Nanoparticle-Based Drug Delivery Systems for Inflammatory Bowel Disease Treatment

Figures & data

Table 1 The Passive Targeting and Functional Effects of Nanoformulations for IBD Treatment

IBD	Type of Targeting	Targeting Mechanism	Delivery route	Loaded Agents/Cargo	NPs Delivery System	Model	Main Results	Ref
UC	Passive	EPR effect	Oral delivery	Bud	NLCs	DSS mice model, J774 cells line model	High encapsulation rate; lower level of inflammatory factors; longer drug residence duration in the colon.	[26]
UC	Passive	EPR effect	Oral delivery	Cyclosporin A	Protamine nanocapsules	Jurkat cells line model	High encapsulation efficiency and good drug loading capacity decrease IL-2 secretion.	[27]
UC	Passive	EPR effect	Oral delivery	Celecoxib	Nanomixed micelles	Acetic acid rabbit model	The nanomixed micelles have good anti-inflammatory and antioxidant properties that help alleviate colitis.	[28]
UC	Passive	EPR effect	Oral delivery	Bud	PLGA	Oxazolone mice model	The NPs target the colonic inflammatory site to release drugs.	[29]
UC	Passive	EPR effect	Oral delivery	5-ASA	Hemoglobin NPs	Caco-2 and HT-29 cell line models	High rate of drug release combined with excellent biocompatibility and biodegradability.	[30]
UC	Passive	EPR effect	Oral delivery	Rifaximin	Tamarind gum NPs	TNBS rats model	The NPs exhibit positive therapeutic effects on colitis and function as antioxidants.	[31]
UC	Passive	EPR effect	Intravenous delivery	H2S donors	ST-H2S liposomes	DSS mice model, Caco-2 model, and RAW 264.7 cell line model	ST-H2S liposomes have an excellent immunomodulatory potential.	[32]
UC	Passive	EPR effect	Oral delivery	Oleuropein	NLCs	DSS mice model, J774 cells line model	Anti-inflammatory and antioxidant effects via lowering TNF-α and ROS production and secretion.	[33]
UC	Passive	EPR effect	Oral delivery	IFX	EAC-IFX-L and AC-IFX-L	DSS mice model	AC-IFX-L and EAC-IFX-L showed better symptom relief than the DSS treatment group.	[34]
UC	Passive	Lysozyme-triggered	Oral delivery	Vancomycin	Chitosan-polyaniline microgels	Caco-2 cell line model	Specific inflammatory colonization, inhibition of Staphylococcus aureus, superior biosafety.	[35]
UC	Passive	Azoreductase enzymes	Oral delivery	Hydrocortisone	MSs	DSS mice model	Excellent stability, drug release rate, and capacity to regulate intestinal flora.	[36]
UC	Passive	Esterases	Oral delivery	5-ASA	SiNP	TNBS mice model	High adhesion and low toxicity.	[37]
UC	Passive	Esterases	Oral delivery	Dex	PPNP	DSS mice model	Biosafety, specific targeting ability, and antioxidant activity.	[38]
UC	Passive	Acid sphingomyelinase	Vein injection	Fluorescent agent ICG	Sphingomyelin liposomes	DSS mice model and Caco-2 cell line model	Target-specific liposomes facilitate macrophage uptake.	[39]
UC	Passive	Azoreductase enzymes	–	Ornidazole and sulfasalazine	Sulfasalazine-polyethylene glycol micelles	HEK 293 cell line model	The excellent stability nanomicelles release the loaded drug by being activated by azo reductase.	[40]
UC	Passive	Azoreductase triggered	Oral delivery	M-Saf M-Bud	MSMs	Mice model	Capable of delivering drugs to targeted colonic sites	[41]
UC	Passive	α-amylase responsive	Oral delivery	Dex	HES-CUR NPs	DSS mice model	The excellent anti-inflammatory and antioxidant properties of NPs enable multi-drug combination therapy.	[42]
