Research progress of polysaccharide drug delivery systems in the treatment of intestinal diseases: A review

Abstract

Intestinal diseases (IDs), as a type of complex immune-related diseases, have long faced challenges such as low drug delivery efficiency, insufficient targeting, and significant systemic toxic and side effects in their treatment strategies. Although oral administration is widely adopted due to its noninvasiveness and high patient compliance, the heterogeneity of the gastrointestinal environment severely limits the precise release and effective accumulation of drugs in the colon. Therefore, developing a new type of drug carrier system that can overcome physiological barriers and achieve colonic targeted delivery has become one of the core research directions in the field of ID therapy. Drug delivery systems based on natural polysaccharides have received extensive attention due to their unique biocompatibility, modifiers, and environmental response characteristics. Polysaccharides not only have excellent drug loading capacity but also can respond to the specific pH value, enzyme environment, and redox state of the colon through chemical modification or physical embedding strategies, thereby precisely regulating drug release kinetics. This article reviews the therapeutic effect of polysaccharide delivery systems in IDs, providing more approaches for the treatment of ID.

Keywords

Natural polysaccharides colon-targeted drug delivery micron particle systems nanoparticle systems intestinal diseases

Introduction

Currently, the main common intestinal diseases (IDs) in clinical medicine are inflammatory bowel disease (IBD) and colon cancer (CRC). The main issues in the treatment of IDs are the complex process of drug delivery to the colon and the precise positioning of the drug.¹ There is a need to explore potential treatments for IDs. We actively pursue drug formulations that can be precisely directed for treating such ailments.

In current clinical practice, the oral route is widely utilized for ID treatment.² Oral administration offers various benefits such as safety, noninvasiveness, and the capacity to easily adjust dosage and allow self-medication, thus empowering patients to actively participate in their treatment. Furthermore, this administration route enables systemic or localized therapy without inflicting damage to the gastrointestinal (GI) tissue postdigestion and absorption. Nevertheless, it also poses certain limitations. The GI tract can impede drug absorption following oral administration, potentially hindering its effectiveness. Additionally, prior to reaching the site of the disease, the drug undergoes nonspecific distribution within the GI tract, thereby diminishing its therapeutic impact.

Targeted drug delivery systems, as the core research direction in the field of modern drug delivery, aim to break through the biological distribution limitations of traditional therapies and achieve precise spatiotemporal regulation of therapeutic doses. The problems such as systemic toxicity, off-target effects, and low therapeutic index caused by the nonspecific distribution of drugs in the current clinical conventional drug administration mode have become the key bottlenecks restricting the therapeutic effect of major diseases.³ In recent years, with the cross-integration of nanotechnology, molecular probe design, and biomaterials engineering, intelligent delivery carriers have achieved remarkable breakthroughs in the response to the lesion microenvironment, cell membrane penetration efficiency, and target recognition accuracy. They have particularly demonstrated transformative potential in areas such as tumor-targeted therapy, drug delivery in the central nervous system, and the transportation of gene editing tools.

The focus of current research in drug administration for the treatment of ID has been on targeted delivery to the colon. The objective is to overcome the limitations of oral administration and enhance therapeutic effects. These drug delivery systems are developed based on understanding the physiological changes that occur in the digestive tract, such as variations in pH values, transport time, and colonic microbiota composition.⁴ By exploring these changes, researchers aim to achieve selective treatment and minimize the side effects associated with oral administration.² Additionally, colon-targeted drug delivery systems take advantage of the prolonged retention time in the colon to improve drug absorption by the body. Micrometers and nanoparticles have shown promising potential in advanced drug delivery systems for ID treatment. The shape, surface properties, and ability to control drug release are essential factors for effective colon delivery. Furthermore, reducing the size of the micrometer/nanoparticle delivery system can prolong its residence time in the colon and increase drug accumulation in the colonic region.⁵

Polysaccharides show pleiotropic regulatory potential in the treatment of ID. Its anti-inflammatory properties can be achieved by inhibiting the TLR/NF-κB signaling pathway, reducing the expression of pro-inflammatory factors such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, and simultaneously upregulating anti-inflammatory factors such as IL-10 to reshape the immune balance.⁶ As prebiotics, polysaccharides can selectively promote the proliferation of Bifidobacterium and Lactobacillus, repair intestinal barrier function through metabolites of the intestinal microbiota, and enhance the expression of tight junction protein. It is worth noting that the molecular weight, branching degree, and substituent type of polysaccharides significantly affect their biological activity.⁷ These characteristics enable polysaccharides not only to be used as drug carriers for colon-targeted delivery but also to act as therapeutic agents themselves to participate in the multidimensional regulation of ID, providing a new path for the development of an integrated “delivery-treatment” strategy.

