zeeshan designed Eudragit S100/PLGA pH-sensitive nanoformulations.[78,79] These drug-loaded, pH-sensitive NPs significantly decreased neutrophil infiltration, as well as levels of TNF-α, IL-1β, IL-6, and nitric oxide in a murine DSS-induced colitis model. Similarly, some inorganic NPs can be coated with a pH-responsive polymer to form a pH-responsive NDDS. For example, a novel pH-triggered oral NDDS was designed based on the mesoporous silica SBA-15 and pH-responsive polymer PAA.[80] PAA brushes were anchored on the pore outlets of mesoporous silica as a gatekeeper to control transport of drug molecules in and out of pore channels. In the colonic environment, pore outlets were opened when PAA brushes swelled and released the drug. However, this system of drug release and biocompatibility have only been verified in vitro, not in a colitis animal model.

Because of differences in the extent and severity of colitis, inherent inter/intraindividual variability, disease states, and dietary intake, the pH of each patient's colon will vary greatly. As such, design of colonic delivery systems merely based on pH is not reliable for the treatment of colon-related diseases.

NPs are typically endocytosed into cells via endosomal compartments and then subsequently trafficked to lysosomes. However, endosomes/lysosomes are not the active site for the majority of biological cargoes, which must successfully escape from endosomes/lysosomes into the cytoplasm to protect their payload from degradation by lysosomal enzymes. Because the pH of endosomes/lysosomes is low (4–6), pH-sensitive polymers can be used to induce endosomal escape via osmotic pressure changes, whereby rapid pH-triggered disassembly increases the particle number and subsequently induces osmolysis.[81] Calcium phosphate (CaP), a natural pH-sensitive material, was synthesized into siRNA-loaded CaP/PLGA NPs,[70] which exhibited a high affinity to nucleic acids but dissolved in the low pH environment inside the lysosome following endocytosis. A rise in osmotic pressure supports the escape of nucleic acids into the cytosol. CaP/PLGA NPs loaded with TNF-α, keratinocyte chemoattractant, or IP-10 siRNA were effectively taken up by gut epithelial cells, leading to a significant decrease of target gene expression in colonic biopsies and mesenteric lymph nodes of mice with DSS-induced colonic inflammation; significant relief of colitis symptoms was attributed to these findings.

Redox-responsive

Oxidative stress is considered to be one of the etiologic factors of IBD. The intestinal mucosa of patients with IBD are characterized by ROS overproduction and an imbalance of important antioxidants, leading to oxidative damage. Generally, ROS are generated by oxygen reduction and its secondary reactive products, including free radicals such as the radical anion superoxide O2•–, hydroxylradical (HO), peroxyl (RO2), alcoxyl (RO), and hydro-peroxyl (HO2), as well as non-radical species such as singlet oxygen (1O2), H2O2, and hydrochlorous acid (HOCl). Neutrophils and macrophages of the GI tract are the main sites of ROS production. Upregulation of ROS can lead to mucosal barrier dysfunction and increased permeability of epithelial cells, which in turn leads to a pathogenic cascade that initiates and perpetuates inflammatory responses in the gut.[82] Therefore, some researchers have designed colon-targeted NDDSs based on excessive ROS to treat IBD.

Vong et al[83] developed a nitroxide radical-containing nanoparticle (RNPO) composed of methoxy-PEG-b-poly(4-[2,2,6,6-tetramethylpiperidine-1-oxyl]oxymethylstyrene), an amphiphilic block copolymer. The hydrophobic segment possesses stable nitroxide radicals via an ether linkage, which can scavenge ROS. Compared with normal cells, ROS-treated epithelial colonic cells significantly increased RNPO uptake in vitro. In DSS-induced colitis mice, orally administered RNPO significantly accumulated in the cells of inflamed colons, whereas almost no RNPO was observed in cells of normal colons; moreover, the symptoms of acute colitis were significantly relieved.[83]

Lee et al[84,85] first used bilirubin, a potent endogenous antioxidant capable of scavenging various ROS, and PEG or hyaluronic acid (HA) to assemble novel ROS-scavenging bilirubin NPs and a HA-bilirubin nanomedicine. Without loading of anti-inflammatory drugs, bilirubin NPs and HA-bilirubin nanomedicine exerted potent anti-inflammatory effects, and could significantly reduce levels of myeloperoxidase and pro-inflammatory cytokines associated with DSS-induced acute colitis. Zhang Jianxiang's group connected 4-phenylboronic acid pinacol ester, which contains oxidation-responsive units-boronic esters, with the hydroxyl groups of β-cyclodextrin to synthesize ROS-responsive and hydrogen peroxide-eliminating NPs (OCD NPs). In the presence of H2O2, OCD NPs can rapidly decompose and efficiently eliminate H2O2 in a dose-dependent manner. In vitro, OCD NPs could significantly attenuate oxidative stress and inhibit inflammatory responses in both inflammatory and epithelial cells. In vivo, OCD NPs effectively reduced oxidative stress and attenuated UC in mice.[86,87] Recently, Li et al[88] developed a self-assembled and oxidation-degradable Janus-prodrug, Bud-ATK-Tem (B-ATK-T), composed of the ROS-responsive aromatized thioketal (ATK), BUD, and the antioxidant tempol (T). In the presence of 1 mM H2O2, B-ATK-T NPs can quickly hydrolyze and release the drug. In DSS-induced colitis mice, B-ATK-T NPs effectively accumulated in diseased colon tissue and significantly relieved the symptom of colitis.

