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Nanoparticle-Based Drug Delivery Systems for

Inflammatory Bowel Disease Treatment
Jian Gao 1 , Jiannan Li 2 , Zengyou Luo 1 , Hongyong Wang 3 , Zhiming Ma 1
1
Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China;
2
Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, People’s Republic of China; 3Department of
Radiotherapy, The Second Hospital of Jilin University, Changchun, People’s Republic of China

Correspondence: Zhiming Ma, Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun,
People’s Republic of China, Email mazhiming@jlu.edu.cn

Abstract: Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory condition characterized by recurring inflamma­
tion of the intestinal mucosa. However, the existing IBD treatments are ineffective and have serious side effects. The etiology of IBD
is multifactorial and encompasses immune, genetic, environmental, dietary, and microbial factors. The nanoparticles (NPs) developed
based on specific targeting methodologies exhibit great potential as nanotechnology advances. Nanoparticles are defined as particles
between 1 and 100 nm in size. Depending on their size and surface functionality, NPs exhibit different properties. A variety of
nanoparticle types have been employed as drug carriers for the treatment of inflammatory bowel disease (IBD), with encouraging
outcomes observed in experimental models. They increase the bioavailability of drugs and enable targeted drug delivery, promoting
localized treatment and thus enhancing efficacy. Nevertheless, numerous challenges persist in the translation from nanomedicine to
clinical application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the
future, it will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery
strategies, and screen new nanomedicines. Nevertheless, numerous challenges persist in the translation from nanomedicine to clinical
application, including enhanced formulations and preparation techniques, enhanced drug safety profiles, and so forth. In the future, it
will be necessary for scientists and clinicians to collaborate in order to study disease mechanisms, develop new drug delivery
strategies, and screen new nanomedicines.
Keywords: nanoparticles, inflammatory bowel diseases, targeted delivery, passive targeting, active targeting, drug delivery system

Introduction
Inflammatory bowel disease (IBD) is a chronic, non-specific inflammatory disease that affects the intestinal tract.1 The
prevalence of IBD is highest in North America and Europe, where it is estimated that 6.9 million people globally have it.2,3
The prevalence of inflammatory bowel disease (IBD) has been on the rise in newly industrialised countries over the past two
decades, reaching a point of accelerated growth.2,3 In contrast, the Western world is currently experiencing a phase of
stabilisation in terms of incidence, with prevalence expected to remain at approximately one percent by 2030.4 This presents
a significant challenge to global public health.
The two main types of IBD are Crohn’s disease,1 which typically affects the gastrointestinal tract in a segmented structure,
and ulcerative colitis, where lesions primarily affect the colonic mucosa and submucosa in a continuous pattern.5 Abdominal
pain, diarrhea, bloody stools, and weight loss are only a few of the primary clinical symptoms. Additionally, the most typical
extra-intestinal problems primarily affect the joints, skin, eyes, and bile ducts, significantly impacting the quality of life.6,7
Although the exact cause of IBD is still unknown,8 several factors, including immunological, gastrointestinal,
environmental, nutritional, and microbial infections, may be linked to IBD.9,10 The pathophysiology of IBD is char­
acterised by a loss of function of the mucosal epithelial cell system, local immune cell responses, dysbiosis of the gut
microbiota, and changes in the local environment of the tissues. Despite the lack of curative treatment for the eradication
of IBD,11 these physiological and pathological changes provide new targets for the development of targeted drug delivery

Drug Design, Development and Therapy 2024:18 2921–2949 2921

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systems for IBD. Inducing an initial remission and preventing relapse during remission are the general principles of
pharmacological treatment of IBD.12 Aminosalicylates, antibiotics, glucocorticoids, immunomodulators, and biologics
are commonly used in conventional drug therapy for IBD. These drugs aim to improve the mucosal lining of the colon
and repair, induce and maintain inflammatory remission.
A significant obstacle to effective treatment is drug delivery to the diseased site. Parenteral, transoral, and rectal enema are
traditional delivery methods for IBD.13 Because of its low cost of production, convenience of handling, and good compliance,
the oral dose form is regarded as the most desirable and acceptable form of daily administration for treating IBD.14,15
However, the active ingredient is absorbed by the mucosal membrane of the alimentary tract and distributed throughout the
body following oral formulation. The development of systemic adverse drug reactions can impact treatment outcomes, as they
are influenced by notable variations in the gastrointestinal environment and between healthy and inflamed intestinal regions.
Intrarectal administration can potentially deliver tissue concentrations even higher than oral administration and provide local
treatment for IBD in the distal colon.16 However, conventional enemas are ineffective in patient compliance because of their
short retention time in the colorectal lumen and the need for frequent administration.17,18 Therefore, it is imperative to design
effective drug delivery systems (DDSs) to deliver more drugs to the site of inflammation precisely.
Medical nanomaterials have come a long way in the last few years. Its goal is to design and manufacture materials
with novel properties and functions on the scale of 1 to 1000 nm, namely nanoparticles (NPs).19 NPs are small, have
a large surface area, and have a unique shape. As a novel bioactive carrier, NPs increase the local drug concentration at
the disease site to maximize drug efficacy. They have been significant in gastrointestinal diseases.20 Significant
advancements have been made in nanoparticle-based strategies for the treatment of inflammation and tumours. Several
chronic diseases, such as osteoarthritis,21 rheumatoid arthritis22 and skin conditions,23 have been treated with NSAIDs
(non-steroidal anti-inflammatory drugs) or Glucocorticoids as either a primary or adjunctive treatment option. These
diseases often require prolonged anti-inflammatory therapy. The developments in nanotechnology have markedly
enhanced the accumulation of anti-inflammatory agents. Targeting is the key to treating IBD. Targeted delivery of
IBD reduces systemic drug exposure and related side effects by releasing the drug directly into the inflamed tissue,
lowering the frequency of administration to obtain the required dosage, and minimizing the non-specific distribution of
the drug throughout the body. Currently, various NPs, including polymeric NPs, lipid-based NPs, liposomes, silica NPs,
nanogels, shell-core NPs, and particle NPs, are used as drug carriers for treating IBD.24
Several targeting strategies have been investigated so far, and they are often predicted by different physiological factors
between the colonic and proximal sections of the gastrointestinal tract.25 Its three primary divisions are passive, active, and hybrid
targeting. This paper has reviewed and discussed the targeting and functional roles of nanopharmaceutical agents in treating IBD
(Tables 1–3). We have summarised the effectiveness and limitations of different types of delivery systems for the treatment of
IBD (Table 4). Additionally, we have summarized the challenges and possible avenues for further study in this area.

Passive Targeting
The primary determinants of passive targeting are the physicochemical characteristics of the particle carrier itself (size,
charge, etc). and the local microenvironment.101 Thus, passive targeting methods for IBD may be achieved by altering
the nanosize of the NPs and exploring the local microenvironmental characteristics of the intestine (pH, reactive oxygen
species [ROS] levels, and overexpression of the digestive enzymes).

Targeting Based on Enhanced Permeability and Retention (EPR) Effect

In normal tissues, microvascular gaps seem to be densified and structurally intact. In contrast, to enable particle
adherence, the inflammatory intestine produces more mucus than normal tissue, and the small size of NPs increases
their capacity to penetrate the mucus.102 Furthermore, increased endothelial barrier permeability has been linked to
epithelial injury and loss of intercellular tight junction chains produced by various factors (inflammatory mediators,
cytokines, etc).103,104 NPs are taken up and retained in the inflammatory site by the infiltrating immune and inflammatory
cells, such as macrophages, dendritic cells, and neutrophils.105 This is known as the epithelial increased permeability and
retention effect (EPR) (Figure 1A).106 As a result, NPs can prolong their stay at the inflammation site by passively
targeting it.

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Table 1 The Passive Targeting and Functional Effects of Nanoformulations for IBD Treatment
IBD Type of Targeting Delivery Loaded NPs Delivery Model Main Results Ref
Targeting Mechanism route Agents/Cargo System

UC Passive EPR effect Oral delivery Bud NLCs DSS mice High encapsulation rate; lower [26]
model, J774 level of inflammatory factors;
cells line model longer drug residence duration
in the colon.

UC Passive EPR effect Oral delivery Cyclosporin A Protamine Jurkat cells line High encapsulation efficiency [27]
nanocapsules model and good drug loading capacity
decrease IL-2 secretion.

UC Passive EPR effect Oral delivery Celecoxib Nanomixed micelles Acetic acid The nanomixed micelles have [28]
rabbit model good anti-inflammatory and
antioxidant properties that help
alleviate colitis.