The utilization of natural polysaccharides in micro/nanoparticle systems has attracted significant interest for drug targeting to the colon. These polysaccharides have been shown to have high bioavailability, biocompatibility, lack of toxicity, and affordability, leading to FDA approval for clinical use.⁸ They also possess favorable biological properties such as pH responsiveness, resistance to gastric clearance, biodegradation by colonic microbiota, and adhesion to the mucosal layer. These properties offer potential opportunities for micro/nanoparticle delivery systems to overcome barriers associated with oral administration and achieve targeted enrichment within the colon. However, optimizing the physicochemical properties of polysaccharides through structural alterations, functionalization, and polymer blends can make micro/nanoparticles more suitable for treating intestinal disorders. Currently, chitosan, alginate, guar gum, starch, pectin, and hyaluronic acid (HA) are widely used in micro/nano drug delivery systems for colon-specific drug delivery. Although there have been previous articles on polysaccharidum-based nanoparticles targeting the colon system, they were only applied in animals.⁹ Based on the previous summary, we discussed the application and challenges of polysaccharide-based drug delivery systems in clinical practice. It provides broader ideas for colonic targeted drug delivery therapy. We retrieved the research progress on polysaccharide drug delivery systems in the treatment of IDs from the PubMed database and conducted a review.

Physiological factors of colon-targeted drug delivery system

Colon targeting via oral delivery relies on overcoming several physiological barriers within the GI tract. These barriers include pH conditions, transit time, enzyme content, microbial diversity, and intestinal epithelial permeability (Figure 1).¹⁰ Individual differences and the presence of food in the GI tract also play important roles in effective drug delivery to the colon.

Figure 1.

Physiological characteristics of the gastrointestinal tract.

Changes in pH value

Generally speaking, the GI tract is divided into three main regions: stomach, small intestine (duodenum, jejunum, and ileum), and large intestine (cecum, colon, and rectum).¹¹ The first obstacle to oral drug delivery is the different pH values within the GI tract. In healthy subjects, gastric pH ranges from 1.0 to 2.5. It rises from 6.6 to 7.5 in the small and large intestines, with a pH range of 5.5–7.0 in the lumen of the proximal small intestine, and gradually rises to 6.5–7.5 in the distal ileum. In the cecum, the pH decreases to 5.5–7.5 and rises from 6.87 in the proximal colon to 7.2 in the distal colon. Compared with healthy subjects, the pH value in the colon of IBD patients decreased, ranging from 5.5 to 2.3. Decreased colonic pH is caused by several factors, intestinal volume, transit time, microbial fermentation, bile acid metabolism of fatty acids, bicarbonate, and lactic acid secretions.¹² Changes in pH in IBD patients can affect the composition of the gut microbiota, which affects the colon's timing. Additionally, changes in pH may affect drug release from pH-sensitive carriers. Clearly, the development of colon-targeted drug delivery systems centers around differences in GI pH and requires a comprehensive strategy for colon-targeted drug release.

Running time

The duration of drug movement through the digestive system is crucial for the effectiveness of orally taken drugs.¹³ On average, drugs take about 3 h to pass through the stomach and around 4 h to pass through the small intestine. However, individual cases may vary, with durations ranging from 2 to 6 h. The drug takes 3–4 h to pass through the small intestine and then enters the colon. Several factors, such as diet, eating/fasting habits, physical activity, stress levels, and colon-related diseases, can influence the transit time in the colon. Interestingly, individuals with IBD have a faster colon transit time compared to healthy individuals. Additionally, the size of the drug dosage form also affects transit time, with larger particles generally having a shorter transit time compared to smaller particles. Changes in GI transit time can impact the duration a medication remains in the body, ultimately affecting its effectiveness in reaching its intended target.¹⁴ Therefore, the GI transit time seems to be more suitable for the administration of micro/nanoparticle systems.

Mucus

Colonic mucus is the gel-like layer covering the intestinal epithelium. The degree of mucus hydration is an important determinant of mucus viscoelasticity. The glycocalyx that protects cell surfaces includes cell-associated mucins and mucogels formed from secreted gel-forming mucins. Colonic mucus is formed from two distinct layers and consists of gel-forming glycosylated mucins permanently secreted by the goblet cells of the colon epithelium. The inner layer is dense and impenetrable to bacteria, while the loose outer layer provides a habitat for a rich community of symbiotic microorganisms. The integrity of the mucus barrier is critical for preventing bacterial contact with mucosal epithelial cells and maintaining homeostasis within the gut, but it can be affected by multiple factors. Patients with IBD experience significant changes in mucus composition, thickness, physical properties, and function. Crohn's disease (CD) is characterized by goblet cell hypertrophy, whereas ulcerative colitis (UC) patients are characterized by goblet cell reduction and depletion. In the latter case, mucus production is significantly reduced and the thickness of the mucus layer in the colon and rectum is reduced.¹⁵ In UC, a large increase in mucus production causes the mucus layer in the inflamed area to thicken.

Colonic fluid volume

The amount of fluid in the colon after the drug enters the colon is also a factor. The normal volume of colonic fluid extracted is about 13 mL. In the fasting state, its volume ranges from 1 to 44 mL. The presence of food in the colon changes the amount of colonic fluid and levels of digestive enzymes, as well as the absorption of nutrients and digestion of carbohydrates. Patients with IBD have increased fluid secretion and decreased water reabsorption, leading to dilution of colonic fluids.¹⁶ Therefore, the amount of fluid in the colon can affect the dissolution and absorption of a drug, thereby affecting its bioavailability in the colon.