To exploit the ability of GSH to break disulfide bonds, a TKPR-modified, PEG-b-poly(trimethylene carbonate-codithiolane trimethylene carbonate)-b-polyethylenimine triblock copolymer system (TKRP-RCP) was developed. By reversibly crosslinking TKPR to polymersome membranes using disulfide bonds, TKRP-RCP can effectively target macrophages. A TKPR-RCP co-encapsulating TNF-α siRNA and dexamethasone sodium phosphate (Dex) was efficiently internalized (∼98%) by macrophages. In response to the reducing agent GSH, the membrane was de-crosslinked to accelerate cargo release into the cytoplasm. Intravenous injection of the co-delivery TKPR-RCP relieved UC and significantly prevented colonic injury in animals.[89]

Enzyme-responsive

There are a large number of microflora in the colon that can produce enzymes such as β-glucosidase, cellulase, azoreductase, and nitroreductase. Various polymer materials (such as pectin, chitosan, dextran, and sodium alginate guar gum) cannot be degraded in the upper part of GI tract, but can be degraded by specific enzymes produced by the colonic microflora. Chen et al[90] developed a chitosan (CSO)-modified, Dex-loaded, esterase-responsive lipid NDDS (CSO/Dex/LNPs), based on 3,3′-dithiodipropionic acid, quercetin, and glyceryl caprylate-caprate, and using ester bonds for surface modification. In vitro results revealed that NPs could rapidly release the drug in esterase-containing artificial intestinal fluid. In a DSS-induced colitis mouse model, CSO/Dex/LNPs could reduce expression levels of pro-inflammatory cytokines, colonic atrophy, and histomorphological changes, but increased colonic expression of E-cadherin. To target 5-flurouracil delivery to the colon, Kumar et al[91] developed mesoporous silica NPs capped with guar gum, a colonic enzyme-responsive material. In colon cancer cell lines, 5-flurouracil was released from guar gum-mesoporous silica NPs in response to a simulated colonic enzyme mixture; however, colitis was not verified in this model. Similarly, Li et al[92] developed an NDSS based on mesoporous MCM-41 capped with silsesquioxane, an azo-reductase-responsive agent. In the presence of azo-reductase, NPs released the drug to the target site. However, these enzyme-responsive colon-targeted NDDSs should be evaluated using in vivo experiments to further verify whether they can successfully release drugs in the complex colon environment of the body.

Multi-responsive

Thus far, approaches employed for colon-targeted NDDSs have mainly included pH-responsive, redox-responsive, and enzyme-responsive drug release. However, there are many limitations of utilizing only a single factor to design a drug delivery system. Therefore, it may a better strategy to treat IBD by combining multiple stimuli factors in a single NDDS.

Oral delivery of siRNA therapeutics is a particularly effective way to treat IBD. However, the instability of siRNA and its degradation in the stomach and small intestine require further consideration. Knipe et al[93] developed an enzyme/pH dual-sensitive nanogel to deliver TNF-α siRNA to the colon. This platform consists of an enzyme-sensitive microgel composed of poly(methacrylic acid-co-N-vinyl-2-pyrrolidone) crosslinked with a trypsin-degradable peptide linker, as well as a pH-sensitive nanogel composed of polycationic 2-(diethylamino)ethyl methacrylate. This combination microgel can protect siRNA from harsh gastric conditions, such as pH increases in the intestine, and gradually swells and degrades in the presence of intestinal enzymes (eg, trypsin) to release the therapeutic nanogels within the intestine. Subsequently, polycationic 2-(diethylamino)ethyl methacrylate can escape from acid endosomes and release TNF-α siRNA into the cytoplasm. In vitro experiments demonstrated that TNF-α siRNA-loaded nanogels released from this platform successfully reduced secreted levels of TNF-α from RAW 264.7 macrophages. Notably, this nanoplatform can be loaded with other drugs to treat IBD. Similarly, Bertoni et al[94] developed pH/ROS dual-sensitive nano-in-micro composites. These phenylboronic esters-modified dextran (OxiDEX) NPs coated with the pH-sensitive polymer hydroxypropyl methylcellulose acetate succinate selectively degrade in response to hydrogen peroxide (H2O2). Thus, this system can protect drugs from being released in low pH gastric conditions. Excessive H2O2 production within the intestinal tract of patients with IBD should cause OxiDEX NPs to release their cargo, thus increasing the drug concentration at the site of colon inflammation. However, this hypothesis was only verified in vitro and not in vivo.

