Recent advances in albumin-based nanoparticle drug delivery systems for intestinal disease treatment

Abstract

Intestinal diseases, particularly inflammatory bowel disease (IBD) and colorectal cancer (CRC), are increasingly prevalent and difficult to manage due to complex pathology, poor drug targeting, and systemic toxicity. Albumin nanoparticles (ANPs) have emerged as a promising drug delivery platform, offering biocompatibility, controlled degradation, and targeting potential. This review summarizes advances in ANP-based therapies for intestinal diseases, briefly outlining key fabrication approaches and focusing on targeting strategies that exploit pathological features such as leaky vasculature, acidic pH, and oxidative stress. ANPs can also be modified for active targeting via receptor-mediated mechanisms. Preclinical studies demonstrate that drug-loaded ANPs enhance local drug accumulation, suppress inflammation, and improve therapeutic efficacy in IBD and CRC models. In addition, the review addresses potential toxicity concerns related to crosslinkers and drug-albumin interactions. Despite ongoing challenges in oral bioavailability, mucus penetration, and scale-up, ANPs represent a promising avenue for precision treatment of intestinal diseases.

Graphical abstract

Highlights

• •Various fabrication strategies enable tunable size, stability, and drug encapsulation of ANPs.
• •ANPs achieve targeted and controlled drug release by leveraging pathological features of intestinal diseases.
• •Preclinical studies confirm that ANPs improve drug retention and therapeutic efficacy in intestinal diseases.
• •Toxicity assessments reveal that ANP safety depends on crosslinkers, drug compatibility, and in vivo behavior.

1. Introduction

The intestine, a vital digestive organ, not only facilitates the absorption of nutrients and water but also protects systemic health by blocking the entry of pathogens and harmful substances. Recent studies have identified high-saturated-fat diets (Mana et al., 2021) and worsening air pollution (Vignal et al., 2021) as major risk factors contributing to the rising global incidence of intestinal diseases. Epidemiological data reveal that gastrointestinal diseases claim approximately 8 million lives worldwide each year (Abuhayi et al., 2024). Furthermore, according to the World Health Organization's Global Cancer Observatory (GLOBOCAN), gastrointestinal malignancies, including colorectal, gastric, and esophageal cancers, accounted for 17.1 % of new cancer diagnoses globally in 2022, with a disproportionately high mortality rate of 20.7 % (Bray et al., 2024). Etiologically, intestinal diseases are classified as inflammatory, functional, infectious, or structural. Among these, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and colorectal cancer (CRC) are the most prevalent clinical entities (Meng et al., 2020). These conditions impair nutrient absorption and often lead to debilitating complications such as chronic pain and anemia, thereby profoundly compromising patients' quality of life.

Current treatment strategies for intestinal diseases primarily rely on conventional pharmacotherapies, including immunosuppressants, miRNA-based therapeutics, antibiotics, and interferons, and surgical intervention when necessary (Liu et al., 2021b). However, these approaches frequently suffer from poor target specificity, systemic side effects, and short-lived efficacy (Tian et al., 2025), underscoring the urgent need for more effective and targeted therapies. Since their conceptualization in the 1950s, nanoparticle-based drug delivery systems have evolved into sophisticated platforms characterized by physicochemical stability, low cytotoxicity, precise tissue targeting, gastric acid resistance, and modifiable surfaces—traits particularly advantageous for gastrointestinal applications. Based on their origin, nanocarriers are broadly divided into synthetic (e.g., polymers, inorganic particles, carbon-based materials) and natural (e.g., proteins, liposomes) categories. Among natural carriers, protein-based nanoparticles are especially attractive due to their intrinsic biocompatibility, low immunogenicity, and predictable degradation profiles.