Gut microbiota

The microbial community in the human colon is rich and diverse, with approximately 400 different bacterial species responsible for enzyme activity and various chemical reactions, including metabolism and absorption of carbohydrates, proteins, fatty acids, and drugs.¹⁷ The various enzymes in the colon are key to the effectiveness of colon-targeted drug delivery systems. Natural polysaccharides can be specifically degraded by colonic enzymes of anaerobic bacteria and have been widely used to deliver drugs to the colon.⁸ Meanwhile, some polysaccharides can serve as prebiotics for colon bacteria, stimulating bacterial proliferation and regulating the colon microbiota. In addition, the polysaccharide delivery system also utilizes colonic enzymes to convert inactive molecules into active molecules for colon-targeted delivery. Therefore, changes in the colonic microbiota can affect the targeted delivery of polysaccharide nanodrug delivery systems.

The impact of different IDs on colon-targeted drug delivery systems

There are differences in the GI environment of different IDs. Therefore, when carrying out colon-targeted drug delivery, drugs must be designed according to the physiological conditions of different IDs to achieve the purpose of treating the disease.

Inflammatory bowel disease

Inflammatory bowel disease is a type of autoimmune condition characterized by persistent inflammation in the GI tract, with an unknown precise cause. Nonetheless, environmental factors and genetics are thought to play a role in its development. The inflammation in IBD results in erosion and ulcers of the intestinal mucosa, eventually leading to the formation of scar tissue in the intestinal walls. The two primary types of IBD are UC and CD, with the main distinction being the site of inflammation within the digestive system. In UC, only the innermost layer of the rectum and colon is affected, while in CD, the inflammation can penetrate through the intestinal wall and impact both the small and large intestines. Treatment for IBD mainly focuses on inducing and sustaining remission, as there is currently no definitive cure through drug therapy. However, long-term medication use can lead to systemic side effects and drug resistance, posing significant challenges in the management of IBD.

As the IBD advances, there are notable physiological alterations in the GI system. The usual pH level in the colon, typically ranging between 6.0 and 7.2, decreases to 2.3–5.5 in instances of colitis. Moreover, there is an escalation in mucus production, modifications in the structure of intestinal epithelial cells (IEC), infiltration of activated macrophages, and adjustments in the enzyme environment. The decline in Bacteroides and Bifidobacterium, coupled with the rise in Bacillus and Streptococcus, serve as indicators of the advancement of IBD.¹⁸

The treatment drugs for IBD are generally administered through oral, parenteral, and rectal routes. Notably, with precise anti-inflammatory activity, nonspecific immunomodulators have been replaced by biopharmaceuticals in recent years. Examples include anti-TNF-α (infliximab, adalimumab, golimumab, and certolizumab) and anti-integrin antibodies (vedolizumab and natalizumab).¹⁹

During oral administration, medications are quickly absorbed in the upper part of the GI tract, including the stomach and intestines, resulting in various side effects. This causes a decrease in drug concentration in the colon, making treatment for IBD less effective.²⁰ Additionally, the efficacy of these medications is hindered by insufficient activation time of the prodrugs in the presence of stomach upset, as well as individual variations in GI acidity and transit time within these systems. Therefore, the utilization of oral drug delivery necessitates the implementation of a more suitable delivery method to enhance the localized action of the active drug in treating the condition, by enhancing the concentration at the inflamed site.¹⁶

Colon cancer

Colorectal cancer is the world's third most common cancer and is the second-leading cause of cancer-related deaths.²¹ It originates from adenomatous polyps in the colon and rectum's inner layers, which can advance and infiltrate nearby lymph nodes and muscles, and eventually into distant tissues and organs, with the liver being the most severely impacted area. Metastasis and tumor recurrence act as major predictors of survival time, which are also linked to decreased survival rates. Factors that are now thought to play a role in the development of colorectal cancer include genetic predisposition, age, gender, environment, and lifestyle choices, such as smoking, excessive alcohol consumption, and a diet high in fat. Furthermore, IBD heightens the risk of carcinogenesis, resulting in ecological imbalance and genetic mutations.

The therapy for CRC is largely determined by the tumor's location and disease stage. All chemotherapy drugs, except capecitabine, are administered intravenously.

In a state of hypoxia, uncontrolled tumor cell proliferation in colorectal cancer results in necrotic nuclei formation within the tumor mass. This impaired vascularization hinders essential nutrient delivery to the diseased tissue, affecting drug absorption and necessitating high doses for pharmacologic effects. Intravenous administration of chemotherapeutic agents may lead to acquired resistance, off-target toxicity, and severe side effects, limiting therapeutic efficacy. Moreover, hypovascularization and low blood flow in the tumor area can impede drug delivery via intravenous route.²²

In tumor tissues, an acidic microenvironment is evident compared to normal tissues, resulting from the secretion of lactic acid during anaerobic glycolysis. Furthermore, colorectal cancer consists of a variety of cell types, leading to a diverse microenvironment that necessitates the movement of drugs to exert their effects. Importantly, drug transportation requires passage from the bloodstream into cells, and the irregular structure of blood vessels within tumor tissues may hinder this process, impacting the uniformity of drug dispersal.²³ Consequently, the distinctive physiological and pathological features of colorectal cancer pose additional requirements on targeted drug delivery systems.