Some natural products can themselves exert multiple responses and, thus, be used to synthesize multi-responsive NPs for the treatment of IBD. Previously, Sun et al[67] used CMI and 4-aminothiophenol to synthesize pH/redox-sensitive NPs. In low-pH solution, an increasing enforcing effect and decreasing electrostatic repulsion between CMI molecules caused a smaller particle size. In contrast, in alkaline media, NPs swelled and formed loose spheres with large diameters. Due to the high reducing potential of GSH, the disulfide bond can be broken, leading to further disintegration of NPs. Importantly, a good effect of CMI NPs was verified in a DSS-induced colitis model. Due to the existence of different functional groups, such as amino groups and disulfide bonds, as well as the β-sheet structures present in natural silk fibroin, Gou et al[95] synthesized CUR-loaded multi-responsive NPs surface functionalized with chondroitin sulfate (CS-CUR-NPs). When triggered with acid pH, GSH, and ROS, CS-CUR-NPs exhibited excellent bioresponsiveness. In animal experiments, CS-CUR-NPs could remarkably alleviate the symptoms of UC, regulate the homeostasis of intestinal microbiota, and improve the survival rate of mice with UC through oral administration or intravenous injection routes.

Active-targeting NDDS

Due to the superiority of size, NDDS could target tumor tissues through the EPR effect, that is, passive targeting. However, as the EPR effect of inflammation is far less than that of tumors, active targeting is needed to further increase the colon-targeting ability of an NDDS. Active targeting is attained by modifying the surface of NPs with ligands that can recognize the target (ie, the inflammation site of the colon), which increases the concentration of drug delivered to the target site, improves the therapeutic effect, and reduces adverse effects. During the inflammatory process of IBD, colon epithelial cells and activated macrophages overexpress a variety of specific antigens and receptors, such as folate receptor (FA), CD44, CD98, peptide transporter 1 (PepT1), mannose receptor, and dectin-1, which can be used as targets for active targeting. Thus, combining EPR and active targeting may synergistically increase the efficiency of delivery to improve colitis treatment.[96]

FA-mediated delivery

Yang et al[97] and Zhang et al[98] used FA-functionalized PLGA/PLA-PEG-FA NPs loaded with 6-shogaol or the Hsp90 inhibitor 17-AAG (NP-PEG-FA/17-AAG) for the treatment of colitis. Ex vivo fluorescence labeling and flow cytometry experiments indicated that FA-functionalized NPs were taken up more by colon-26 epithelial-like and activated RAW264.7 cells than non-functionalized NPs. FA-NPs were orally administered and their uptake efficiency in colon was increased as a result of FA-mediated intracellular delivery. These two inflamed colitis-targeted nanoformulations significantly alleviated colitis symptoms and accelerated colitis wound repair in DSS-treated mice. Notably, NP-PEG-FA/17-AAG yielded a similar therapeutic response at a dose 10 times less than that of intraperitoneally administered 17-AAG.

CD44-mediated delivery

CD44, a single-chain transmembrane glycoprotein with a molecular mass of 80 to 250 kD, is overexpressed on the surface of colon epithelial cells and macrophages in UC tissues. HA can selectively bind to CD44 and block its release of a drug because of its large and biocompatible molecular size, not to mentions its ability to be readily degraded by HAase after being taken up by cells.[99] These characteristics of HA inspire utilization of HA-functionalized NPs for targeted treatment of colitis. As described above, HA–bilirubin nanomedicine increased colonic targeting of bilirubin, which accumulated in inflamed colonic epithelium and restored epithelial barriers in a murine model of acute colitis.[85] HA-functionalized polymeric NPs were loaded with CD98 siRNA and CUR to treat UC. CD98 is overexpressed in active colitis, and siRNA technology can reduce CD98 expression in colonic epithelial cells. CUR has numerous attractive pharmacological effects, such as anti-inflammatory and wound-healing activities. HA-functionalization of NPs increased their uptake by colon-26 and RAW264.7 cells. Compared with siCD98 or CUR-based monotherapy, HA-siCD98/CUR NPs exerted combinational effects against UC by protecting the mucosal layer and alleviating inflammation, both in vitro and in vivo.[100] HA-modified polymer NPs have also been used for targeted delivery of a natural tripeptide, lysine-proline-valine (KPV), which has been shown to attenuate the inflammatory responses of colonic cells. HA-KPV-NPs could delivery KPV to colonic epithelial cells and macrophages. Oral administration of HA-KPV-NPs prevented mucosal damage, downregulated pro-inflammatory cytokine levels, and exhibited better therapeutic efficacy in a DSS-induced UC mouse model.[101] Additionally, chondroitin sulfate can target the CD44 receptor. Chondroitin sulfate-modified CUR NPs yielded notable targeting of CUR to macrophages, and animal experiments revealed that either oral administration or intravenous injection of these NPs remarkably alleviated the symptoms of UC and improved the survival rate of mice with UC.[95]