Albumin nanoparticles (ANPs), derived from endogenous protein sources, have gained considerable attention in nanodrug delivery. Their well-defined amino acid sequence and high lysine content enable electrostatic adsorption of both positively (e.g., ganciclovir) and negatively charged (e.g., oligonucleotide) molecules without additional carriers (Irache et al., 2005; Weber et al., 2000). Compared to synthetic carriers such as PLGA, ANPs have lower immunogenicity due to their biological origin (Mehta et al., 2023; Sivadasan et al., 2021). Notably, ANPs exploit FcRn receptor-mediated transcytosis to bypass lysosomal degradation and prolong drug retention at inflammatory sites (Lamichhane and Lee, 2020; Schmidt et al., 2017). Their targeting efficacy can be further enhanced through surface modification strategies, thereby increasing drug accumulation at lesion sites while minimizing off-target toxicity (Bhushan et al., 2017). Despite these advantages, limitations such as poor aqueous solubility, low oral bioavailability, and potential non-specific distribution remain barriers to clinical translation (Younis et al., 2022). Addressing these issues calls for hybrid engineering approaches, such as enzyme-resistant coatings and conjugation with mucosal repair peptides, to bridge the gap between localized therapeutic action and broader mucosal healing.

Several prior reviews have discussed albumin-based nanocarriers for various indications, particularly in oncology and IBD. For example, Kratz (2008) outlined three major albumin-based drug delivery strategies and their clinical relevance in tumor targeting Other reviews have focused on the use of ANPs in controlled release and site-specific cancer therapy (Elzoghby et al., 2012; Qu et al., 2024). However, these are predominantly cancer-oriented and lack depth regarding colorectal-specific pathology. Similarly, reviews on oral nanodelivery systems in IBD often cover diverse nanocarriers without focusing specifically on albumin-based platforms (Liu et al., 2021b). While some mention the advantages of ANPs in treating IBD (Hua et al., 2015), few offer in-depth discussions linking albumin nanoparticle design to distinct intestinal disease mechanisms.

In light of this gap, there is a clear need for a comprehensive review focused exclusively on the application of ANPs in intestinal diseases. Compared with previous reviews that primarily focus on cancer applications or general nanocarrier strategies, our work highlights several distinctive aspects of ANPs in the treatment of intestinal diseases. Specifically, this review is the first to comprehensively correlate ANP design strategies, such as size-dependent delivery, microenvironment responsiveness, and receptor targeting, with the pathological features of IBD, irritable IBS, and CRC. In addition, we emphasize the translational relevance of ANPs by incorporating toxicity analyses and clinical considerations, which are often overlooked in earlier literature. These unique perspectives contribute to the novelty and practical value of this review.

Therefore, we hypothesize that ANPs, through their tunable surface properties, biocompatibility, and responsiveness to pathological cues (e.g., pH, ROS, enzymes), represent a uniquely suited nanoplatform for targeted drug delivery in various intestinal diseases. This review aims to systematically evaluate their mechanisms, therapeutic potentials, safety profiles, and translational challenges to establish a comprehensive foundation for future research and clinical translation.

2. Literature search and selection

To ensure a rigorous and up-to-date foundation for this review, we conducted a systematic literature search focusing on recent advances in ANPs for intestinal disease therapy. As depicted in Fig. 1A, the annual publication trend indicates steadily increasing research interest in ANP-based drug delivery systems over the past decade. Moreover, Fig. 1B illustrates the disease-specific distribution of ANP-related studies, highlighting CRC as the most extensively investigated condition (1911 articles, ∼82 %), followed by IBD (416 articles, 17.9 %), with only 3 articles (0.1 %) addressing the other intestinal diseases. By systematically summarizing these findings, this review aims to enhance the current understanding of ANP applications in intestinal disease therapy, serve as a valuable reference for researchers, and support the clinical translation of ANP-based therapeutic strategies.

Fig. 1.

(A) Annual publication trends related to ANP-based nanoformulations from January 2015 to May 2025. (B) Proportional distribution of ANP research across different categories of intestinal diseases.

3. Types of albumin

The most frequently used albumins include human serum albumin (HSA), bovine serum albumin (BSA), ovalbumin (OVA) derived from egg whites, α-lactalbumin extracted from milk, and storage albumins sourced from plant seeds, such as legumes, amaranth, and soybeans (Visentini et al., 2023). Among these, OVA, BSA, and HSA are predominantly utilized for the fabrication of ANPs, especially for drug loading aimed at treating intestinal diseases.