UC Passive EPR effect Oral delivery Bud PLGA Oxazolone The NPs target the colonic [29]
mice model inflammatory site to release
drugs.

UC Passive EPR effect Oral delivery 5-ASA Hemoglobin NPs Caco-2 and HT- High rate of drug release [30]
29 cell line combined with excellent
models biocompatibility and
biodegradability.

UC Passive EPR effect Oral delivery Rifaximin Tamarind gum NPs TNBS rats The NPs exhibit positive [31]
model therapeutic effects on colitis and
function as antioxidants.

UC Passive EPR effect Intravenous H2S donors ST-H2S liposomes DSS mice ST-H2S liposomes have an [32]
delivery model, Caco-2 excellent immunomodulatory
model, and potential.
RAW 264.7 cell
line model

UC Passive EPR effect Oral delivery Oleuropein NLCs DSS mice Anti-inflammatory and [33]
model, J774 antioxidant effects via lowering
cells line model TNF-α and ROS production and
secretion.

UC Passive EPR effect Oral delivery IFX EAC-IFX-L and AC- DSS mice AC-IFX-L and EAC-IFX-L [34]
IFX-L model showed better symptom relief
than the DSS treatment group.

UC Passive Lysozyme- Oral delivery Vancomycin Chitosan-polyaniline Caco-2 cell line Specific inflammatory [35]
triggered microgels model colonization, inhibition of
Staphylococcus aureus, superior
biosafety.

UC Passive Azoreductase Oral delivery Hydrocortisone MSs DSS mice Excellent stability, drug release [36]
enzymes model rate, and capacity to regulate
intestinal flora.

UC Passive Esterases Oral delivery 5-ASA SiNP TNBS mice High adhesion and low toxicity. [37]
model

UC Passive Esterases Oral delivery Dex PPNP DSS mice Biosafety, specific targeting [38]
model ability, and antioxidant activity.

(Continued)

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Table 1 (Continued).

IBD Type of Targeting Delivery Loaded NPs Delivery Model Main Results Ref
Targeting Mechanism route Agents/Cargo System

UC Passive Acid Vein injection Fluorescent Sphingomyelin DSS mice Target-specific liposomes [39]
sphingomyelinase agent ICG liposomes model and facilitate macrophage uptake.
Caco-2 cell line
model

UC Passive Azoreductase – Ornidazole and Sulfasalazine- HEK 293 cell The excellent stability [40]
enzymes sulfasalazine polyethylene glycol line model nanomicelles release the loaded
micelles drug by being activated by azo
reductase.

UC Passive Azoreductase Oral delivery M-Saf MSMs Mice model Capable of delivering drugs to [41]
triggered M-Bud targeted colonic sites

UC Passive α-amylase Oral delivery Dex HES-CUR NPs DSS mice The excellent anti-inflammatory [42]
responsive model and antioxidant properties of
NPs enable multi-drug
combination therapy.

UC Passive ROS-responsive Oral delivery Bud and Tpl Bud-ATK-Tpl DSS mice High drug release to minimize [43]
model and adverse effects; colitis treatment
RAW264.7 cell that combines anti-inflammatory
line model and antioxidant treatment.

UC Passive ROS-responsive Oral delivery Tpl OxbCD DSS mice and Excellent biosafety and [44]
TNBS mice antioxidant function are
model achieved via drug molecule
release from multiple
components that eliminate ROS.

UC Passive ROS responsive Oral delivery Silymarin SiRNP DSS mice Effective elimination of ROS, [45]
model and biodegradable, and improved
RAW 264.7 bioavailability of the drug.
cells model

UC Passive ROS-responsive Oral delivery SeM SeM@EM DSS mice SeM@EM improves drug [46]
model and adherence, alleviates
HT29 cell line inflammation, and promotes the
model growth of beneficial intestinal
microbiota.

UC Passive ROS-responsive Intravenous – OxbCD NPs Guinea pigs Superior ROS sensitivity and [47]
and model B16F10 biocompatibility.
subcutaneous cells and MDA-
injection MB-231 cells
lines model

UC Passive pH-sensitive Oral delivery OVA PLGA NPs DSS mice Superior stability and specificity [14]
model and in targeting the colon.
Caco-2 cell line
model

UC Passive pH-sensitive Oral delivery Bud Eudragit S 100/ Acetic acid rat Favorable drug release rate and [48]
Capryol 90 model effective targeting for colonic
nanocapsules drug delivery.

UC Passive pH-sensitive Oral delivery BBR PLGA NPs DSS mice Dual drug release properties to [49]
model reduce the frequency of drug
administration.

(Continued)

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Table 1 (Continued).

IBD Type of Targeting Delivery Loaded NPs Delivery Model Main Results Ref
Targeting Mechanism route Agents/Cargo System

UC Passive pH-sensitive Oral delivery Cur Polyacrylamide-grafted Acetic acid rat NPs have a high degree of [50]
-xanthan gum NPs model colonic targeting and alleviate
myeloperoxidase and nitrite
levels to relieve colitis
symptoms.

UC Passive pH-sensitive Oral delivery IL-1Ra Alginate/chitosan DSS mice Microcapsules can release the [51]
microcapsules model drug in situ in the colon,
reducing systemic adverse
effects.

UC Passive pH-sensitive Oral delivery Tacrolimus P-4135F NP DSS mice High drug loading and release [52]
model rates.

UC Passive pH-sensitive Oral delivery Cur and Dex HPMCAS-HF RAW 264.7, Microcapsules have burst and [53]
microencapsulated HT29-MTX, sustained drug release with
PLGA NPs and T84 cell excellent anti-inflammatory
line model properties.

UC Passive pH-sensitive Oral delivery Bud PLGA NPs DSS mice Relieves colitis and has pH- [54]
model dependent drug-releasing
properties.

UC Passive pH-sensitive – 5-ASA Ginger-derived In vitro High encapsulation rate, [55]

nanocarriers outstanding stability, and
excellent target specificity.

UC Passive pH-sensitive – 5-ASA Polyvinyl alcohol/ – Controlled release of [56]

sodium alginate/ therapeutic drugs through good
polylactic acid blend pH sensitivity.
carrier

UC Passive pH-sensitive In vitro GAR PLGA NPs Caco-2 cell line NPs can alleviate the response [57]
model to inflammation by decreasing
MPO activity.

UC Passive pH-sensitive Oral delivery 5-ASA and Cur Sulfated chitosan/ TNBS rats Releases two drugs into the [58]
alginate composite model target area; its therapeutic effect
microparticles is better than a single-dose
treatment.

UC Passive pH-sensitive Oral delivery Bud and MSNs DSS mice The particles resulted in lower [59]
prednisolone model levels of pro-inflammatory
cytokines than uncoated
particles.

UC Passive pH-sensitive Oral delivery Cur Curcumin coupled DSS mice Great stability and loading rates; [60]
with Eudragit® S100 model, inhibits inflammatory response.
HCT116, and
HT-29 cell line
model

UC Passive pH-sensitive Oral delivery Prednisolone Prednisolone wrapped In vitro The nanocapsules specifically [61]
by Eudragit S100 release the drug into the colon.

(Continued)

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Table 1 (Continued).

IBD Type of Targeting Delivery Loaded NPs Delivery Model Main Results Ref
Targeting Mechanism route Agents/Cargo System

UC Passive pH-responsive Oral delivery Prednisolone Encapsulated by RAW 264.7, LS MCM-NH2 is pH sensitive, [62]
succinylated ε- 174T, and allowing for targeted colonic
polylysine Caco-2 cell line delivery.
3-aminopropyl- model
functionalized
mesoporous silica NPs

UC Passive pH-sensitive azo- Oral delivery Bud ES-Azo. Pu NPs TNBS mice NPs are sensitive to enzymes [63]
reductase model and pH, allowing for sustained
targeted drug release.

UC Passive pH-sensitive Oral delivery Safranin O dye MSNs Rat model and, Dual targeting improves the [64]
amylase enzyme Caco-2 cell line inflammatory colonic tissue
model specificity of the drug.

UC Passive pH-sensitive, – Rifaximin OxiDEX NPs Caco-2 and Highly adhesive, sensitive to [65]
H2O2- encapsulated in HT29-MTX cell H2O2 and pH; capable of
responsive HPMCAS line model reducing the systemic adverse
effect of drugs.