UC	Passive	ROS-responsive	Oral delivery	Bud and Tpl	Bud-ATK-Tpl	DSS mice model and RAW264.7 cell line model	High drug release to minimize adverse effects; colitis treatment that combines anti-inflammatory and antioxidant treatment.	[43]
UC	Passive	ROS-responsive	Oral delivery	Tpl	OxbCD	DSS mice and TNBS mice model	Excellent biosafety and antioxidant function are achieved via drug molecule release from multiple components that eliminate ROS.	[44]
UC	Passive	ROS responsive	Oral delivery	Silymarin	SiRNP	DSS mice model and RAW 264.7 cells model	Effective elimination of ROS, biodegradable, and improved bioavailability of the drug.	[45]
UC	Passive	ROS-responsive	Oral delivery	SeM	SeM@EM	DSS mice model and HT29 cell line model	SeM@EM improves drug adherence, alleviates inflammation, and promotes the growth of beneficial intestinal microbiota.	[46]
UC	Passive	ROS-responsive	Intravenous and subcutaneous injection	–	OxbCD NPs	Guinea pigs model B16F10 cells and MDA-MB-231 cells lines model	Superior ROS sensitivity and biocompatibility.	[47]
UC	Passive	pH-sensitive	Oral delivery	OVA	PLGA NPs	DSS mice model and Caco-2 cell line model	Superior stability and specificity in targeting the colon.	[14]
UC	Passive	pH-sensitive	Oral delivery	Bud	Eudragit S 100/Capryol 90 nanocapsules	Acetic acid rat model	Favorable drug release rate and effective targeting for colonic drug delivery.	[48]
UC	Passive	pH-sensitive	Oral delivery	BBR	PLGA NPs	DSS mice model	Dual drug release properties to reduce the frequency of drug administration.	[49]
UC	Passive	pH-sensitive	Oral delivery	Cur	Polyacrylamide-grafted-xanthan gum NPs	Acetic acid rat model	NPs have a high degree of colonic targeting and alleviate myeloperoxidase and nitrite levels to relieve colitis symptoms.	[50]
UC	Passive	pH-sensitive	Oral delivery	IL-1Ra	Alginate/chitosan microcapsules	DSS mice model	Microcapsules can release the drug in situ in the colon, reducing systemic adverse effects.	[51]
UC	Passive	pH-sensitive	Oral delivery	Tacrolimus	P-4135F NP	DSS mice model	High drug loading and release rates.	[52]
UC	Passive	pH-sensitive	Oral delivery	Cur and Dex	HPMCAS-HF microencapsulated PLGA NPs	RAW 264.7, HT29-MTX, and T84 cell line model	Microcapsules have burst and sustained drug release with excellent anti-inflammatory properties.	[53]
UC	Passive	pH-sensitive	Oral delivery	Bud	PLGA NPs	DSS mice model	Relieves colitis and has pH-dependent drug-releasing properties.	[54]
UC	Passive	pH-sensitive	–	5-ASA	Ginger-derived nanocarriers	In vitro	High encapsulation rate, outstanding stability, and excellent target specificity.	[55]
UC	Passive	pH-sensitive	–	5-ASA	Polyvinyl alcohol/sodium alginate/polylactic acid blend carrier	–	Controlled release of therapeutic drugs through good pH sensitivity.	[56]
UC	Passive	pH-sensitive	In vitro	GAR	PLGA NPs	Caco-2 cell line model	NPs can alleviate the response to inflammation by decreasing MPO activity.	[57]
UC	Passive	pH-sensitive	Oral delivery	5-ASA and Cur	Sulfated chitosan/alginate composite microparticles	TNBS rats model	Releases two drugs into the target area; its therapeutic effect is better than a single-dose treatment.	[58]
UC	Passive	pH-sensitive	Oral delivery	Bud and prednisolone	MSNs	DSS mice model	The particles resulted in lower levels of pro-inflammatory cytokines than uncoated particles.	[59]