3.1. Ovalbumin

OVA, accounting for approximately 54–60 % of egg white proteins, is a 45 kDa globular protein consisting of 386 amino acids (Xiong et al., 2024). Its structure features four free thiol groups and one disulfide bond, and is primarily composed of α-helices and β-sheets (Guha et al., 2019). The hydrophobic core of OVA serves as a binding site, particularly suitable for lipophilic molecules and small-molecule therapeutic agents. With an isoelectric point (pI) of approximately 4.8, OVA maintains a net negative charge at physiological pH, enabling electrostatic interactions with positively charged inflammatory mediators (Vesković et al., 2022). Furthermore, OVA exhibits pH- and temperature-sensitive characteristics, facilitating targeted drug delivery within the intestinal environment and modulating inflammatory responses (Wongsasulak et al., 2010). Despite its demonstrated therapeutic potential for intestinal conditions, clinical application of OVA-based ANPs remains relatively limited, suggesting a significant opportunity for further exploration.

3.2. Bovine serum albumin

Compared to OVA, BSA is more extensively employed in drug delivery due to its superior biocompatibility, biodegradability, and reduced immunogenicity (Elzoghby et al., 2012; Spada et al., 2021). BSA is a single-chain protein composed of 583 amino acids, with a molecular weight of approximately 66.5 kDa (Koh et al., 2019). Structurally, BSA comprises three homologous domains (I–III), each further subdivided into two subdomains (A and B) (Szymaszek et al., 2022). The primary drug-binding sites reside within domains IIA and IIIA, effectively accommodating fatty acids, pharmaceuticals, and metal ions. At physiological pH, BSA carries a net negative surface charge due to its low isoelectric point (∼4.7), which facilitates the electrostatic adsorption of positively charged inflammatory factors (Kubiak-Ossowska et al., 2019). Due to its high stability, minimal toxicity, and osmotic regulatory properties, BSA-based ANPs enhance intestinal drug retention, protect the mucosal barrier, and thus offer significant therapeutic potential in managing various intestinal diseases (Duan et al., 2022b; Yu et al., 2022).

3.3. Human serum albumin

HSA, an abundant protein found in human plasma, is often selected over BSA to minimize potential immunogenic responses in clinical applications. HSA consists of 585 amino acids with a molecular weight of approximately 66.5 kDa. Its three-dimensional structure includes three highly conserved domains (I–III), each containing six α-helices (Tao et al., 2021). The primary ligand-binding sites are located in domains IIA and IIIA, capable of binding both endogenous molecules (e.g., bilirubin and fatty acids) and exogenous therapeutic drugs (Zsila et al., 2011). Similar to BSA, HSA carries a net negative charge at physiological pH, with an isoelectric point typically ranging between 4.7 and 5.2, facilitating effective neutralization of positively charged inflammatory agents in the gastrointestinal environment (Kubiak-Ossowska et al., 2019). Additionally, the degradation products of HSA provide amino acids as nutritional substrates for peripheral tissues. Given its favorable characteristics, including preferential uptake in inflamed or tumor tissues, ready availability, biodegradability, and minimal toxicity, HSA-based ANPs are increasingly recognized as optimal candidates for intestinal drug delivery applications (Fasano et al., 2005; Kratz, 2008).

To facilitate the comparison among different albumin sources, we summarized their key characteristics in Table 1, including molecular weight, isoelectric point, drug-binding domains, advantages and disadvantages as nanoparticle carriers, and therapeutic efficacy. These parameters are essential for selecting suitable albumin types for specific disease applications and guiding future formulation optimizations.

Table 1.

Comparative properties and therapeutic efficacy of different types of albumin.

Albumin type	Molecular weight	Isoelectric point	Drug-binding domains	Advantages	Disadvantages	Therapeutic efficacy	References
OVA	45 kDa	∼4.8	Hydrophobic core	Responsive to pH and temperature; High loading of lipophilic drugs	Potential allergenicity; Limited stability	Targeted anti-inflammatory modulation	(Vesković et al., 2022; Wongsasulak et al., 2010; Xiong et al., 2024)
BSA	66.5 kDa	∼4.7	Domains IIA & IIIA	Good mucosal adhesion; Low production cost	Immunogenicity risks; Batch-to-batch variability	Enhanced mucosal protection	(Duan et al., 2022b; Kubiak-Ossowska et al., 2019; Koh et al., 2019; Szymaszek et al., 2022; Yu et al., 2022)
HSA	66.5 kDa	4.7–5.2	Domains IIA & IIIA	High affinity to human tissues; Minimal immunogenicity	High production costs; Endogenous competition risks	Preferential uptake in inflamed or CRC tissues	(Fasano et al., 2005; Kratz, 2008; Kubiak-Ossowska et al., 2019; Tao et al., 2021; Zsila et al., 2011)