UC Passive pH-sensitive, Oral delivery Infliximab Polyphenol-PEG- DSS mice Higher adhesion, excellent [66]
Positive charges, containing polymers model target specificity, and biosafety
and ROS- NPs
responsive

UC Passive pH-sensitive and Oral delivery Safranin O and Magnetic mesoporous TNBS rats The NPS increases the delivery [67]
azo-reductase hydrocortisone silica microparticles model efficiency of loaded drugs and
enzymes functionalized by azo improves therapeutic efficacy.
derivatives

UC Passive Positive charges Intrarectally Betamethasone Ethylcellulose TNBS mice Negatively charged: the ability to [68]
administered nanospheres coated model, target areas of inflammation
with polysorbate 20 C2BBe1, and with favorable adhesion.
RAW 264.7 cell
line model

UC Passive Positive charges Intrarectally Bud and HEP-HSA NPs DSS mice Simultaneous loading of drugs [69]
administered colony- model and and biologics. Better anti-
stimulating RAW 264.7 inflammatory effect than a single
cells line model drug-loaded NP.

UC Passive Positive charges Oral delivery CeO2 NPs CeO2@MMT DSS mice CeO2@MMT treats [70]
model and inflammation via target
RAW 264.7 specificity and antioxidant
cells line model action.

UC Passive Positive charges Oral delivery TNF-α Polymeric NPs DSS mice PLGA-PEG2K NPs are more [71]
coupled by two model, Caco-2 protective of drugs and more
different chain lengths cells, and J774 effective in treatment than the
(2 kDa and 5 kDa) of cells lines PLGA-PEG5K NPs.
PEG and PLEG model

UC Passive Positive charges Oral delivery Infliximab IFX NM TNBS mice Sustained release function and [72]
model and anti-inflammatory properties
HT29 cell promote mucosal healing.
model

(Continued)

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Table 1 (Continued).

IBD Type of Targeting Delivery Loaded NPs Delivery Model Main Results Ref
Targeting Mechanism route Agents/Cargo System

UC Passive Positive charges – Zingerone Zin-SLNPs RAW 264.7 cell Negative surface charge for [73]
line model better adhesion; superior
biosafety.

UC Passive Positive charges Intrarectally Dex Inflammation targeting DSS mice and IT-hydrogel reduces systemic [74]
and esterase administered hydrogel TRUC mice drug exposure, prolongs local
model, Caco2, drug release, and improves
and HT-29 cell efficacy more than free Dex
line model enemas.

Abbreviations: ST, Spleen targeting; H2S, H2S donor; NLCs, nanostructured lipid carriers; SiNP, silica nanoparticles; PPNP, polymers self-assembled nano-particle; IFX,
infliximab; PLGA, poly(lactic-co-glycolic acid); 5-ASA, 5-Amino salicylic acid; siRNP, silica-containing redox nanoparticles; SeM, diselenide-bridged mesoporous silica
nanoparticles; AC, aminoclay-liposome-coated; EAC, Eudragit S100-liposome-coated; MSMs, mesoporous silica materials; MSs, multilayer-coated mesoporous silica; Cur,
curcumin; EM, Escherichia coli strain Nissle 1917-(EcN) membrane; Bud, budesonide; Azo.pu, azo-polyurethane; HES, hydroxyethyl starch; Tpl, tempol; OxbCD, Oxidation-
responsive b-cyclodextrin; OVA, oval-bumin; BBR, berberine; HPMCAS, hydroxypropyl methylcellulose acetate succinate; GAR, garcinol; MSNs, mesoporous silica
nanoparticles; OxiDEX, oxidation-sensitive dextran; TNF- α, tumor necrosis factor-α; PEG, polyethylene glycol; HEP, heparin; HAS, human serum albumin; NP, nanopoly­
plexe; SLNPs, solid lipid nanoparticles; MMT, montmorillonite.

Table 2 The Active Targeting and Functional Effects of Nanoformulations for IBD Treatment
IBD Type of Targeting Delivery Loaded Nps Delivery Model Main Results Ref
Targeting Mechanism route Agents/ System
Cargo

UC Active Mannose Oral Cur Cur–AceKGM NPs RAW264.7 Cur-AceKGM NPs are [75]
receptors delivery cells lines more targeted and have
model superior therapeutic
efficacy compared to
oral doses of free Cur.

UC Active SRA1 Oral SOD ARC-SOD J774 A.1 Potent antioxidant and [76]
delivery cells and anti-inflammatory
Caco-2 properties promote
cells lines macrophage
model endocytosis of drug
loading.

UC Active Folate receptors Intrarectally SOD SNP-FA TNBS mice Good stability and [77]
administered model and biological activity;
RAW264.7 capable of targeted
cells line colonic delivery to
model reduce drug side effects

UC Active CD44 receptors – Bud HANPs Caco-2 and Excellent biosafety; [78]
NIH3T3 better ability to inhibit
cells lines inflammatory factors
model than free drugs

UC Active CCR5 receptor Oral Piceatannol Piceatannol–PLGA– UC Excellent [79]

delivery CCL4 patients, biocompatibility; inhibits
DSS mice the expression of pro-
model and inflammatory genes;
Caco-2 regulates the balance of
cells line intestinal flora
model

(Continued)

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Table 2 (Continued).

IBD Type of Targeting Delivery Loaded Nps Delivery Model Main Results Ref
Targeting Mechanism route Agents/ System
Cargo

UC Active Cytoplasmic/ Oral – GDNPs 2 DSS mice GDNPs 2 are natural [80]
membrane delivery model and NPs that reduce the
proteins of the RAW264.7 production of pro-
intestinal mucosa cells lines inflammatory factors
model and improve the
treatment of colitis

UC Active Mannose Oral Apremilast CDs.EP/Man/Meth.Cs Caco-2 and CDs.EP/Man/Meth.Cs [81]

receptors delivery NPs RAW 264.7 NPs enable specific
cells line accumulation of drugs at
model the site of inflammation
allowing uptake by
macrophages

UC Active Mannose Oral Anti-TNF cKGM and ASO DSS mice, cKGM and ASO can [82]
receptors delivery -a CT-26 cells transfer ASO to colonic
nucleotides and RAW macrophages and
264.7 cells reduce the symptoms of
lines model colitis by decreasing
TNF-a levels

UC Active Mannose – Bud Mn-NLCs Oxazolone Excellent encapsulation [83]

receptors rat model rate; great
and biocompatibility;
J774A.1 capable of reducing the
cells line level of inflammatory
model factors

UC Active CAR1 Oral Inf INF/LMSN@GE DSS mice Transmission stability; [84]
delivery model colonic targeting
specificity; anti-
inflammatory effects

UC Active SRA1 Oral Dex NAC-Dex THP-1 cells NAC-Dex reduces the [85]
delivery and Caco-2 release of inflammatory
cells lines factors and the
model production of reactive
oxygen species; repairs
the intestinal barrier

UC Active SRA1 – Dex SAN-Dex J774A.1 Compared to free Dex, [86]

cells and SAN-Dex is more
Caco-2 effective in reducing
cells lines inflammatory factors
model

UC Active Scavenger Oral Bud hMnO2 NPs. DSS mice NPs carriers with [87]
receptors (SRs) delivery model and antioxidant function
RAW 264.7 synergize with loaded
cells line drugs for the treatment
model of colitis

(Continued)

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Table 2 (Continued).

IBD Type of Targeting Delivery Loaded Nps Delivery Model Main Results Ref
Targeting Mechanism route Agents/ System
Cargo

UC Active Adhesion Oral PDA PDA@mCRAMP@MM DSS mice Inflammatory targeting; [88]
molecule delivery model and anti-inflammatory effect
receptors and RAW264.7 through regulation of
proinflammatory cells line immune function;
cytokine model regulation of intestinal
receptors flora

UC Active Folate-targeted Oral Resveratro PLGA-FA-RSV TNBS rats PLGA-FA-RSV enhances [89]
delivery model and the targeted transport
Caco-2 of the drug with
cells line excellent therapeutic
model efficacy

UC Active Galactose Oral TNF-α PLA-PEG DSS mice Improved drug [90]
receptors delivery siRNA model, utilization and delivery
RAW264.7 efficiency;
cells and biodegradability; anti-
Caco-2 inflammatory effects
cells lines through inhibition of
model inflammatory factor
production

UC Active CD44 receptors Oral OPN BSA/OPN-NPs DSS mice Exerts anti-inflammatory [91]
delivery model effects by inhibiting MPO
and inflammatory factor
levels

UC Active CD44 receptors Oral Bilirubin HABN DSS mice Greater target [92]
delivery model and specificity of HABN
J774A.1 compared to NPs
cells line without HA function
model painting

UC Active CD44 receptors Oral Cur Cur-HA NPs DSS mice Improve intestinal [93]
delivery model and mucosal barrier;
HT-29 cells regulate intestinal flora
line model diversity