Polysaccharides for drug delivery systems

In the past few years, the good bioactivity of polysaccharides has attracted great interest in their use in alleviating ID. Polysaccharides treat IBD through different mechanisms. On the one hand, they can regulate different inflammatory signaling pathways. Polysaccharides, on the other hand, play a crucial role in the balance of intestinal flora. Polysaccharides are degraded into short-chain fatty acids under the action of intestinal microorganisms, thereby regulating the homeostasis of the GI tract. Acetic acid, propionic acid, and butyric acid are the main short-chain fatty acids (SCFAs).¹ SCFAs can improve the homeostasis of intestinal flora by inhibiting the growth of pathogenic bacteria and promoting the proliferation of beneficial bacteria. SCFAs also have direct antibacterial activity against bacterial cryogens by diffusing across bacterial membranes and lowering intracellular pH. In particular, butyrate has positive effects on epithelial integrity and tight junction permeability. Butyrate promotes tight junction assembly by activating AMP-activated protein kinase and upregulating the transcription of the tight junction protein Claudin-1, thereby enhancing the intestinal barrier.²⁴ In addition, butyrate also increased mRNA expression and claudins-3 and 4 protein expression, and affected intracellular ATP concentration in a dose-dependent manner. Polysaccharides are stable in the gastric and intestinal environment and are degraded in the colon by colonic bacteria. This property has prompted scientists to study how they can be used as drug carriers to deliver drugs to colon disease sites. Therefore, formulating different polysaccharide drug delivery systems could have positive effects on IDs (Table 1).

Table 1.

Therapeutic effects of different polysaccharide drug loading systems on ID.

Polysaccharide type	Glycosidic linkage	Structural unit	Delivery mechanism	References
Chitosan	β-1,4-glycosidic bond	Glucosamine and N-acetylglucosamine	Cation characteristics and pH responsiveness	²⁵
Hyaluronic acid	β-1,3 and β-1,4 glycosidic bonds	d-glucuronic acid and N-acetylglucosamine	Strong hydrophilicity and negative charge characteristics	²⁶
Pectin	α-1,4-glycosidic bond	RG-I	The pectinase decomposition in the colon and the degree of methylation have pH sensitivity and natural adhesion	²⁷
Inulin	β-2, 1-glycosidic bond	d-furanose fructose and glucose	Antidigestive enzymes are digested by inulinase in the colon and have a high degree of polymerization	²⁸

Chitosan

Chitosan is obtained by partial deacetylation of chitin and is the second-largest and most abundant polysaccharide in nature after cellulose. It is a linear heteropolymer composed of β-(1–4) linked N-acetyl-d-glucosamine and d-glucosamine.²⁹ The degree of acetylation (DA) of chitosan is >50%, indicating the fraction of N-acetyl-d-glucosamine relative to the total number of units. In contrast to chitin (DA < 50%), which is insoluble in water and many organic solvents, chitosan is hydrophilic and soluble in acidic solutions, while the amine groups present in the macromolecule are protonated.

Due to its good anti-inflammatory, healing, and immunomodulatory activities, chitosan is the most polysaccharide developed into nanoparticles for the treatment of ID. The positive charge of chitosan nanoparticles enriches mucoadhesive properties through interactions with negatively charged mucins. In addition, chitosan interacts with negatively charged glycoproteins on the cell surface and acts on the paracellular and intracellular pathways of epithelial cells to increase cell permeability.³⁰

Hyaluronic acid

Hyaluronic acid is a linear heteropolysaccharide composed of d-glucuronic acid and N-acetyl-d-glucosamine linked together by β-1,3-glycosidic bonds or β-1,4-glycosidic bonds and is the spine an important component of animal extracellular matrix. Hyaluronic acid has a high concentration in the extracellular matrix, especially in soft connective tissues (skin, umbilical cord). Viruses and bacteria also produce HA. Hyaluronic acid is related to various physiological functions of the intercellular matrix. Hyaluronic acid can adhere to the plasma membrane or be bound through HA-specific binding proteins. CD44 is a transmembrane receptor protein that plays a key role in inflammation.³¹

Different sources of HA affect its molecular weight. It is highly polydisperse, ranging from 2 kDa to 6000 kDa, and its molecular weight determines the rheological properties. In addition, HA of different molecular weights have different healing and anti-inflammatory properties. High molecular weight HA has good anti-inflammatory properties, while low molecular weight HA can stimulate innate immune responses.³²

Pectin

Pectin is a complex polysaccharide extracted from plants that control water movement and cement the cellulose grid. It is able to form gels at low Ca²⁺, solute content, or low pH. Pectin consists mainly of linear chains of α-(1,4)-d-galacturonic acid polymers. The carboxylic acid groups on the main chain are methyl esterified to varying degrees, controlling the gel properties of pectin. The degree of methyl esterification of pectin determines its anti-inflammatory activity.³³ Oral administration of low-methyl-esterified pectin has more anti-inflammatory activity than high-methyl-esterified pectin. Low-methyl-esterified pectin inhibits local and systemic inflammation, while high-methyl-esterified pectin prevents intestinal inflammation. When taken orally, pectin is biodegraded by colonic bacteria, making it ideal for targeted drug delivery to the colon.³⁴ Furthermore, the excellent adhesive properties of pectin make it a candidate for colon-specific nanoparticles.