CD98-mediated delivery

The cytoplasmic domains of CD98, a type II transmembrane protein, can interact with β1 integrin to regulate integrin signaling-mediated functions. CD98 is overexpressed in intestinal macrophages and colonic tissues in mice with active colitis. Single-chain CD98 antibody (scCD98)-PEG-urocanic acid-modified chitosan NPs prepared for colitis treatment significantly reduced levels of CD98 and inflammatory cytokines in Colon-26 cells and RAW 264.7 macrophages. Moreover, oral administration of these scCD98-modified NPs embedded in a hydrogel could alleviate the severity of chronic and acute colitis in a mouse model.[102]

PepT1-mediated delivery

KPV not only has anti-inflammatory properties, but can be combined with the polypeptide PepT1 to target macrophages. CyA–PLGA–KPV/montmorillonite/chitosan NPs were designed using KPV as a surface modification to target therapy-related cells (colonic epithelial cells and macrophages). KPV modification increased intracellular uptake by inflammatory cells. Oral administration of these NPs reduced levels of inflammatory cytokines and relieved acute UC.[103]

Mannose receptor-mediated delivery

Mannose receptor is highly expressed on the surface of colon epithelial cells and macrophages. To exploit this for treatment of colitis, trimethyl chitosan (MTC) modification of NPs has been used to target delivery of miR-146b (MTC-miR146b NPs) to intestinal macrophages. MiR-146b can inhibit activation of M1 macrophages, which produce pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-23) and promote inflammation. MTC-based NPs could selectively target F4/80-positive intestinal macrophages. MTC-miR146b NPs promoted mucosal regeneration and relieved acute UC in a DSS-induced colitis model.[104]

Intestinal microbiota-related NDDS

Intestinal microbiota play a key role in IBD. Several anaerobic microbiota in the distal ileum and colon can interact with host epithelial cells and the mucosal immune system. In IBD, changes in microbial composition and function result in persistent pathogenic immune responses, epithelial dysfunction, and increased mucosal permeability.[12] Reportedly, eight types of microbiota are highly related to IBD, including Faecalibacterium prausnitzii, Clostridium clusters IV and XIVa, Bacteroides, Roseburia species, Eubacterium rectale, Escherichia coli, Fusobacterium, and Candida albicans.[105] As mentioned above, ZnO NPs,[22] bilirubin nanoparticles,[84] and CUR[100] can regulate the microbiota, and also have a certain therapeutic effect on colitis.

NPs that affect the intestinal microbiota are mostly inorganic NPs, including metal NPs, metal oxide NPs, and transition metal NPs. For instance, separate addition of three metal oxide NPs (ZnO, CeO2, and TiO2 NPs) into a model colon (to study the complex matrix and microbial community in situ) clearly affected phenotypes and stability of the microbial community.[106] Oral administration of AgNP to mice induced colitis-like symptoms, including high disease activity index and histological scores, disruption of microvilli and tight junctions in the intestinal epithelium, and upregulation of pro-inflammatory cytokines. In addition, AgNP-exposed mice exhibited changes in intra- and interphyla abundance of Bacteroidetes and Firmicutes, such as reduced ratios of Firmicutes/Bacteroidetes to the probiotic bacteria genus Lactobacillus, indicating an increase in lowly abundant families of bacteria. SiO2NP-exposed mice exhibited increased microbial species richness and diversity. Mice that ingested TiO2NPs did not exhibit obvious changes in their intestinal microflora.[19] Some NPs can alleviate the symptoms of colitis by regulating the intestinal microflora. For example, intragastric administration of variously sized gold NPs (AuNPs) or platinum NPs (PtNPs) into a DSS-induced colitis model mice prior to model establishment revealed that Au(5 nm)/citrate and Au(5 nm)/PVP had more marked anti-colitis effects than differently sized TA-stabilized AuNPs. PtNPs size-dependently alleviated DSS-induced murine colitis and enhanced gut-barrier function by upregulating colonic expression of heat-shock protein 25 and tight junction proteins. In addition AuNPs or PtNPs could induce gut dysbiosis in mice by decreasing α-diversity, the Firmicutes/Bacteroidetes ratio, certain short-chain fatty acid-producing bacteria, and Lactobacillus.[21,107] Biogenic polyphosphate NPs derived from Synechococcus sp. PCC 7002 effectively maintained gut microbial homeostasis and relieved DSS-induced colitis in mice.[108] Although these NPs have been shown to affect the intestinal microbiota, specific mechanisms need further verification. Regardless, when designing an NDDS for IBD treatment, integration of these NPs should be considered.

Undoubtedly, the intestinal microbiota can also be used as a target, and treatment of IBD by remotely and precisely changing specific flora represents a new therapeutic strategy. Xiao et al[26] utilized magnetic iron oxide nanoparticles to internalize Roseburia intestinalis, thus realizing the directional delivery of probiotics under an external magnetic field in vitro and in rats with colitis. This novel strategy showed a better therapeutic effect than traditional intragastric administration and altered the bacterial composition, leading to a higher diversity of microbial taxa in rats with CD. Plant-derived exosome-like nanoparticles (ELNs) containing small RNAs and microRNAs (miRNAs) capable of targeting various genes in Lactobacillus rhamnosus (LGG) were extracted from ginger (GELNs). GELNs can be preferentially taken up by lactobacillaceae. ELN RNAs regulated the composition, metabolism, growth, and localization of gut microbiota, thus shaping the homeostatic balance between immunity and gut microbiota. Specifically, GELN-RNAs were found to ameliorate mouse colitis by promoting expression of IL-22.[109] Thus, we can use nanotechnology to remotely and precisely regulate biological systems, and provide novel strategies for the intelligent treatment of IBD. Moreover, this work represents a step towards wireless magnetic manipulation of living biological entities in microbiology.