4. Preparation of ANPs

ANPs are promising drug delivery carriers due to their biocompatibility, low immunogenicity, and biodegradability. Optimizing ANP preparation techniques is essential for enhancing drug-loading and targeted delivery efficiency. Current fabrication methods can be broadly categorized as crosslinking-dependent or crosslinking-free. Crosslinking-dependent approaches, including desolvation (Langer et al., 2003), pH-induced coagulation (Merodio et al., 2001), and thermal gelation (Hassanin and Elzoghby, 2020), typically use chemical (e.g., glutaraldehyde) or physical crosslinking to stabilize nanoparticles. These methods provide high stability and controlled particle sizes, but may compromise biocompatibility and induce protein denaturation. Crosslinking-free techniques, such as emulsification (Szczech and Szczepanowicz, 2020), Nab™ technology (Fu et al., 2009), spray drying (Heng et al., 2011), self-assembly (Asghar et al., 2014), and microfluidics (Minetti et al., 2022), form nanoparticles through hydrophobic interactions, solvent evaporation, or hydrodynamic forces. They preserve albumin's native structure and bioactivity, making them ideal for sensitive drugs. However, they may exhibit reduced long-term stability, necessitating further formulation optimization. Table 2 summarizes the mechanisms, advantages, and disadvantages of these ANP preparation methods.

Table 2.

Mechanism, advantages, and disadvantages of various ANP preparation methods.

Methods	Mechanism	Advantages	Disadvantages	Reference
Desolvation	Adding a desolvating agent to reduce the solubility of albumin, causing it to precipitate and form nanoparticles	Offers high drug loading, controllable particle size, and well-established protocols for precise nanoparticle engineering	Requires organic solvents and toxic crosslinkers, posing biocompatibility concerns	(Jahanban-Esfahlan et al., 2016; Langer et al., 2003; Lei et al., 2021)
Emulsification	Utilizing oil-water interfacial tension to encapsulate oil droplets with albumin in the aqueous phase, forming nanoparticles after solidification	Provides formulation flexibility and is particularly suitable for lipophilic drugs with customizable systems	Involves potentially toxic surfactants and complex purification steps	(Bilati et al., 2005; Qu et al., 2024; Verma et al., 2020; Zhou et al., 2013)
Nab™ technology	High-pressure homogenization binds hydrophobic drugs with albumin to form stable nanoparticles	Clinically validated, crosslinker-free, and scalable for hydrophobic drug delivery	Relies on energy-intensive processes like high-pressure homogenization with limited drug applicability	(Kim et al., 2017; Min et al., 2015)
pH coagulation	Adjusting the pH near albumin's isoelectric point to induce aggregation and solidification into nanoparticles	Simple and cost-effective method using pH adjustment for particle formation	Difficult to control particle size distribution and potential protein denaturation	(Merodio et al., 2001; Qu et al., 2024)
Thermal gelation	Heating induces albumin denaturation and cross-linking, forming thermally stable nanogel particles	Simple, solvent-free process suitable for rapid production of basic nanoparticles	Exhibits poor drug compatibility and inconsistent particle size control with limited applications	(Monahan et al., 1995)
Spray drying	Rapid solvent evaporation via spray drying solidifies albumin into nano-sized dry powder particles	Continuous process enabling high-yield production of dry powder formulations	High equipment costs and potential thermal degradation of sensitive drugs	(Fatima et al., 2023; Meng et al., 2022)
Self-assembly	Exploiting albumin's amphiphilicity to spontaneously form micellar or nanoparticle structures	Enables mild, solvent-free preparation of multifunctional hybrid nanoparticles	Suffers from lower drug loading efficiency and potential stability issues requiring optimization	(Abolhassani and Shojaosadati, 2019; Safavi et al., 2017; Thao et al., 2016a; Xu et al., 2011)
Microfluidics	Precise fluid mixing via microfluidic technology enables controlled and uniform albumin nanoparticle preparation	Exceptional control over particle characteristics with excellent reproducibility	Complex setup requirements and limited scalability for industrial production	(Minetti et al., 2022; Zhang et al., 2023b)