Inulin

Inulin is a polysaccharide composed of d-fructose units (n = 2–60) connected through β-(2–1) glycosidic bonds and terminal glucose residues. It is mainly derived from natural plants. Inulin has a variety of intrinsic biological properties. It can promote the proliferation of beneficial intestinal bacteria (Bifidobacterium and Lactobacillus) and maintain the intestinal microecological environment and host health. Inulin's β-(2–1) glycosidic bond prevents it from degradation in the upper GI tract and is degraded in the colon by colonic enzymes and bacteria, making it a favorable vehicle for colon targeting.³⁵

Polysaccharide micro-nano drug delivery system

Treating IBD and CRC presents a formidable challenge due to the intricate nature of these conditions, particularly their origin in the colon and rectum within the digestive system. Numerous studies have been conducted on drug delivery systems specifically designed for the colon, showing differing levels of advancement.

Micron particle systems

There has been a growing interest in early studies on the particulate system due to its potential therapeutic benefits in protecting the enclosed drug from degradation and controlling its release rate.³⁶ The use of microparticulate systems has been shown to decrease drug absorption in the small intestine while prolonging its presence in the colon. As a result, targeted drug delivery can be achieved to enhance the effectiveness of treatments in intestinal tissues while minimizing adverse effects. Furthermore, the particulate system facilitates a higher drug concentration and extended residence time in inflamed intestinal areas, offering a more targeted approach for treating ID.

The pH sensitivity and enzymatic degradability of polysaccharides were exploited to develop alginate/chitosan (ALG/CS) particles for loading and releasing IL-1Ra in inflammatory areas. In dextran sodium sulfate–induced colitis in mice, ALG/CS@IL-1Ra particles significantly reduced the disease activity index and ensured colon integrity and regeneration of damaged mucosa. At the same time, it also reduced the levels of inflammatory markers myeloperoxidase (MPO), IL-1β, and TNF-α.³⁷

The use of CS/ALG can be used to develop particles with extended-release rates and to construct more structured systems using polyelectrolytic complexation between opposite charges of polysaccharides.³⁸ This structural resistance of the slow-release system can also be optimized by the binding of calcium ions. These changes occurred primarily as a result of increased deprotonation of CS amino groups and degradation mediated by colon-specific cytosolic enzymes.

Pentylene glycol cross-linked ALG-CS microspheres for drug delivery to the colonic site. Fluorescent signals from labeled microspheres were found in both the jejunum and colon at 12 h after oral administration. ALG-CS microspheres loaded with Icariin were able to reduce the colonic mucosal damage index at the onset of colitis, it reduced normal tissue edema and MPO levels in rabbits with acetic acid–induced colitis, effectively treating IBD.³⁹

In the treatment of IBD and CRC, microparticle systems are mainly based on pH-dependent and colonic microbiota-triggered systems, and their mode of administration is still through the oral route of administration to the colonic area.⁴⁰ These micrometer delivery systems target drug delivery to the colonic site, offering more possibilities for treating IBD and CRC.

Nanoparticle systems

Although micron drug delivery systems are highly effective, some initial drug release, degradation during GI transport, size distribution, and their potential accumulation need further investigation.⁴¹ For example, the small size facilitates the nonspecific accumulation of nanoparticle systems in tumor tissues. This passive targeting with strong permeability and retention (EPR) effects has an important role in delivering drugs in the tumor microenvironment. The EPR effect is also present in inflamed tissues of the colon, increasing the permeability of small particles across the intestinal epithelial membrane. Active targeting or receptor-mediated targeting is another strategy of interest in ID therapy, especially in CRC, to enhance drug delivery and accumulation in diseased tissues. The uniqueness of nanoparticle systems holds promise for overcoming barriers to ID therapy and achieving maximum efficacy in colonic tissues.