UC Active Integrin αv Oral PA cRGD–PA-SF NPs DSS mice, cRGD-PASFNs can [94]
delivery Caco-2 and alleviate inflammation
RAW 264.7 and improve the colonic
cell line barrier with good
therapeutic effects.
Abbreviations: AceKGM, acetylated konjac glucomannan; CDs.EP, carbon dots functionalized Enteromorpha polysaccharide; Man, mannose; Meth.Cs, methionine
functionalized Chitosan; cKGM, cationic konjac glucomannan; ASO, antisense nucleotide; Mn, mannosylated nanostructured; LMSN, large mesoporous silicon nanoparticle;
GE, ginger-derived exosome; ARC, archaeolipids; SOD, superoxide dismutase; NAC, nanostructured archaeolipid carriers; Dex, dexamethasone; SAN, solid archaeolipid
nanoparticles; hMnO2, hollow mesoporous manganese dioxide; PDA, polydopamine; mCRAMP, mouse cathelicidin-related antimicrobial peptide; SNP, lipid−polymer hybrid
nanoparticles; FA, folic acid; RSV, resveratrol; mCRAMP, mouse cathelicidin-related antimicrobial peptide; MM, macrophage membrane; PLA, poly (lactic acid); PEG, poly
(ethylene glycol); OPN, osteopontin; BSA, bovine serum albumin; HA, hyaluronic acid; HABN, hyaluronic acid–bilirubin nanomedicine; CCL4, chemokine C–C motif ligand 4.

Lamprecht et al107 showed the advantageous impacts of nanoscale particle size for UC treatment by comparing the
bioadhesive capabilities of fluorescent polystyrene particles measuring 10 µm, 1 µm, and 100 nm. When compared to
a healthy colon, it was discovered that 100 nm particles adhered to an inflammatory colon in rats under oral

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Table 3 The Hybrid Targeting and Functional Effects of Nanoformulations for IBD Treatment
IBD Type of Targeting Delivery Loaded NSPs Model Main results Ref
Targeting Mechanism route Agents/ delivery
Cargo system

UC Passive, pH-sensitive, Oral cKGM and GelMA DSS mice The microspheres can target [95]
active mannose delivery ASO model, CT-26 macrophages, thereby reducing
receptor cells, and inflammation and drug toxicity.
RAW 264.7
cells lines
model

UC Passive, ROS- Oral Thioketa Ra@TH DSS mice The Ra@TH system enables the [96]
active responsive delivery model, RAW delivery of rapamycin to sites of
CD44 264.7 and HT- colitis-specific inflammation through
receptor 29 cells the active targeting of the CD44
receptor. This allows for the
controlled release of rapamycin at
ROS-sensitive lesions.

UC Passive, ROS- Oral Infliximab IFXSS@HA TNBS mice The nanocomposite has a high [97]
active responsive delivery or model and HT drug-loading capacity and high
CD44 IFXTK@HA 29 cell line specificity, which reduces systemic
receptor model exposure and provides better
therapeutic results than intravenous
drugs.

UC Passive Positive – Man-NPs CDs/Man- DSS mice CDs/Man-NPs target macrophages [98]
active charges, NPs model, RAW and are internalized by absorption,
mannose 264.7, and reduce adverse effects of drugs, and
receptor Caco-2 cell improve drug utilization.
line model

UC Passive pH-sensitive Oral SK ES100/HA/ TNBS mice ES100/HA/CS NPs exert [99]
active CD44 delivery CS NPs model and therapeutic effects by reducing ROS
receptor RAW 264.7 production and inhibiting the
cell line model release of inflammatory factors.

UC Passive pH-sensitive Oral Methotrexate HA-CS TNBS mice HA-CS/ES100/PLGA NPs are [100]
active CD44 delivery /ES100/ model RAW specific; they alleviate intestinal
receptor PLGA NPs 264.7 cell line inflammation by reducing
model inflammatory cell infiltration and
decreasing intestinal mucosal
damage.
Abbreviations: GelMA, gelatin methacryloyl; SK, shikonin; CS, chitosan; ES100, Eudragits S100; MTX, methotrexate; CDs, carbon dots; Man, mannosylated; PA, patchouli
alcohol; cRGD, cyclo RGD peptide; and SF, silk fibroin.

administration compared to a healthy colon. Furthermore, the faster the drug was absorbed and the greater the therapeutic
effect, the smaller the particle size.
Solid lipid NPs (SLNs) have become an appealing drug delivery mechanism among the available nanocarriers.108
Compared to other lipid NPs (liposomes, etc)., SLNs have superior stability, biocompatibility, and degradability in the
gastrointestinal tract, along with the capacity to influence immune responses and anti-inflammatory properties.109,110
Beloqui et al developed nanostructured lipid carriers (BDS-NLC) containing budesonide (BDS) with an average diameter
of approximately 200 nm.26 Research conducted in vitro showed that BDS-NLC could encapsulate up to 95% of the drug
and prolong its half-life in the colon. Similarly, it produced therapeutic benefits comparable to those of healthy control

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Table 4 The Effectiveness and Limitations of Different Types of Drug Delivery Systems for the Treatment of IBD
Type of Targeting Effectiveness Limitations
Targeting Mechanism

Passive EPR effect The NPs developed based on the EPR effect accumulate The EPR effect only promotes the accumulation of DDSs
targeting at the site of inflammation, prolonging the residence in colitis tissues, whereas inefficient target cell uptake
time in the inflamed intestinal area and avoiding the rapid and insufficient intracellular drug release limit the
clearance of the carrier. It could reduce the adverse therapeutic efficacy of anti-inflammatory drugs.
effects of the loaded drug and improve the utilisation of Moreover, the instability of NPs drugs may increase
the drug compared to the free drug. during the preparation process or when the formulation
is changed.

Enzymes Enzyme-targeted NPs with a favourable biosafety profile Shorter gastrointestinal transit times may reduce drug
can selectively accumulate in inflamed tissues and release under disease conditions.
achieve therapeutic efficacy through delayed release.
Some NPs drugs protect the integrity of the intestinal
barrier and enhance intestinal homeostasis.

ROS- The drug release of ROS-dependent NPs is efficient and Oxidative stress may not be the main causative agent of
responsive less toxic, while its synergy of anti-inflammatory and the disease. If the loaded drug was released in bursts, its
antioxidant effects can attenuate the inflammatory excessively rapid release rate may make the duration of
damage in the colonic mucosa. the drug quite short.

pH-sensitive The pH-dependent delivery system protects the drug The design of drug delivery systems based solely on the
from gastrointestinal disorders, resists unfavourable pH of the gastrointestinal tract is unreliable due to
gastrointestinal conditions and reduces premature drug differences of pH between individuals and the variation
release. of pH in the intestinal lumen caused by disease states. It
can result in incomplete or premature drug release from
the colonic target site.

Positive The positive charge-targeted NPs promote cellular The charge-dependent nanoparticles have the potential
charge uptake and drug release, allowing better drug contact to bind to other charge-modified substances during
with mucosal surfaces and increasing targeting and gastrointestinal transport. There are fewer studies on
retention of the drug delivery system. charge-dependent delivery system loading and further
experimental exploration is needed.

Active / Actively targeted drugs are highly specific and selective Further in vivo studies are needed to assess the efficacy
targeting for the site of targeting, reducing drug redistribution in and stability of different targeting ligands and
healthy tissues, improving therapeutic efficacy and formulations in animal models of colitis.
reducing systemic adverse events of the drug.

Hybrid / Integrated systems with different release triggering The release triggering mechanisms of different hybrid-
targeting mechanisms help overcome pathophysiological variability targeted nanoparticles still need to be further refined.
more than single systems. Passive targeting reduces the And the differences between animal models and human
non-specific uptake of drug carriers at non-target sites patients should be fully recognised, which requires more
and improves the targeting of active targeting systems. experimental data models to validate the biosafety and
Active targeting promotes specificity of the drug system. efficacy of the newly developed NPs.
Thus hybrid targeting systems enable precise targeting of
drug-carrying nanoparticles and further reduce their side
effects.

colon tissue by lowering the levels of myeloperoxidase (MPO), interleukin (IL) IL-1β, and tumor necrosis factor (TNF)
TNF-α (Figure 2).
Furthermore, protamine has been used to develop stable nanocapsules.111 Jakubiak et al encapsulated cyclosporine A in
protamine-coated nanocapsules.27 The average particle size of these NPs was 160–180 nm. Although this nanocapsule showed

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Figure 1 Strategies for inflammatory bowel disease treatment using nanoparticle-based drug delivery systems. Nanoparticles specifically target inflammatory colonic
epithelial cells based on enhanced permeability and retention effects (A), specific enzyme levels (B), reactive oxygen species (ROS) levels (C), specific pH levels (D),
electrostatic interactions (E), and ligand-receptor interactions (F).