Natural NDDS

NP derived from natural sources has been widely used in the treatment of various diseases for their high biosecurity and low cost. Natural NP mainly include exosomes secreted by mammalian cells and PDNPs, which share common characteristics such as nanosized vesicles, involvement in cell-to-cell communication, and cargos containing bioactive molecules-nucleic acids, proteins, and lipids. Recent developments in nanotechnology have permitted the structure and components of exosomes and PDNPs to be detected, and an increasing number of studies have applied them to the treatment of IBD. This section will summarize the application of exosomes and PNDPs for the treatment of IBD.

Exosomes

Exosomes originate as intraluminal vesicles within multivesicular bodies that, once mature, fuse with the plasma membrane and release their cargo into the extracellular space. Exosomes are relatively homogenously sized with diameters between 50 and 150 nm and contain various biological components, such as nucleic acids (mRNAs, miRNAs, etc), proteins, lipids, and other components.[110] Exosomes are found in almost all living cells and various body fluids, such as dendritic cells, lymphocytes, epithelial cells, blood, urine, and saliva. Circulating exosomes participate in intercellular communication and can mediate immune responses; moreover, they play a role in the pathogenesis of IBD.[111]

Exosomes and their components and functions in various diseases are gradually being explored. Proteomic analysis of exosomes isolated from the serum of mice with acute colitis revealed 56 proteins, most were acute-phase proteins and immunoglobulins. Notably, DSS exosomes activated the mitogen-activated protein kinase signaling pathway and triggered a pro-inflammatory response in RAW264.7 macrophages in vitro. The results of this study provide insight into the immunomodulatory role of serum exosomes in acute colitis.[112] Liquid chromatography-mass spectrometry of saliva exosomes extracted from UC and CD patients identified more than 2000 proteins — among them were eight proteins that only existed in IBD patients (both CD and CD). Gene ontology analysis indicated that proteasome subunit alpha type 7 (PSMA7) was expressed at much higher levels in patients with CD and UC compared with healthy controls. Thus, salivary exosomal PSMA7 may be a very promising biomarker to release patients from the pain of colonoscopy.[113]

Exosomes derived from mesenchymal stem cells (MSCs) not only have the ability to self-renew and reparative effects on injury or disease of several tissue, but also exhibit anti-inflammatory and immunomodulatory properties. In a DSS-induced colitis mouse model, exosomes released from human umbilical cord-derived MSCs reduced the expression of pro-inflammatory cytokines IFN-γ, TNF-α, and IL-1β, and increased the secretion of anti-inflammatory cytokines TGF-β1 and IL-10. In addition, exosomes from MSCs may exhibit therapeutic capabilities by inhibiting increased IL-7 expression in macrophages to alleviate DSS-induced IBD.[114–117] Likewise, exosomes isolated from adipose-derived MSCs exhibit anti-inflammatory properties. In vitro, increased expression of NADPH oxidases 1 and 2, nuclear factor κB, inducible nitric oxide synthase, intercellular adhesion molecule 1, cyclooxygenase 2, and MMP-9 in HT-29 cells in response to lipopolysaccharide exposure was significantly reduced by either exosome or melatonin treatment. In vivo, a combination of melanin-exosome therapy significantly decreased the number of circulating inflammatory cells, expression of inflammation markers, oxidative stress, apoptosis, and fibrosis in Sprague-Dawley rats with DSS-induced acute inflammatory colitis.[117] These results demonstrate the role of MSCs in anti-inflammatory and immune regulation, and support their use as a new treatment for inflammatory diseases.

Intestinal epithelial cells can protect the intestine from pathogenic stimuli or harmful substances in food, and play an important role in the intestinal mucosal barrier. Exosomes isolated from intestinal epithelial cells can communicate with microbiota and host immune cells, and thus help maintain a homeostatic environment in the gut. Therefore, intestinal epithelial cells exosomes may have crucial diagnostic or therapeutic implications in IBD. Yang et al[118] developed an autologous intestinal epithelial cell exosome-transfer strategy to treat UC by extracting intestinal exosomes from the feces of DSS-induced colitis mice at four disease stages (before treatment, during DSS treatment, healing-phase, and back to normal/recovered) with a multi-step sucrose gradient ultracentrifugation method. In vitro studies revealed that only the healing-stage exosomes had anti-inflammatory activity. Oral administration of healing-stage exosomes to DSS mice significantly reduced colitis.[118] Thus, healing-phase autologous exosomes may be a novel personalized approach to effectively treat UC in human patients.