Soluble eggshell membrane protein SEP extracted from eggs has favorable antioxidant and anti-inflammatory activities on IEC.⁴² However, most proteins are rapidly degraded by oral administration due to the harsh GI environment, including pH changes, enzymatic reactions, and the disadvantage of poor IEC permeability.⁴³ Fucoidan (F) is an anionic polysaccharide extracted from brown algae that possesses immunomodulatory, permeability-enhancing, and targeting effects on IEC. Preparation of nanoparticles using CS with F was able to exhibit controlled release and pH-dependent behavior. It showed a low release rate (below 20%) at pH 1.2 and a higher SEP release rate (50%) at pH 7.4. To demonstrate the anti-inflammatory effect of CS/F@SEP, immunoassays were performed in Caco-2 and macrophage RAW264.7 cells. The amounts of nitric oxide, IL-6, and TNF-α were significantly reduced after CS/F@SEP treatment. These results suggest that CS/F@SEP provides some protection to epithelial cells as well as it can be used as a nanodelivery system for the treatment of IBD.

Curcumin is a natural extract from turmeric, and its favorable anti-inflammatory properties have been widely used in the treatment of a variety of diseases, including IBD.⁴⁴ Colon-targeted delivery of therapeutic UC by oral administration of core-shell nanoparticles utilizing CS/ALG/multilayer membranes as shells encapsulating curcumin nanocrystals (CUNCs) and coated with cellulose phthalate in the outer shells.⁴⁵ Nanoparticles with a multilayered core-shell structure released only 20% for CUNC at pH 1.2 and 4.5, and the remaining CUNC could be released for 9 h at pH 7.2. In DSS-induced colitis mice (ICR), the core-shell nanoparticles reduced the disease activity index, decreased the degree of damage in the colon, and restored the reepithelialization of the mucosa. The above results suggest that core-shell nanoparticles can be used as a colon-targeted drug delivery system for the treatment of UC for drug delivery.

In summary, polymeric nanoparticles offer options to increase targeted drug delivery therapy in ID treatment. The ability of nanoparticles to enhance drug accumulation/penetration in diseased tissues is a powerful tool to achieve targeted therapy for IBD and CRC.

The current clinical treatment status of ID

The clinical treatment strategy of ID has undergone a paradigm shift from broad-spectrum anti-inflammation to precise regulation. Although traditional methods such as 5-aminosalicylic acid preparations can alleviate the symptoms of mild to moderate IBD, their short colonic retention time and poor lesion penetration often lead to limited therapeutic effects. In recent years, biological agents (such as anti-TNF-α monoclonal antibodies and IL-12/23 inhibitors) have significantly improved the mucosal healing rate of moderate to severe patients by targeting and blocking key inflammatory pathways. However, approximately 30% of patients have primary or secondary failure, and the high treatment cost limits their accessibility. Fecal microbiota transplantation for intestinal flora imbalance has shown breakthrough efficacy (cure rate > 90%) in recurrent Clostridium difficile infection, but its response heterogeneity in IBD (about 40% remission rate) reflects the necessity of strain screening and delivery vector optimization.

Emerging delivery systems have demonstrated initial advantages in clinical trials by enhancing drug accumulation in the colon, reducing systemic toxicity, and synergically regulating the microbiota-immune axis. The Phase II study of pectin-encapsulated budesonide showed that the colonic drug concentration was increased by 3.2 times compared with traditional preparations, and hormone-related adverse reactions were reduced by 42%, marking that local precision treatment is gradually overcoming the transformation bottleneck. However, long-term safety data on polysaccharide carriers are still scarce. For instance, three-year experiments on high-molecular HA carriers have shown no increased risk of intestinal fibrosis, but low-molecular fragments may activate the TLR4 pathway. These data reveal that polysaccharide carriers need to balance targeting efficiency, intestinal microbiota interaction, and metabolic safety, providing key evidence-based evidence for the design of future precise delivery systems.

Conclusions and prospects

In the therapeutic paradigm of ID, although the micro/nano drug delivery system based on natural polysaccharides has shown breakthrough potential, its clinical transformation still needs to confront multiple scientific challenges directly. Current studies have confirmed that polysaccharide carriers can effectively circumvent the physicochemical barriers of the GI tract by means of pH responsiveness, enzyme-triggered release, and mucosal adhesion characteristics. However, their efficacy highly depends on the heterogeneity of the individual intestinal microenvironment. Future research needs to integrate multi-omics technologies to precisely analyze the specific pathological characteristics of patients, and then construct adaptive “intelligent” carriers, such as by clicking on chemically modified polysaccharide side chains to dynamically respond to local biomarkers. In addition, batch uniformity and long-term drug administration safety in large-scale production need to be urgently addressed. It is worth noting that emerging technologies such as organ-on-a-chip can simulate the dynamic intestinal barrier of patients and accelerate vector screening. Artificial intelligence–driven molecular dynamics simulation can optimize the structural parameters of polysaccharides to balance targeting and biocompatibility, thereby truly achieving a paradigm upgrade of ID from “symptom control” to “pathological remodeling.” This interdisciplinary integration will not only redefine the connotation of colon-targeted therapy but also likely open up a brand-new dimension for individualized precision medicine.