UC	Passive	pH-sensitive	Oral delivery	Cur	Curcumin coupled with Eudragit^® S100	DSS mice model, HCT116, and HT-29 cell line model	Great stability and loading rates; inhibits inflammatory response.	[60]
UC	Passive	pH-sensitive	Oral delivery	Prednisolone	Prednisolone wrapped by Eudragit S100	In vitro	The nanocapsules specifically release the drug into the colon.	[61]
UC	Passive	pH-responsive	Oral delivery	Prednisolone	Encapsulated by succinylated ε-polylysine 3-aminopropyl-functionalized mesoporous silica NPs	RAW 264.7, LS 174T, and Caco-2 cell line model	MCM-NH2 is pH sensitive, allowing for targeted colonic delivery.	[62]
UC	Passive	pH-sensitive azo-reductase	Oral delivery	Bud	ES-Azo. Pu NPs	TNBS mice model	NPs are sensitive to enzymes and pH, allowing for sustained targeted drug release.	[63]
UC	Passive	pH-sensitive amylase enzyme	Oral delivery	Safranin O dye	MSNs	Rat model and, Caco-2 cell line model	Dual targeting improves the inflammatory colonic tissue specificity of the drug.	[64]
UC	Passive	pH-sensitive, H2O2-responsive	–	Rifaximin	OxiDEX NPs encapsulated in HPMCAS	Caco-2 and HT29-MTX cell line model	Highly adhesive, sensitive to H2O2 and pH; capable of reducing the systemic adverse effect of drugs.	[65]
UC	Passive	pH-sensitive, Positive charges, and ROS-responsive	Oral delivery	Infliximab	Polyphenol-PEG-containing polymers NPs	DSS mice model	Higher adhesion, excellent target specificity, and biosafety	[66]
UC	Passive	pH-sensitive and azo-reductase enzymes	Oral delivery	Safranin O and hydrocortisone	Magnetic mesoporous silica microparticles functionalized by azo derivatives	TNBS rats model	The NPS increases the delivery efficiency of loaded drugs and improves therapeutic efficacy.	[67]
UC	Passive	Positive charges	Intrarectally administered	Betamethasone	Ethylcellulose nanospheres coated with polysorbate 20	TNBS mice model, C2BBe1, and RAW 264.7 cell line model	Negatively charged: the ability to target areas of inflammation with favorable adhesion.	[68]
UC	Passive	Positive charges	Intrarectally administered	Bud and colony-stimulating	HEP-HSA NPs	DSS mice model and RAW 264.7 cells line model	Simultaneous loading of drugs and biologics. Better anti-inflammatory effect than a single drug-loaded NP.	[69]
UC	Passive	Positive charges	Oral delivery	CeO2 NPs	CeO2@MMT	DSS mice model and RAW 264.7 cells line model	CeO2@MMT treats inflammation via target specificity and antioxidant action.	[70]
UC	Passive	Positive charges	Oral delivery	TNF-α	Polymeric NPs coupled by two different chain lengths (2 kDa and 5 kDa) of PEG and PLEG	DSS mice model, Caco-2 cells, and J774 cells lines model	PLGA-PEG2K NPs are more protective of drugs and more effective in treatment than the PLGA-PEG5K NPs.	[71]
UC	Passive	Positive charges	Oral delivery	Infliximab	IFX NM	TNBS mice model and HT29 cell model	Sustained release function and anti-inflammatory properties promote mucosal healing.	[72]
UC	Passive	Positive charges	–	Zingerone	Zin-SLNPs	RAW 264.7 cell line model	Negative surface charge for better adhesion; superior biosafety.	[73]
UC	Passive	Positive charges and esterase	Intrarectally administered	Dex	Inflammation targeting hydrogel	DSS mice and TRUC mice model, Caco2, and HT-29 cell line model	IT-hydrogel reduces systemic drug exposure, prolongs local drug release, and improves efficacy more than free Dex enemas.	[74]