Figure 2 The expression of myeloperoxidase activity (A), TNF-α (B), and IL-1β (C) was significantly decreased in the colon of mice treated with budesonide-
nanostructured lipid carriers compared to the control group. Reprinted from Int J Pharm, volume 454(2), Beloqui A, Coco R, Alhouayek M, et al. Budesonide-loaded
nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis. 775–783, Copyright 2013, with permission from Elsevier.26

good stability against trypsin in simulated trials, predicting its stability and drug release in vivo is challenging. In vitro
experiments demonstrated that these NPs were superior to commercial agents in their ability to decrease IL-2 levels.
The treatment of experimental colitis with celecoxib (CXB) has demonstrated significant efficacy.112,113 A formulation of
CXB nanomixed micelles (NMMs) was developed to investigate the adverse effects of colon-targeted agents to reduce CXB.
The NMMs were then integrated into a novel pulsatile capsule with an average particle size <290 nm.28 The capsule could be
released in vitro in 88.35% of cases if the capsule is designed to target the colonic site. Furthermore, it demonstrates superior
defense against acetic acid-induced experimental colitis models compared to regular capsules.
Ali et al designed NPs that target inflammatory colonic mucosa by inserting budesonide into poly(l-propylene-
glycoside lactone) (PLGA) NPs with an average particle size of 200 nm.29 Fluorescence analysis showed that while the
NPs could be dispersed throughout the digestive tract in the colonic tissues of healthy mice, the particles appeared more
at the inflamed site in inflamed mice. It is also important to note that the drug displayed a biphasic release pattern in vitro,
releasing rapid at first, then slowly and continuously after that. They suggest that the initial rapid release could be
because the drug molecules are just attached to the surface of the NPs rather than fully encapsulated.
Protein NPs have gathered attention recently because of their excellent biocompatibility and advantages in
biodegradability.114,115 Covalently binding 5-aminosalicylic acid to hemoglobin produced the NPs with a diameter of

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about 220 nm.30 Only 8% of the drug was absorbed and released within 4 h following the vitro simulation test. Data from
their vivo trials also showed that 85% of the NPs could reach the colon and release the drug. This suggests that the
system has outstanding stability and is able to slow drug release in the stomach.
The lack of polysaccharide-degrading enzymes in the human body may prevent the natural polysaccharide found in
sawdust gum from being degraded in the upper gastrointestinal tract.116 However, the microflora enzymes present in the
colorectum can degrade it to produce fatty acids.117,118 A regimen with a mean particle size of 228 nm was shown to be
optimized by Amaldoss et al after developing tamarind gum NPs loaded with rifaximin.31 Compared to the control group,
the NPs effectively lowered colonic inflammation. Furthermore, studies conducted on patients with IBD have demon­
strated a significant increase in platelet counts in the literature.119 However, they performed testing studies and
discovered that neither the treatment group nor the blood fractions had significantly higher platelet levels.
Additionally, passive targeting based on the EPR effect has been observed by others. This could lead to some passive
accumulation of NPs at the inflammation site and decrease the loaded drug’s adverse effects.32–34 However, this single
effect-based approach to drug delivery is not ideal. Furthermore, during the synthesis of NPs, the drug encapsulation rate
may be satisfactory. However, variations in the preparation processes or formulations may cause NPs to have unstable
properties, making it challenging to achieve acceptable outcomes. Furthermore, it is unlikely that the interactions of NPs
with the tissues or cells in the inflamed colon will be the primary means of targeting the colon.34

Targeting Based on Enzymes

The gastrointestinal tract contains various enzymes, including lysozyme, azo reductase, esterases, sphingomyelinase, etc.11,120
Furthermore, the enzyme secretion of patients with IBD significantly differed from that of healthy individuals. These digestive
enzymes quickly degrade drugs, which reduces their therapeutic efficacy. The enzyme reaction pattern depends on certain
enzymes to catalyze chemical reactions. The drug is released at the lesion site by surface-modified DDSs, which use the
enzymes as stimuli to cause their degradation or morphological transformation (Figure 1B).35–41
Intestinal pathogens cause aberrant lysozyme secretion in the colon by interfering with cellular function.121,122 Li et al
developed a lysozyme-triggered chitosan polyaniline microgels loaded with vancomycin (VM).35 The biodegradation of
the microgel was triggered by lysozyme, which also cleaved the glycosidic bond and released VM (Figure 3). According
to an in vitro test, the drug was released in the inflammatory colon within 30 min, up to 76.9%. The microgel system
inhibited S. aureus at the same concentration as the control without lysozyme. The Caco-2 cell line had an excellent
biosafety profile with a cell survival rate of >86.1% in experiments.
Moreover, azo reductase is the most widely used enzyme for azo polymer adhesion, hydrogels, coatings, etc.123
Additionally, the researchers developed multilayer-coated mesoporous silica (MSs), which activates azo reductase
generated by intestinal microorganisms to release loaded drugs.36 According to the test findings, mice in the oral-free
drug group had a drug concentration 35 times lower at the colonic site than the mice. Notably, aryl hydrocarbon receptor
activation by tryptophan-functionalized chitosan can protect the integrity of the intestinal barrier and enhance intestinal
homeostasis when it is transformed into metabolites by intestinal flora.
Silica as a drug carrier NP in biomedical applications has advanced significantly. Researchers have developed a pre-
drug system to treat colitis by loading 5-aminosalicylic acid onto silica NPs (SiNP).37 Studies revealed that mice in the
SiNP group accumulated six times as much drug in the inflamed tissue as in the control group, significantly decreasing
the drug dosage needed for treatment. Experiments conducted on mice have demonstrated that the nanodrug selectively
accumulates in inflamed tissues and prolongs the presentation duration to achieve a therapeutic impact with a delayed
release. Although esterases can gradually initiate the catabolic conversion of precursor drugs, as demonstrated by drug
release experiments, further in vivo research is required to understand this phenomenon fully.
Furthermore, natural polyphenols have drawn much attention as safe compounds with free radical scavenging and
antioxidant properties.124,125 Consequently, researchers designed a DDSs encapsulated with dexamethasone (DEX) by
self-assembling polyphenols (tannins) and polymers.38 When esterase is present at a concentration of 30 U/mL, up to
62% of DEX is released. According to pharmacofluorescence imaging, the fluorescence intensity of the inflamed mouse
colon was shown to be four times higher than that of the healthy colon. Furthermore, PPNP-DEX had a better therapeutic
impact on colitis-affected mice than PPNP and free DEX. Research has shown that non-degradable polyethylene glycol

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Figure 3 Lysozyme-triggered release of vancomycin from chitosan microgels for treating inflammatory bowel disease. (A) Schematic representation and mechanism of action of
lysozyme-triggered nanoparticles. (B) Determination of Caco-2 cell activity in various treatment groups. (C) Inhibitory effect of N-CH-PANI@VM MGs on Staphylococcus aureus in
various environments. (D) Cumulative release of lysozyme-induced VM in various simulated environments. Adapted from J Adv Res, volume 43, Li X, Hetjens L, Wolter N, et al.
Charge-reversible and biodegradable chitosan-based microgels for lysozyme-triggered release of vancomycin. 87–96, Copyright 2023, with permission from Elsevier.35

(PEG) compounds can produce anti-polyethylene glycol antibodies in vivo, making PEG drugs biologically inactive.126
However, they discovered little impact of anti-PEG antibodies on oral PEG drugs by fluorescence imaging, contrary to
the report.
Sphingolipid liposomes were also used to develop the NPs,39 and ICG was fluorescently labeled because sphingo­
myelinase is present outside of cells during cellular stress.127 The results of the experiment showed that liposomes could
be taken up by both epithelial cells and macrophages, thus accomplishing drug delivery. In the inflammatory colon,
macrophages produced higher sphingomyelinase activity and greater drug phagocytosis than epithelial cells.
Furthermore, materials made of naturally occurring chemicals offer good biosafety and biocompatibility. Xu et al
produced NP formulations with anti-inflammatory and antioxidant properties by packing DEX within curcumin and
hydroxyethyl starch micelles.42 In vitro release assays demonstrated that the negatively charged outer surface of NPs
aided in their binding to inflammatory colon cells, and the α-amylase increased the drug release rate. NPs decreased the
severity of inflammatory lesions and improved the effectiveness of free DEX compared to the untreated group.