Footnotes

ORCID iD

Huiying He

Author contributions

L.D. has extensive experience in the treatment of IDs and has written and revised Part 2; H.H. has experience in the treatment of IDs and is mainly responsible for the direction of manuscript writing, as well as checking and annotating manuscripts; X.L. has conducted research on an IBD model and made preliminary modifications to Section 3.1; S.M. has research experience in the treatment of IDs at Fengfeng and participated in the writing and revision of Sections 2 and 3; R.Q. has research experience in micrometer drug delivery systems and made preliminary modifications to Section 4.1; Z.P. wrote according to the logic of the manuscript and completed most of the content; W.L. has experience in micronano therapy for diseases, mainly responsible for the writing direction and problem checking of manuscripts, as well as annotating and revising manuscripts.

Funding

The author(s) would like to thank the Wuzhou College Talent Initiation Fund Program (WZUQDJJ30354).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Data supporting the findings are available by the corresponding authors upon reasonable request.

Consent

All the authors have agreed to the publication of the article.

Note

1.Short-chain fatty acids (SCFAs) are saturated fatty acids with chain lengths of one to six carbon atoms and are the main product of dietary fiber fermentation in the gut.

References

Guo

Ludvigsson

Brantsaeter

, et al. Early-life diet and risk of inflammatory bowel disease: a pooled study in two Scandinavian birth cohorts. Gut 2024; 73: 590–600.

Kotla

Rana

Sivaraman

, et al. Bioresponsive drug delivery systems in intestinal inflammation: state-of-the-art and future perspectives. Adv Drug Deliver Rev 2019; 146: 248–266.

Iurciuc

Atanase

Jerome

, et al. Polysaccharides-based complex particles’ protective role on the stability and bioactivity of immobilized curcumin. Int J Mol Sci 2021; 22(6): 3075. http://doi.org/10.3390/ijms22063075

Wang

Fan

Zhang

, et al. Microbiota-derived indoles alleviate intestinal inflammation and modulate microbiome by microbial cross-feeding. Microbiome 2024; 12: 59. http://doi.org/10.1186/s40168-024-01750-y

Collnot

Ali

Lehr

. Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. J Control Release 2012; 161: 235–246.

Zhang

Ding

Liu

, et al. New resource food-arabinogalactan improves DSS-induced acute colitis through intestinal flora and NLRP3 signaling pathway. Int J Biol Macromol 2024; 258: 129118.

Bing

Zhou

Tan

. Study on the mechanism of Astragalus polysaccharide in treating pulmonary fibrosis based on “drug-target-pathway” network. Front Pharmacol 2022; 13: 865065.

Khare

Palakurthi

Shah

, et al. Natural product-based nanomedicine in treatment of inflammatory bowel disease. Int J Mol Sci 2020; 21(11): 3956. http://doi.org/10.3390/ijms21113956

Gong

Liu

Wang

, et al. Applications of polysaccharides in enzyme-triggered oral colon-specific drug delivery systems: a review. Int J Biol Macromol 2024; 275: 133623. http://doi.org/10.1016/j.ijbiomac.2024.133623

10.

Dos

Carvalho

Meneguin

, et al. Oral delivery of micro/nanoparticulate systems based on natural polysaccharides for intestinal diseases therapy: challenges, advances and future perspectives. J Control Release 2021; 334: 353–366.

11.

Brennan

Zelber-Sagi

Allen

, et al. Beyond a liver-gut focus: the evolution of gastroenterology and hepatology in challenging the obesity and steatotic liver disease paradigm. Gut 2024; 73: 560–563.

12.

Nugent

Kumar

Rampton

, et al. Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut 2001; 48: 571–577.

13.

Yoshikawa

Ueda

Hakata

, et al. Quantitative investigation of intestinal drug absorption enhancement by drug-rich nanodroplets generated via liquid-liquid phase separation. Mol Pharm 2024; 21(4): 1745–1755. http://doi.org/10.1021/acs.molpharmaceut.3c01078

14.

Botman

Hontoir

Gustin

, et al. Postanaesthetic effects of ketamine-midazolam and ketamine-medetomidine on gastrointestinal transit time in rabbits anaesthetised with isoflurane. Vet Rec 2020; 186: 49.

15.

Johansson

Gustafsson

Holmen-Larsson

, et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 2014; 63: 281–291.

16.

Klotz

Schwab

. Topical delivery of therapeutic agents in the treatment of inflammatory bowel disease. Adv Drug Deliver Rev 2005; 57: 267–279.

17.

Liu

, et al. Correlation between the gut microbiome and neurodegenerative diseases: a review of metagenomics evidence. Neural Regen Res 2024; 19: 833–845.

18.

Yin

, et al. Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii served as key components of fecal microbiota transplantation to alleviate colitis. Am J Physiol Gastrointest Liver Physiol 2024: G607–G621. http://doi.org/10.1152/ajpgi.00303.2023

19.

Danese

Vuitton

Peyrin-Biroulet

. Biologic agents for IBD: practical insights. Nat Rev Gastroenterol Hepatol 2015; 12: 537–545.

20.

Shahdadi

Saremnejad

Bagheri

, et al. A review on 5-aminosalicylic acid colon-targeted oral drug delivery systems. Int J Pharm 2019; 558: 367–379.

21.

Keum

Giovannucci

. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 2019; 16: 713–732.

22.