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, nanopolyplexe; SLNPs, solid lipid nanoparticles; MMT, montmorillonite.

Table 2 The Active Targeting and Functional Effects of Nanoformulations for IBD Treatment

IBD	Type of Targeting	Targeting Mechanism	Delivery route	Loaded Agents/ Cargo	Nps Delivery System	Model	Main Results	Ref
UC	Active	Mannose receptors	Oral delivery	Cur	Cur–AceKGM NPs	RAW264.7 cells lines model	Cur-AceKGM NPs are more targeted and have superior therapeutic efficacy compared to oral doses of free Cur.	[75]
UC	Active	SRA1	Oral delivery	SOD	ARC-SOD	J774 A.1 cells and Caco-2 cells lines model	Potent antioxidant and anti-inflammatory properties promote macrophage endocytosis of drug loading.	[76]
UC	Active	Folate receptors	Intrarectally administered	SOD	SNP-FA	TNBS mice model and RAW264.7 cells line model	Good stability and biological activity; capable of targeted colonic delivery to reduce drug side effects	[77]
UC	Active	CD44 receptors	–	Bud	HANPs	Caco-2 and NIH3T3 cells lines model	Excellent biosafety; better ability to inhibit inflammatory factors than free drugs	[78]
UC	Active	CCR5 receptor	Oral delivery	Piceatannol	Piceatannol–PLGA–CCL4	UC patients, DSS mice model and Caco-2 cells line model	Excellent biocompatibility; inhibits the expression of pro-inflammatory genes; regulates the balance of intestinal flora	[79]
UC	Active	Cytoplasmic/membrane proteins of the intestinal mucosa	Oral delivery	–	GDNPs 2	DSS mice model and RAW264.7 cells lines model	GDNPs 2 are natural NPs that reduce the production of pro-inflammatory factors and improve the treatment of colitis	[80]
UC	Active	Mannose receptors	Oral delivery	Apremilast	CDs.EP/Man/Meth.Cs NPs	Caco-2 and RAW 264.7 cells line model	CDs.EP/Man/Meth.Cs NPs enable specific accumulation of drugs at the site of inflammation allowing uptake by macrophages	[81]
UC	Active	Mannose receptors	Oral delivery	Anti-TNF-a nucleotides	cKGM and ASO	DSS mice, CT-26 cells and RAW 264.7 cells lines model	cKGM and ASO can transfer ASO to colonic macrophages and reduce the symptoms of colitis by decreasing TNF-a levels	[82]
UC	Active	Mannose receptors	–	Bud	Mn-NLCs	Oxazolone rat model and J774A.1 cells line model	Excellent encapsulation rate; great biocompatibility; capable of reducing the level of inflammatory factors	[83]
UC	Active	CAR1	Oral delivery	Inf	INF/LMSN@GE	DSS mice model	Transmission stability; colonic targeting specificity; anti-inflammatory effects	[84]
UC	Active	SRA1	Oral delivery	Dex	NAC-Dex	THP-1 cells and Caco-2 cells lines model	NAC-Dex reduces the release of inflammatory factors and the production of reactive oxygen species; repairs the intestinal barrier	[85]
UC	Active	SRA1	–	Dex	SAN-Dex	J774A.1 cells and Caco-2 cells lines model	Compared to free Dex, SAN-Dex is more effective in reducing inflammatory factors	[86]
UC	Active	Scavenger receptors (SRs)	Oral delivery	Bud	hMnO2 NPs.	DSS mice model and RAW 264.7 cells line model	NPs carriers with antioxidant function synergize with loaded drugs for the treatment of colitis	[87]
UC	Active	Adhesion molecule receptors and proinflammatory cytokine receptors	Oral delivery	PDA	PDA@mCRAMP@MM	DSS mice model and RAW264.7 cells line model	Inflammatory targeting; anti-inflammatory effect through regulation of immune function; regulation of intestinal flora	[88]
UC	Active	Folate-targeted	Oral delivery	Resveratro	PLGA-FA-RSV	TNBS rats model and Caco-2 cells line model	PLGA-FA-RSV enhances the targeted transport of the drug with excellent therapeutic efficacy	[89]
UC	Active	Galactose receptors	Oral delivery	TNF-α siRNA	PLA-PEG	DSS mice model, RAW264.7 cells and Caco-2 cells lines model	Improved drug utilization and delivery efficiency; biodegradability; anti-inflammatory effects through inhibition of inflammatory factor production	[90]
UC	Active	CD44 receptors	Oral delivery	OPN	BSA/OPN-NPs	DSS mice model	Exerts anti-inflammatory effects by inhibiting MPO and inflammatory factor levels	[91]
UC	Active	CD44 receptors	Oral delivery	Bilirubin	HABN	DSS mice model and J774A.1 cells line model	Greater target specificity of HABN compared to NPs without HA function painting	[92]
UC	Active	CD44 receptors	Oral delivery	Cur	Cur-HA NPs	DSS mice model and HT-29 cells line model	Improve intestinal mucosal barrier; regulate intestinal flora diversity	[93]
UC	Active	Integrin αv	Oral delivery	PA	cRGD–PA-SF NPs	DSS mice, Caco-2 and RAW 264.7 cell line	cRGD-PASFNs can alleviate inflammation and improve the colonic barrier with good therapeutic effects.	[94]

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.

Table 3 The Hybrid Targeting and Functional Effects of Nanoformulations for IBD Treatment