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Targeting Based on ROS

Free radicals, such as superoxide (O2) and −OH, and non-free radicals, like singlet oxygen (1O2) and hydrogen peroxide
(H2O2), make up the majority of ROS.128,129 Bowel inflammation is caused by pro-inflammatory mediators, including
TNF-α and IL-1, produced when ROS triggers the NF-κB signaling cascade.130 Oxidative damage in the colon is caused
by an excess of ROS and an imbalance of antioxidants in the intestinal mucosa of patients with IBD.129,131,132 Activated
phagocytes and leukocytes at the site of colitis are the primary source of the increased production of ROS.133 According
to a study, patients with IBD had 10- to 100-fold higher ROS concentrations in intestinal inflammation than healthy
individuals.134,135 Redox-responsive DDSs have gained attention from researchers to improve targeted drug delivery in
inflamed intestinal areas (Figure 1C).43–47
Drug-drug coupling systems, with their high drug loading and minimal side effects, have been suggested as a novel
approach. Li et al developed spherical nanostructures by self-assembling ROS-sensitive aromatized thione linkers with
the anti-inflammatory drug budesonide and the antioxidant tempol (Figure 4).43 Interestingly, the drug loading of the NPs
was more significant (41% and 16%) than the loading of the two drugs in the PLGA NPs (6% and 3%). In the simulated
environment experiment, the ROS-dependent release pattern led to nearly full release (99% and 98%) of these NPs for
both drugs. Conversely, only 44% and 18% of the drug was released from PLGA NPs. The concurrent release of the two
drugs allowed for the synergistic anti-inflammatory and antioxidant effects.
Additionally, superoxide dismutase (SOD) breaks down superoxide to form hydrogen peroxide, which catalase then
breaks down into water. Zhang et al produced NPs (Tpl/OxbCD NP) by encapsulating the free radical scavenger Tempol
(Tpl) in oxidation-responsive b-cyclodextrin, which releases cargo molecules by scavenging ROS components.
According to drug imaging, OxbCD NPs had a higher targeting effectiveness than control PLGA NPs and accumulated
2.5 times more fluorescence intensity in mouse colon tissue than in normal mice. The oral Tpl/OxbCD NPs group
showed a significant reduction in symptoms in three mice colitis models, with more efficacy than the free radical
scavenger Tpl and -based control nanomedicine.44
In addition, IBD makes it easier for pathogens, such as intestinal bacteria, to enter the bloodstream and invade other organs.
The goal of the design was a drug delivery system that scavenges ROS from the inflamed colon while also delivering
antioxidant drugs to the bloodstream to reduce systemic inflammation. Researchers have developed silica-containing redox
NPs that can scavenge ROS when loaded with silymarin.45 According to the findings of in vivo experiments conducted on
mice, the blood uptake of silymarin was significantly increased by the antioxidant carrier (siRNP). Additionally, the damage to
the inflamed colonic mucosa was decreased considerably by the synergistic antioxidant effect of the drug and carrier.

Targeting Based on pH Levels

In contrast to the colon and rectum, which have pH values between 7.1 and 7.5, the stomach has an acidic pH.136 Drug
protection from gastrointestinal conditions and delayed drug release in acidic pH conditions can be achieved by NPs with
a pH-sensitive design (Figure 1D). Scientists have developed drugs that are unique to the colon due to variations in the
pH of the various gastrointestinal tract organs. Several pH-sensitive nanostructures, such as nanospheres, nanocapsules,
and nano-polymers encapsulating other materials, have been developed. Additionally, colon-targeted drug delivery
systems were designed using pH-dependent polymers, including methacrylic acid and methyl methacrylate (Eudragit®
S 100, Eudragit® L, Eudragit® FS and Eudragit® P4135 F),137 hydroxypropyl methyl phthalate cellulose, and few other
polymers.14,48–62 Eudragit® polymer is one of the most widely used synthetic copolymers for colonic drug delivery.138
The ionization of carboxyl functional groups makes the Eudragit® s100 resistant to invasion of the upper gastro­
intestinal tract, and it becomes soluble at pH >7.139,140 Qelliny et al48 synthesized NPs were loaded with budesonide, and
their surface was coated with pH-sensitive Eudragit® s100. Studies conducted in vitro show that up to 72% of its
maximum short-term cumulative release occurs at pH 7.4. Additionally, studies conducted on animals suggested that it
had a more significant therapeutic effect on UC than the drug suspension in its free form.
Furthermore, Zhang et al developed hybrid drug delivery systems by encapsulating PLGA NPs loaded with berberine
within an Eudragit® FS 30D matrix that has already been pre-encapsulated with berberine (Figure 5).49 This pH-sensitive
system immediately releases the drug-loaded NPs and berberine upon reaching the colon for lysis. The PLGA NPs are
then absorbed by the colonic mucosa and gradually breakdown to maintain the sustained release of the drug. This pH-

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Figure 4 Sensitive reactive oxygen species-responsive B-ATK-T nanoparticles (NP) for treating irritable bowel disease. (A) The synthetic process of B-ATK-T. (B)
Hydrolysis rate of B-ATK-T NP at various concentrations of hydrogen peroxide (H2O2). The release profiles of 9-fluorenone (C), budesonide (D), and tempol (E) from
B-ATK-T NP at varying concentrations of H2O2 concentrations. Reprinted from J Control Release, volume 316, Li S, Xie A, Li H, et al. A self-assembled, ROS-responsive
Janus-prodrug for targeted therapy of inflammatory bowel disease. 66–78, copyright 2019, with permission from Elsevier.43

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Figure 5 The novel nano-delivery system MNEHDS for treating irritable bowel disease. (A) The manufacturing process of MNEHDS. (B) Berberine (BBR) drug release
rates in various simulated environments. The changes in BBR concentrations were investigated at various intervals in the plasma (C), colon (D), and feces (E). Reprinted
from Zhang L, Li M, Zhang G, et al. Micro- and nanoencapsulated hybrid delivery system (MNEHDS): a novel approach for colon-targeted oral delivery of berberine. Mol
Pharmaceut. 2021;18(4):1573–1581. Copyright © 2021 American Chemical Society.49

sensitive nanosystem accomplishes drug release into the tissue instantly and continuously. It promotes better therapeutic
efficacy and patient compliance by lowering the amount of drug required and the frequency of administration.
The process of creating polymer NPs involves grafting polyacrylamide (PAAm) onto the backbone of xanthan gum
(XG).50 Upon additional NP hydrolysis, the PAAm amide functional group is transformed into a carboxylic acid (-COOH)
group, creating a pH-sensitive copolymer.141 Moreover, coliform bacteria can activate XG. Therefore, the NPs are very
selective for colonic targeting. At a pH of 6.8, 3 h were needed to release approximately 65% of the drug. In vitro tests on rats

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have revealed that the drug release rate is <15% with an acidic pH. However, within 8 h, the drug release rate may reach 100%
if the pH of the solution is increased to 6.8 and intestinal contents are added.
Additionally, IL-1 receptor antagonist (IL-1Ra)-containing alginate/chitosan microcapsules were prepared.51 Chitosan is
a cationic polysaccharide.142 The electrostatic interaction between the two is diminished in weak alkaline solutions because
chitosan has a lower positive charge than alginate. This lets alginate absorb water and swell in an inflammatory colon
environment, releasing the drug.143 Furthermore, the microcapsules acquired an ultimate cumulative release rate of 86.2%
in vitro. The microcapsules decreased the dose-induced colitis in mice, partially allowing the drug to accumulate in the colon.
Meissner et al developed a pH-sensitive Eudragit P-4135F polymer for colonic delivery of drug-loaded NPs to increase
drug delivery efficiency and tolerability.52 The polymer can break down and release the drug at pH >7.2. In vitro tests
demonstrated that after 30 min, 100% of the loaded drug release at pH 7.4 could be achieved. Moreover, the oral NP
formulation outperformed the free oral drug, although it was less effective in alleviating experimental colitis than subcuta­
neous administration.
The pH-dependent delivery mechanism may keep the drugs from dispersing before they reach the colon site.
However, patients with IBD have a more acidic pH range in their colons,136 which leads to partial drug release from
the target site.144 Researchers have created pH-dependent systems with alternative drug delivery systems, such as ROS-
dependent or enzyme-triggered systems, to overcome the limitations of single pH-dependent DDSs.63–67
Naeem et al developed a pH- and azo reductase-sensitive azo polyurethane and Eudragit® S100 NPs.63 Compared to
single-trigger ES NPs, the NPs provide superior therapeutic efficacy by preventing a sudden release of the drug in the
ileum and delivering an adequate amount to the inflamed colon. Budesonide is then sustained and released by an
enzymatic reaction compared to single-trigger ES NPs. Pilot tests have demonstrated that the NPs are more stable than
the pH-dependent type alone, preventing early drug release and enabling targeted colonic drug delivery.
The researchers developed mesoporous silica NPs, coated them with hydrolyzed starch, and placed them inside
capsules containing Eudragit® FS 30D.64 The nanosystem made it possible to alleviate the adverse effects of the drug and
increase drug concentration at the colonic inflammatory site. Mesoporous silica NPs are released from the nanocapsules
at colonic pH and are endocytically transported into colon cells after amylase stimulation.
The researchers developed an antioxidant-responsive dextrose (OxiDEX) NPs loaded with rifaximin.65 The pH-
responsive polymer hydroxypropyl methylcellulose acetate succinate was then used to encapsulate the NPs in chitosan
surfaces. A pH- and ROS-responsive nanodelivery system was formed. Upon entering the colon and passing the acidic
environment of the stomach, the NPs will release RIF in response to a trigger that increases ROS levels. In vitro
experiments have demonstrated that the system can initiate the release mechanism at intestinal pH (6.8) and that, in the
presence of H2O2, NPs can release >60% of the drug.
In addition, Wang et al developed infliximab-loaded polyphenol-containing PEG polymer self-assembled NPs.66 In the
stomach, the NPs aggregated into large-sized NPs. Then, at neutral pH in the colon, they reversibly transformed into small-
sized negatively charged NPs (~100 nm). The antibody drug is then released from the NPs when they bind to the inflammatory
colonic site through charge interactions and are impacted by high ROS concentrations in the mucosa. The favorable colonic
targeting specificity and excellent therapeutic efficacy of the NPs were demonstrated in vivo in mice with colitis.