Exosomes from other immune cells have also been explored for potential use in IBD. In DSS-induced murine colitis, exosomes isolated from granulocytic myeloid-derived suppressor cells attenuated DSS-induced colitis by inhibiting Th1 cell proliferation and promoting regulatory T cell expansion.[119] Dendritic cell-derived exosomes treated with S. japonicum soluble egg antigen decreased both body weight loss and the disease activity index, increased colon lengths, and prevented colon damage in mice with acute DSS-induced colitis.[120] Macrophages are divided into M1 and M2 types based on their phenotypes. M1 macrophages secrete higher levels of pro-inflammatory cytokines, whereas activated M2 macrophages produce higher levels of the immunoregulatory cytokine IL-10, thus exerting an anti-inflammatory effect. Depending on the activating stimulus, M2 macrophages can be classified as M2a, M2b, M2c, or M2d subtypes. Exosomes derived from M2a, M2b, and M2c macrophages have been analyzed in DSS-induced colitis; M2b macrophage exosomes suppressed IL-1b, IL-6, and IL-17A expression, and significantly attenuated the severity of colitis in mice, whose effective were obvious than those M2a and M2c macrophages exosomes.[121] These findings provide new insight into the role of macrophage exosomes in IBD, as well as a new approach to treat IBD. exosomes derived from M2b macrophages were more effective

Recently, Wei et al[122] revealed the link between obesity and colitis risk using visceral fat exosomes. High-fat diet changed the miRNA profile (increased expression of miR-155) of visceral fat exosomes, and changed the phenotype of exosomes from anti-inflammatory to pro-inflammatory. It is worth noting that these inflammatory exosomes effectively accumulated in the intestinal lamina propria, and promoted macrophage polarization to an M1 type, which are more likely to cause intestinal inflammation. In addition, exosome-mediated release of an miR-155 inhibitor significantly prevented DSS-induced colitis.[122] In summary, this study revealed how obesity exacerbates the exosome pathway of colitis, and proposed an exosome-based intervention strategy for the treatment of colitis.

Plant-derived nanoparticles (PDNPs)

Similar to mammalian exosomes, PDNPs contain and transport miRNA, bioactive lipids, and proteins to mediate communication between plant cells. Therefore, PDNPs may be used as natural therapeutics or drug carriers to efficiently deliver specific drugs.[45] As previously mentioned, plant-derived ELNs can maintain homeostasis of the gut microbiota and relieve colitis. For example, Zhang et al[73] created lipid NPs from edible ginger. These ginger-derived nanoparticles (GDNPs, average diameter ∼230 nm) contained high levels of lipids, a few proteins, ∼125 microRNAs (miRNAs), and large amounts of ginger bioactive constituents (6-gingerol and 6-shogaol). Most importantly, GDNPs seemed resistant to degradation by saliva, the acidic environment of the stomach, and the highly active proteolytic enzymes present along the intestinal tract; thus, GDNPs may be an excellent oral colon-targeted drug nanocarrier. Notably, as GDNPs were mainly taken up by intestinal epithelial cells and macrophages, oral administration of GDNPs to mice naturally targeted colonic tissues. GDNPs not only exhibited a good therapeutic effect on colitis, but can also be efficiently loaded with doxorubicin or siRNA CD98, and targeted the site of colon inflammation.[45,123,124]

Recently, the functions NPs derived from other edible plants, such as broccoli and Lycium barbarum, have also been studied. Orally broccoli-derived NPs could protect mice against colitis by mediating activation of adenosine monophosphate-activated protein kinase (AMPK) in dendritic cells, thus playing a potential role in inhibiting intestinal dendritic cell activation and monocyte recruitment associated with mouse colitis.[125]Lycium barbarum lipid-based edible nanoparticles (LBLNs) also showed therapeutic effects in UC and could be efficiently taken up by macrophages. In vitro, LBLNs inhibited secretion of the pro-inflammatory cytokines TNF-α and IL-12, and upregulated expression of the anti-inflammatory factor IL-10. In vivo, oral administration of LBLNs resulted in accumulation in inflamed colon tissues, which attenuated UC-relevant symptoms.[126] These PDNPs not only have anti-inflammatory, anticancer, and antibacterial activities, but can also be used as nanocarriers to load anti-inflammatory drugs to treat IBD. Chung et al[127] used rosemary-derived rosmarinic acid to synthesize PEG-modified rosmarinic acid NPs that, once loaded with Dex, could effectively relieve the symptoms of DSS-induced acute colitis.[127] These findings demonstrate that PDNPs can be used as novel therapeutics and targeted NDDSs to treat IBD.