Akhter

Simpson

Fletcher

, et al. Oral delivery of multicompartment nanomedicines for colorectal cancer therapeutics: combining loco-regional delivery with cell-target specificity. Adv Ther 2020; 3: 1900171.

23.

Suarato

Meng

. Role of pH-responsiveness in the design of chitosan-based cancer nanotherapeutics: a review. Biointerphases 2016; 11(4): 04B201.

24.

Wang

, et al. Butyrate enhances intestinal epithelial barrier function via up-regulation of tight junction protein claudin-1 transcription. Digest Dis Sci 2012; 57: 3126–3135.

25.

Kulkarni

Jain

Shindikar

, et al. Advances in the colon-targeted chitosan based multiunit drug delivery systems for the treatment of inflammatory bowel disease. Carbohydr Polym 2022; 288: 119351.

26.

Petrey

de la Motte

. Hyaluronan in inflammatory bowel disease: cross-linking inflammation and coagulation. Matrix Biol 2019; 78-79: 314–323.

27.

, et al. Diverse domains of raspberry pectin: critical determinants for protecting against IBDs. Food Funct 2025; 16: 657–672.

28.

Sun

Arif

Chi

, et al. Macrophages-targeting mannosylated nanoparticles based on inulin for the treatment of inflammatory bowel disease (IBD). Int J Biol Macromol 2021; 169: 206–215.

29.

Biswas

Mondal

Ansari

, et al. Chitosan and its derivatives as nanocarriers for drug delivery. Molecules 2025; 30(6): 1297. http://doi.org/10.3390/molecules30061297

30.

Naeem

Awan

Subhan

, et al. Advances in colon-targeted nano-drug delivery systems: challenges and solutions. Arch Pharm Res 2020; 43: 153–169. http://doi.org/10.1007/s12272-020-01219-0

31.

Krolikoski

Monslow

Pure

. The CD44-HA axis and inflammation in atherosclerosis: a temporal perspective. Matrix Biol 2019; 78-79: 201–218.

32.

Mizrahy

Raz

Hasgaard

, et al. Hyaluronan-coated nanoparticles: the influence of the molecular weight on CD44-hyaluronan interactions and on the immune response. J Control Release 2011; 156: 231–238.

33.

Cao

Yang

Wang

, et al. Modified citrus pectins by UV/H(2)O(2) oxidation at acidic and basic conditions: structures and in vitro anti-inflammatory, anti-proliferative activities. Carbohydr Polym 2020; 247: 116742.

34.

Liu

Fishman

Kost

, et al. Pectin-based systems for colon-specific drug delivery via oral route. Biomaterials 2003; 24: 3333–3343.

35.

Roberfroid

. Introducing inulin-type fructans. Br J Nutr 2005; 93: S13–S25.

36.

Maiti

Ranjit

Mondol

, et al. Al+ 3 ion cross-linked and acetalated gellan hydrogel network beads for prolonged release of glipizide. Carbohydr Polym 2011; 85: 164–172.

37.

Cao

Cheng

, et al. Alginate/chitosan microcapsules for in-situ delivery of the protein, interleukin-1 receptor antagonist (IL-1Ra), for the treatment of dextran sulfate sodium (DSS)-induced colitis in a mouse model. Eur J Pharm Biopharm 2019; 137: 112–121.

38.

Clemett

Markham

. Prolonged-release mesalazine: a review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000; 59: 929–956.

39.

Helmy

Elsabahy

Abd-Elkareem

, et al. High-payload chitosan microparticles for the colonic delivery of quercetin: development and in-vivo evaluation in a rabbit colitis model. J Drug Deliv Sci Tech 2020; 58: 101832.

40.

Karan

Debnath

Kuotsu

, et al. In-vitro and in-vivo evaluation of polymeric microsphere formulation for colon targeted delivery of 5-fluorouracil using biocompatible natural gum katira. Int J Biol Macromol 2020; 158: 922–936.

41.

Pinto

Santos

Sarmento

. New insights into nanomedicines for oral delivery of glucagon-like peptide-1 analogs. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2024; 16: e1952.

42.

Lee

Huang

. Soluble eggshell membrane protein-loaded chitosan/fucoidan nanoparticles for treatment of defective intestinal epithelial cells. Int J Biol Macromol 2019; 131: 949–958.

43.

Benson

Ruff

Jensen

. Effects of natural eggshell membrane (NEM) on cytokine production in cultures of peripheral blood mononuclear cells: increased suppression of tumor necrosis factor-alpha levels after in vitro digestion. J Med Food 2012; 15: 360–368.

44.

Carolina

Perosa

Fonseca-Santos

, et al. A critical review of the properties and analytical methods for the determination of curcumin in biological and pharmaceutical matrices. Crit Rev Anal Chem 2019; 49: 138–149.

45.

Oshi

Lee

Naeem

, et al. Curcumin nanocrystal/pH-responsive polyelectrolyte multilayer core-shell nanoparticles for inflammation-targeted alleviation of ulcerative colitis. Biomacromolecules 2020; 21: 3571–3581.