Targeting Based on Positive Charge

Surface-negatively charged DDSs has a high molecular target in the form of the positively charged protein (transferrin),
which is overexpressed on the inflamed epithelial surface of IBD.145 Negatively charged particles exhibit preferential
adherence to injured sections of the colon through electrostatic interactions with these proteins (Figure 1E).68–73
Surfactants can impact the targeting efficiency of NPs. The NPs with negatively charged surfaces were created using
polysorbate 20 as a surfactant.68 In 30 min, the colonic site may release 80% of the loaded drug. The same NPs interacted
two to three times more with macrophages (RAW 264.7 cells) than with enterocytes (C2BBe1 cells), which is an
interesting aspect that implies a simple cell line is not a sufficient model of inflamed tissue in vivo.
Furthermore, heparin has a significant negative charge on the outer surface. Zhang et al developed NPs targeting
inflammatory colon (HEP-HSA NPs) that use the electrostatic interactions at the region of intestinal inflammation to load
both biological agents and small molecule drugs.69 In vitro assays revealed that the NPs had a more potent anti-

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inflammatory impact than NPs loaded with a single drug. Notably, it was discovered that there was a negative correlation
between the diameter of HEP-HSA NPs and mucosal binding, with larger NPs preferentially binding to inflamed mucosa.
And the investigation indicates that the smaller particle-size NPs enter the submucosa deeper.

Active Targeting
Drug distribution was improved in the inflamed areas of the colon by the EPR effect, which was facilitated by the particle
size and surface physicochemical properties of NPs. However, this only promoted the accumulation of DDSs in colitis
tissues. Insufficient target cell absorption efficiency and low intracellular drug release restrict anti-inflammatory drug
therapeutic efficacy. Therefore, developing nanocarriers capable of actively targeting inflammatory cells may enable
more precise targeting of colonic disease and minimize adverse side effects more effectively.
Specific antigens or receptors, such as the mannose, scavenger, folate, CD44, and chemokine receptors, are significantly
overexpressed by epithelial cells and activated macrophages during the development of IBD. The interaction between
particular receptors expressed at the diseased site and targeting ligands on the surface of the vector has increased targeting
specificity. It also increases the degree of endocytosis and the bioadhesion of drug agents to particular cells (Figure 1F).75–94
The mannose receptor is overexpressed explicitly on the surface of macrophages at the site of inflammation.146 Upon
contact with this receptor system, NPs are rapidly internalized through receptor-mediated endocytosis, resulting in
targeted drug delivery. Wang et al developed a naturally occurring polysaccharide-based NP that targets binding to
macrophage mannose receptors.75 According to the experimental results, NPs exhibited 81% drug release within 48 h,
and the MPO levels of the mice were decreased. The NPs offer sustained release of curcumin and effective therapeutic
outcomes compared to oral free curcumin administration (Figure 6).
Phosphatidylglycerophosphate methyl ester (PGP-Me) is a ligand for the scavenger receptor, which is highly
expressed in macrophages and dendritic cells.147 SOD was delivered via nanovesicles containing PGP-Me, which also
could promote endocytosis of the drug carried by macrophages.76 The study showed that mouse macrophages took up the
nanosystem 6.4 times more than liposomal NPs. The activity of the enzymes it contains remained unchanged when
exposed to conditions similar to oral administration, compared to the control group.
Furthermore, Le et al developed NPs functionalized on folic acid surfaces that were loaded with antioxidant
enzymes.77 They next evaluated a mechanism dependent on cellular endocytosis mediated by the folic acid receptor.
Its PEG coating keeps antioxidant enzymes from breaking down. In vitro, cellular uptake tests demonstrated that the NPs
could be absorbed by macrophages and epithelial cells and displayed a powerful solid fluorescent signal compared to
controls. Moreover, the results of in vivo tests showed that intrarectal administration significantly decreased colitis
symptoms in mice models by downregulating the production of pro-inflammatory cytokines.
Moreover, hyaluronic acid is a primary gastrointestinal mucosal epithelial extracellular matrix component, enabling
interaction with overexpressed CD44 receptors.148,149 Budesonide-loaded hyaluronic acid nanosystems (HANPs) were
designed.78 Compared to uncoated nanocomplexes, the HANPs enhanced cell adhesion and uptake in vitro experiments.
Moreover, when HANPs and the exact dosage of free drugs were used in inflammatory cell models, HANPs showed
higher anti-inflammatory effects on the secretion of inflammatory factors.
Chemokine receptor (CCR5) can be expressed on the macrophage surface.150 Gong et al combined the chemokine
ligand CCL4 with PLGA NPs to allow it to bind to the macrophage surface receptor CCR5, significantly improving the
targeting ability of the drug.79 Fluorescence staining showed that colonic macrophages could take up the NPs. The NPs
not only improved the dysbiosis of the intestinal flora, but also promoted the repair of the intestinal barrier function by
loading spleen tyrosine kinase inhibitors and decreasing the production of cytokines and chemokines.
Overall, the active targeting of ligands attached to the surface of nanodelivery systems is a promising strategy for
treating IBD. Targeted ligands and targeted receptors expressed at inflammatory areas may improve the bioadhesion of
drug formulations to particular cells and increase the degree of drug endocytosis. However, further in vivo research is
required to evaluate the effectiveness of different strategies.

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Figure 6 AceKGM nanoparticles for the treatment of irritable bowel disease. The percentage change in mice from various treatment groups body weight (A), Disease
Activity Index score (B), myeloperoxidase activity (C), colon length (D), and TNF-α content (E). (F) Mice colonic tissues from various treatment groups. Reprinted from
Wang C, Guo Z, Liang J, et al. An oral delivery vehicle based on konjac glucomannan acetate targeting the colon for inflammatory bowel disease therapy. Front Bioeng
Biotechnol. 2022;10:1025155. Creative Commons.75

Hybrid Targeting
Apart from the above mentioned passive or active targeting strategies that rely on single factors (pH, enzymes, ROS,
receptors, etc)., researchers have attempted to design targeting strategies that rely on multiple factors to overcome the
multiple biological challenges encountered with orally delivered nanoparticle systems.95,97–100 These targeting strategies,
which combine different NP triggers, take advantage of the benefits of a single form while potentially mitigating its
disadvantages to attain maximum effectiveness.
Mannose was abundant in cationic konjac glucomannan (cKGM) and selectively identified mannose receptors on the
membranes of macrophages.151,152 The researchers used methacrylate-based gelatin (GelMA) loaded with cKGM and

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ASO nanocomposite and embedded in pH-sensitive Eudragit FS30D to create pH and mannose receptor-responsive
nanocomposites.95 The alkaline environment of the colon promotes the release of nanocomplexes, and colonic macro­
phages can absorb ASO through mannose receptor-mediated endocytosis. According to the experimental data, colitis
mice may benefit from the targeted release of nanonucleic acids into their colons, which may help reduce inflammation
and mitigate damage. This could have an impact on how IBD is treated.
Additionally, infliximab was loaded into the oral NP delivery system by combining it with ROS-reactive cross-linkers
and altering it with hyaluronic acid.97 Two synthetic ROS-responsive cross-linkers, SS and TK linkers, are highly
sensitive to ROS to protect the integrity of NPs and allow the release of antibodies in the inflamed intestinal mucosa.
Hyaluronic acid-modified NPs target CD44 receptors and improve NP uptake by macrophages and colonic epithelial
cells. In vivo experiments revealed that the NPs were more effective in terms of therapeutic efficacy than in the
intravenous administration of infliximab (Figure 7).
Furthermore, carbon dots (CDs) have become essential nanomaterials due to their excellent stability and
biocompatibility.153 Researchers have prepared mannosylated nanocomposites by covalent polymerization of mannosy­
lated NPs (Man-NPs) with CDs, and the glycosylation process is negatively charged due to the carboxyl group possessed
on the main chain of inulin.98 Man-NPs can bind selectively to the mannose receptor on the macrophage surface, leading
to preferential cellular absorption.