Therapeutic effect of nanozymes on IBD

Nanozymes are a type of nanomaterial with nanoscale sizes (1−100 nm) and enzymatic catalytic properties. Because of their low cost, high stability, and durability, nanozymes have been applied in biosensing, environmental treatment, clinical diagnostics and treatment, antibacterial agents, cytoprotection against biomolecules in the cell, and so on. Nanozymes are mainly divided into four families: oxidase (OXD), peroxidase (POD), catalase (CAT), and superoxide dismutase (SOD).[128] Considering that ROS is overproduced in IBD, nanozymes with ROS-scavenging activity are expected to be an effective therapeutic agent (Fig. 3). Through POD, CAT, and SOD activities, Prussian blue (PB) could effectively scavenge ROS, including •OH, H2O2, and •OOH. Therefore, PVP-modified PB (PPB) nanozyme-like NPs were synthesized. PPBs with POD, CAT, and SOD enzymes-like activities could effectively scavenge ROS. In mouse models of DSS-induced colitis, PPBs could scavenge ROS and inhibit pro-inflammatory cytokine levels without distinct side effects, contributing to alleviation of colitis progression.[129] To further explore the enzyme activity of PB, manganese Prussian blue nanozymes (MPBZs) with SOD-, CAT-, and/or POD-like activities were constructed using an Mn2+ ion source solution and [Fe(CN)6]4− ion source with PVP via a facile and efficient strategy. MPBZs showed distinct therapeutic efficacy in mice with DSS-induced colitis via a primary effect on the Toll-like receptor signaling pathway, and did not cause any adverse side effects.[130] Recently, more researchers have gradually discovered the multiple enzymatic activities of some metal elements, such as manganese, platinum,[131] and rhodium ions,[132] which have better synergistic ROS-scavenging capacities. Doping of these ions into NPs to synthesize nanoenzymes can effectively treat IBDs both in vivo and in vitro. Additionally, nanozymes with multi-enzyme activities have been developed; for example, hollow porous carbon spheres co-doped with nitrogen and iron (Fe/N-HCNs) were synthesized using a one-pot strategy. Fe/N-HCNs with CTAB/F127 as the micellar template and iron acetylacetonate [Fe(acac)3] as the iron source have POD-, OXD-, CAT-, and SOD-like activities. In a DSS-induced colitis model, Fe/N-HCNs significantly reduced the daily activity index; decreased expression of myeloperoxidase, TNF-α, and IL-1β; increased the length of the colon; and effectively improved the symptoms of colitis.[133]

Figure 3
Figure 3:
Therapeutic effect of nanozymes on IBD. Neutrophils and macrophages could produce excessive ROS and pro-inflammatory cytokines during inflammatory episodes. Nanozymes could effectively scavenge excess ROS and some cytokines via multi-enzyme like activity including superoxide dismutase, catalase, or peroxidase like activities in intestine with inflammatory bowel disease. DC=dendritic cells, GI tract=gastrointestinal tract, ROS=reactive oxygen.

Nanoparticle-based imaging of IBD

Thus far, clinical diagnostic imaging of IBD technologies mainly includes single-proton emission computed tomography, positron emission tomography, computed tomography, and magnetic resonance imaging. However, these methods have disadvantages such as low sensitivity, ionizing radiation, or low accuracy. As such, development of a safe and effective IBD imaging method is needed. Nano-based imaging, which incorporates nanotechnology and imaging modalities, can facilitate early detection of IBD, observations of disease activity, and may be used to monitor therapeutic responses at a cellular and/or molecular level.[134] Thus, nano-based imaging is a promising strategy for imaging IBD. During the pathological process of IBD, a unique inflammatory environment develops in the intestinal cavity, including changes in hypoxia, intestinal pH, mucus, intestinal barrier function, and overexpression of specific markers[135] such as myeloperoxidase[136] and matrix metalloproteinases 2, 7, and 9 (MMP-2/7/9).[137] (Fig. 4). These specific markers can be used to design NP-based imaging systems to achieve safe, sensitive, and early detection of IBD.

Figure 4
Figure 4:
Designing nanoparticle-mediated imaging strategies based on the specific biomarkers or excessive ROS during the pathological development of IBD. The response or luminous intensity of these nanoparticles corresponds to the symptoms of IBD to achieve detection IBD. IBD = inflammatory bowel diseases, ROS = reactive oxygen species.

Xu et al[138] designed self-illuminating NPs for inflammation imaging and cancer therapy. These core-shell structured NPs are based on luminol (a luminescent donor), Ce6 (a fluorescent acceptor and photosensitizer), and PEG. Under inflammatory oxidative conditions with excess ROS, luminol emits bioluminescence with an emission peak of 450 nm; through the bioluminescence resonance energy transfer effect, the fluorescent receptor (Ce6) generates 675-nm fluorescence and singlet oxygen (1O2), enabling direct in vivo detection of inflammation and tumor photodynamic therapy respectively. This system was used to evaluate the effect of Ce6-luminol-PEG (CLP) in vivo imaging in three different animal inflammation models, including DSS-induced colitis mice model. Local administration of CLP and free luminol revealed that CLP could accumulate in the inflammation site and the luminescent signal from CLP was much stronger than that of luminol molecules. These results demonstrate that the CLP nanoparticle is an effective nanoprobe for in vivo luminescence imaging of IBD or other diseases associated with high myeloperoxidase and ROS expression.[138]