IBD	Type of Targeting	Targeting Mechanism	Delivery route	Loaded Agents/ Cargo	NSPs delivery system	Model	Main results	Ref
UC	Passive, active	pH-sensitive, mannose receptor	Oral delivery	cKGM and ASO	GelMA	DSS mice model, CT-26 cells, and RAW 264.7 cells lines model	The microspheres can target macrophages, thereby reducing inflammation and drug toxicity.	[95]
UC	Passive, active	ROS-responsive CD44 receptor	Oral delivery	Thioketa	Ra@TH	DSS mice model, RAW 264.7 and HT-29 cells	The Ra@TH system enables the delivery of rapamycin to sites of colitis-specific inflammation through the active targeting of the CD44 receptor. This allows for the controlled release of rapamycin at ROS-sensitive lesions.	[96]
UC	Passive, active	ROS-responsive CD44 receptor	Oral delivery	Infliximab	IFXSS@HA or IFXTK@HA	TNBS mice model and HT 29 cell line model	The nanocomposite has a high drug-loading capacity and high specificity, which reduces systemic exposure and provides better therapeutic results than intravenous drugs.	[97]
UC	Passive active	Positive charges, mannose receptor	–	Man-NPs	CDs/Man-NPs	DSS mice model, RAW 264.7, and Caco-2 cell line model	CDs/Man-NPs target macrophages and are internalized by absorption, reduce adverse effects of drugs, and improve drug utilization.	[98]
UC	Passive active	pH-sensitive CD44 receptor	Oral delivery	SK	ES100/HA/CS NPs	TNBS mice model and RAW 264.7 cell line model	ES100/HA/CS NPs exert therapeutic effects by reducing ROS production and inhibiting the release of inflammatory factors.	[99]
UC	Passive active	pH-sensitive CD44 receptor	Oral delivery	Methotrexate	HA-CS/ES100/PLGA NPs	TNBS mice model RAW 264.7 cell line model	HA-CS/ES100/PLGA NPs are specific; they alleviate intestinal inflammation by reducing inflammatory cell infiltration and decreasing intestinal mucosal damage.	[100]

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.

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

Type of Targeting	Targeting Mechanism	Effectiveness	Limitations
Passive targeting	EPR effect	The NPs developed based on the EPR effect accumulate at the site of inflammation, prolonging the residence time in the inflamed intestinal area and avoiding the rapid clearance of the carrier. It could reduce the adverse effects of the loaded drug and improve the utilisation of the drug compared to the free drug.	The EPR effect only promotes the accumulation of DDSs in colitis tissues, whereas inefficient target cell uptake and insufficient intracellular drug release limit the therapeutic efficacy of anti-inflammatory drugs. Moreover, the instability of NPs drugs may increase during the preparation process or when the formulation is changed.
	Enzymes	Enzyme-targeted NPs with a favourable biosafety profile can selectively accumulate in inflamed tissues and achieve therapeutic efficacy through delayed release. Some NPs drugs protect the integrity of the intestinal barrier and enhance intestinal homeostasis.	Shorter gastrointestinal transit times may reduce drug release under disease conditions.
	ROS-responsive	The drug release of ROS-dependent NPs is efficient and less toxic, while its synergy of anti-inflammatory and antioxidant effects can attenuate the inflammatory damage in the colonic mucosa.	Oxidative stress may not be the main causative agent of the disease. If the loaded drug was released in bursts, its excessively rapid release rate may make the duration of the drug quite short.
	pH-sensitive	The pH-dependent delivery system protects the drug from gastrointestinal disorders, resists unfavourable gastrointestinal conditions and reduces premature drug release.	The design of drug delivery systems based solely on the pH of the gastrointestinal tract is unreliable due to differences of pH between individuals and the variation 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 charge	The positive charge-targeted NPs promote cellular uptake and drug release, allowing better drug contact with mucosal surfaces and increasing targeting and retention of the drug delivery system.	The charge-dependent nanoparticles have the potential to bind to other charge-modified substances during gastrointestinal transport. There are fewer studies on charge-dependent delivery system loading and further experimental exploration is needed.
Active targeting	/	Actively targeted drugs are highly specific and selective for the site of targeting, reducing drug redistribution in healthy tissues, improving therapeutic efficacy and reducing systemic adverse events of the drug.	Further in vivo studies are needed to assess the efficacy and stability of different targeting ligands and formulations in animal models of colitis.
Hybrid targeting	/	Integrated systems with different release triggering mechanisms help overcome pathophysiological variability more than single systems. Passive targeting reduces the non-specific uptake of drug carriers at non-target sites and improves the targeting of active targeting systems. Active targeting promotes specificity of the drug system. Thus hybrid targeting systems enable precise targeting of drug-carrying nanoparticles and further reduce their side effects.	The release triggering mechanisms of different hybrid-targeted nanoparticles still need to be further refined. And the differences between animal models and human patients should be fully recognised, which requires more experimental data models to validate the biosafety and efficacy of the newly developed NPs.

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

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

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

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

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

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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