Other Functional Effects

Other methods based on nano-delivery systems can be used to treat and diagnose IBD, in addition to using passive and
active targeting strategies to target inflammatory colon tissue for drug action.
Immune regulation has a role in the pathogenesis of IBD. The spleen is the largest lymphoid organ and can
regulate the immune system. A splenic-targeted PEG liposome (ST-H2S lipo) loaded with H2S donors was developed
to treat UC by immunomodulation.32 According to a fluorescence assay against drug release, the fluorescence intensity
of liposomes loaded with H2S donors was higher than that of controls. ST-H2S lipo exhibited significant absorption in
the spleen following the intravenous drug administration. On the other hand, both conventional long-circulating
liposomes (LC-H2S lipo) and ST-H2S lipo accumulated in the colon, with LC-H2S lipo demonstrating a higher
absorption rate. Compared to LC-H2S liposomes, ST-H2S liposomes had a more substantial immunomodulatory effect
and a better therapeutic effect.
Restoring colon homeostasis using a microbiota-based strategy may be an effective IBD treatment. Nanomedicines
containing components of cell membranes show promise as a therapeutic approach for managing a range of inflammatory
diseases.46 Scientists have recently developed a nanosystem with both antioxidant and anti-inflammatory functions
(SeM@EM) by coating the surface of mesoporous silica NPs with a natural E. coli membrane that acted as a ROS
scavenger. It was demonstrated that the NPs reduced inflammation and improved the adhesion of the drug. It is also
remarkable how the NPs regulated the intestinal homeostatic balance and the growth of good intestinal microbiota.
Imaging IBD can be complex because the routinely used contrast agents (iodine-based and barium-based) are usually
non-specific for the site of inflammation in IBD. Nahaet al developed a cerium oxide NP (Dex-CeNP) coated with
dextrose anhydride as a contrast agent for IBD diagnostic imaging.154 The presence of dextran provides good NP
stability, biocompatibility, and specificity. Cerium oxide is also an antioxidant, neutralizing free radicals and reducing
inflammation. Dex-CeNPs provide significant computed tomography contrast in the colon and accumulate in colitis-
affected tissues. Notably, oral doses can nearly completely leave the body in 24 h.
Cerium dioxide NPs exhibit diverse enzymatic properties, such as superoxide dismutase and catalase activities, in
addition to their capacity to scavenge hydroxyl radicals. Zhao et al combined cerium dioxide NPs and negatively charged
montmorillonite to create the nanoenzyme complex.70 When administered orally, the nanosystem targets the positively
charged, inflamed colon and, in addition to its antioxidant properties, acts as montmorillonite to reduce bleeding.

Challenges and Future Perspectives

Despite substantial advancements in treating IBD based on nanodelivery techniques, there are still some issues and
inefficiencies in the development process.

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Figure 7 (A) IFXSS@HA/IFXTK@HA drug synthesis process and irritable bowel disease treatment mechanism. Colonic tissues (B), colonic length, and histopathologic
histologic scores (C) of mice post-treatment in each group. Adapted from Chem Eng J, volume 445, Li X, Fang S, Yu Y, et al. Oral administration of inflammatory
microenvironment-responsive carrier-free infliximab nanocomplex for the targeted treatment of inflammatory bowel disease. 136438, Copyright 2022, with permission from
Elsevier.97

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Formulation improvement of drug preparation. Increased drug release from the colonic site and improved therapeutic
efficacy can arise from formulation optimization of the product. For instance, multiple NPs were developed using various
formulation ratios, and it was ultimately discovered that capryol 90 may be used as the carrier to enable complete drug release.48
Improvement of the preparation process. Some preparation methods require a time-consuming, multi-step process
with production scale restrictions, making the prepared NPs less stable The drugs made partially by self-assembly have
inadequate drug loading and low encapsulation rates. Problems regarding drug stability, loading discrepancies, and
dimensional variations in the nano-delivery platform may also occur in large-scale production, whereas they do not occur
in small batch production. Therefore, additional research on nano/micro-targeted drug delivery and developing new
preparation processes is required to obtain a straightforward and dependable medication production.
Different results may stem from different experimental models. In vitro simulation experiments using NPs can
produce positive findings regarding anti-inflammatory and antioxidant results. However, there are differences
between experimental models (rodents) and human patient species. In vivo modeling of drug release and predict­
ing stability of the gastrointestinal tract is challenging due to the complexity and individual heterogeneity of the
gastrointestinal tract. For instance, the relevant targeting and therapeutic effect will be lessened if inflammation
exists in other sites. Further research should be done to find an animal model that can accurately represent human
IBD disease and imitate the pathophysiological environment of human IBD.
Optimal drug properties. Despite the excellent performance of the prepared NPs in trials, new designs must still be
found to increase the precise release rate of the drug. The intended clinical outcome cannot be achieved by focusing on
just one factor; instead, multiple combinations of strategies must be used. IBD treatment should include improving
intestinal flora and re-establishing intestinal balance. Drug biocompatibility and biosafety should also be considered
because nanocarriers may be toxic to the liver, kidneys, or other organs during their breakdown, metabolism, and
excretion. Further experimental design and validation are required for some experimental results that did not investigate
and understand the origins of the occurrence.
There are a number of potential issues to be addressed from the translation of nanomedicines to the clinic,
including insufficient understanding of the mechanisms and chemical structure materials of NPs, safety profiles,
regulatory and legal challenges. Therefore, the absorption and binding mechanisms during gastrointestinal transit
still need to be studied in depth for the development of more advanced DDSs with more rational use of the
pathological and physiological microenvironment. It is also essential to assess the long-term toxicity of DDSs and
to develop relevant regulatory programmes. For drugs, more extensive multi-centre clinical studies are also needed
to validate their efficacy. Concerted efforts by scientists and clinicians are needed in the development of
nanomaterial drug delivery systems for the treatment of inflammatory diseases. The regulatory situation and
ethical considerations pertaining to the development and application of nanoparticle-based therapeutics are also
important factors to be taken into account in the context of translational research and clinical applications.
We are glad to note the innovative theories and strategies that nanotechnology has contributed to treating IBD and the
diagnostic advancements it has brought about. The following qualities should be included in a perfect nanomedicine: A) it
should be simple to make and can be mass-produced; B) it should be stable, with high drug loading and excellent drug release
rates; C) it should have high target specificity, acting directly on the inflammatory colon site and releasing the drug
continuously; and D) it should be easy to breakdown and absorb by the human body and should have good biosafety.

Conclusions
There is no complete treatment plan for IBD because it is a chronic idiopathic inflammatory disease with an unknown
etiology. Every traditional therapeutic drug and treatment has disadvantages and causes more adverse effects and causes
more adverse effects. Nano-agents, which can target and have various functional effects through both passive and active
targeting, have been produced with the advancement of nanotechnology. Nanomedicines have demonstrated superior
experimental therapeutic results. Currently, research on the clinical application of drug preparation, experimental design,
and clinical application of drugs is still unsatisfactory. But these will be the areas of focus for future research. Future
research will tend to the following aspects. Investigate the pathophysiological mechanism of the disease in more detail;
develop novel drug delivery strategies by combining the research features of active and passive targeting; examine novel

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experimental animal models to provide adequate pathological information for experiments; and screen optimal targeting
drugs for early release into clinical practice.

Author Contributions
JG: Writing-reviewing and editing. JL: Conceptualization and methodology. ZL: Software. HW: Visualization and
supervision. ZM: Funding acquisition. All authors made a significant contribution to the work reported, whether that
is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took
part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed
on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding
This study was supported by Science and Technology Department of Jilin Province (Grant No. 20220505041ZP).

Disclosure
The authors declare that the research was conducted in the absence of any commercial or financial relationships that
could be construed as a potential conflict of interest.

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