Recently, a nano-based imaging system involving a cytoplasmic protein-powered fluorescence cascade amplifier (HCFA) was developed to detect the degree of hypoxia in IBD. 4-Aminobenzoic acid (azo)-modified mesoporous silica NPs loaded with Black Hole Quencher 2, cytoplasmic protein-binding squarylium dye, and the β-cyclodextrin polymer combined with azo through a host−guest interaction. The azo band was reduced to amino derivatives through a complete reduction reaction in the hypoxic microenvironment, while the released squarylium dye could then bind to cytoplasmic proteins to drastically enhance fluorescence intensity, thus realizing fluorescence signal amplification for imaging of hypoxia. Intraperitoneal injection of HCFA in a mouse colitis model revealed that the fluorescence intensity of HCFA increased with the severity of colitis. Moreover, compared with the commercial small-molecule fluorescent probe hypoxyprobe-1, the sensitivity of HCFA was much higher.[139]

Clinically, iodinated small molecules and barium sulfate suspensions are mainly used for computed tomography (CT) imaging of the gastrointestinal tract (GIT). However, it has been found that these small molecules could be absorbed through the GIT when administered orally. Thus this would not only affect the accuracy of diagnosis, but also increased the accumulated radiation exposure with IBD patients. Therefore, Naha et al[140] used dextran-coated cerium oxide NPs as the contrast agent for GIT imaging with or without IBD. Cerium oxide NPs are inexpensive and have the functions of scavenging ROS, protecting cells from radiation-induced toxic and side effects, and promoting wound healing. Dextran coating on cerium oxide nanoparticle surfaces provides stability in aqueous media, biocompatibility, and specificity toward inflammation sites. Therefore, IBD patients would benefit from these contrast agents and reduce the effects of radiation exposure.

Conclusion and prospects

This review summarizes recent applications of nanotechnology in the treatment of IBD. This chapter just summarizes part of the application of nanotechnology that are widely used and researched clearly in IBD, and general overview of some design strategies of colon-targeted NDDSs. The application of many other nanomaterials in IBD and other new nanotechnology-mediated therapy has not yet been summarized. The main focus of these smart NP-based drug delivery systems is development of a variety of inexpensive and safe nanomaterials, efficient targeting of disease sites, escaping the immune system, and quick release of cargoes from nanomaterials. Although many hurdles must be overcome when designing a highly efficient NDDS to the colon, its realization is possible through changes in the size, shape, and surface modification of nanocarriers. Therefore, nanotechnology has great prospects in the diagnosis and treatment of IBD. However, most existing NDDSs are targeted to the site of inflammation in UC, and there are few treatments for CD. Therefore, more NDDSs capable of targeting the small and large intestines should be a focus of future research to treat CD.

Although significant progress has been made in the treatment of IBD, there is room to design more efficient NDDSs through combination with new strategies. For example, gas therapy, an emerging and promising treatment method, has been widely applied in the treatment of inflammation-related diseases, especially cancer. Therapeutic/therapy-assisted gases (NO, CO, H2S, H2, O2, SO2, and CO2) can regulate vasodilatation, neurotransmission, anti-inflammatory, and anti-oxidative reactions. Combination nanomedicine with these gas prodrugs has realized tumor-targeted, controlled release of these gases, which reduces their side effects.[141] However, gas therapy has not been used for the treatment of IBD and may be a novel therapeutic strategy. Macrophages play an important role in the pathogenesis of IBD. In response to stimulation by inflammation, macrophages polarize toward a pro-inflammatory M1 phenotype; in contrast, during the resolution of inflammation, macrophages switch to an anti-inflammatory M2-like phenotype. Therefore, modulation of macrophage phenotype from an M1 to M2 state is a promising approach for the treatment of inflammatory diseases.[142] Indeed, a growing body of evidence suggests that NPs can act as a nanocarrier to deliver drugs to polarize macrophages from an M1 to M2 type, which can effectively treat inflammatory diseases and tumors.[143,144] Therefore, NP-based macrophage polarization is a very promising method for future treatment of IBD.

Of course, to realize clinical translation of these smart NDDSs, many obstacles need to be overcome. For example, the safety of nanomaterials needs further study in vitro and in vivo before clinical and translational studies. Moreover, how to simplify the drug delivery system and convert these designs into oral or injectable preparations with high human acceptance is pivotal for large-scale production. Once these problems are resolved, NDDSs have enormous and immediate potential to be applied for clinical treatment of patients with IBD.

Acknowledgments

None.

Author contributions

MZ and BZ contributed to the conception of the manuscript. MY prepared the manuscript. YZ, YM, XY and LG contributed to the constructive discussions. All authors read and approved the final manuscript.

Financial support

This work was supported by the National Natural Science Foundation of China (No. 82000523), the Natural Science Foundation of Shaanxi Province of China (Nos. 2020JQ-087 and 2020JQ-095), the “Young Talent Support Plan” of Xi’an Jiaotong University, China (No. YX6J001), the Fundamental Research Funds for the Central Universities, China (No. xzy012019070), the China Postdoctoral Science Foundation, China (No. 2019M663657).

Conflicts of interest

The authors have no conflicts of interest to disclose.

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Keywords:

drug delivery system; imaging; inflammatory bowel diseases; nanoparticles; nanozymes

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