5. Mechanisms of action of drug-loaded ANPs in the treatment of intestinal diseases

Although traditional drug therapies can alleviate symptoms of intestinal diseases such as IBD and CRC to some extent, their clinical application faces significant limitations due to poor drug stability, low bioavailability, and considerable systemic toxicity. In recent years, ANP-based drug delivery systems have emerged as a research focus for intestinal disease treatment owing to their exceptional biocompatibility, targeting capability, and drug stabilization properties. Accumulating evidence demonstrates that drug-loaded ANPs can leverage unique pathological features of inflammatory regions and tumor microenvironments to achieve efficient drug delivery, thereby markedly enhancing therapeutic efficacy while minimizing adverse effects.

5.1. Key pathological features and therapeutic challenges of intestinal diseases

Key pathological features of intestinal diseases include chronic inflammation, impaired barrier function, gut flora imbalance (dysbiosis), and, in the case of intestinal cancers, an abnormal tumor microenvironment.

• •Inflammatory response: Patients with IBD (and to some extent IBS) often exhibit persistent inflammation. Clinical studies have shown decreased levels of anti-inflammatory cytokines and increased levels of pro-inflammatory cytokines in these patients, resulting in an imbalance between the two (Bashashati et al., 2017; Macsharry et al., 2008; Schmulson et al., 2012). Inflammation can disrupt intestinal tight junctions and cellular integrity, leading to massive immune cell infiltration. This significantly increases the permeability of inflamed colonic tissue and can result in dysplastic changes and eventual progression to small bowel cancer or CRC (Fig. 2) (Porter et al., 2021).
• •Impaired barrier function: Normally, the intestinal barrier effectively blocks the invasion of harmful substances. However, when various internal or external factors disrupt the intestinal barrier, intestinal permeability increases, triggering pathological changes such as bacterial translocation and endotoxin absorption (Chelakkot et al., 2018). Moreover, loss of barrier integrity may cause abnormal activation of the local immune response, creating a vicious cycle that exacerbates inflammation. This loss of barrier integrity not only undermines the structural integrity of the intestine but also provides a potential window for targeted drug delivery.
• •Abnormal tumor microenvironment: In malignant tumors such as CRC, the tumor microenvironment is often characterized by poor perfusion, hypoxia, and immunosuppression. These features impede the penetration of traditional chemotherapeutics into tumor tissue and readily induce drug resistance and recurrence (Bejarano et al., 2021). Furthermore, the accumulation of high levels of growth factors, inflammatory mediators, and stromal components in the tumor microenvironment constitutes an additional therapeutic barrier, enabling tumor cells to resist treatment. Thus, targeted strategies to modulate or exploit the properties of the tumor microenvironment have become important for improving therapeutic efficacy.

Fig. 2.

Role of IL-22 in the inflammatory environment. Prolonged or uncontrolled expression of IL-22 (as in colitis) can promote tumor progression (Arshad et al., 2020). IL-22, interleukin-22; AMPs, antimicrobial peptides; MUC, mucins. Copyright 2020, adapted with permission from Arshad et al. under the Creative Commons Attribution-Non Commercial license.

Traditional treatments (e.g., aminosalicylic acid, corticosteroids, immunosuppressants, surgery) can effectively relieve symptoms, but long-term use is often associated with drug resistance, reduced immune function, and multi-organ damage (Ouyang et al., 2023). Furthermore, although biologics have been introduced in clinical practice, some patients do not respond adequately, and surgical or radiotherapy treatments are highly invasive with substantial risks of complications and side effects (Kajiwara and Ueno, 2024). Therefore, there is an urgent need for therapeutic strategies that increase drug concentrations at the lesion site while reducing systemic toxicity.

5.2. Targeted delivery mechanisms of drug-loaded ANPs

Drug-loaded ANPs can harness the unique physiological and pathological characteristics of disease sites to achieve precise drug delivery and controlled release, thereby overcoming the limitations of traditional drug therapy. Their mechanisms of action mainly encompass two broad strategies: passive targeting by leveraging pathological cues (e.g., size-dependent, pH-dependent, ROS-responsive, enzyme-dependent, or microenvironment-responsive) and active targeting via specific ligand–receptor interactions.

5.2.1. Size-dependent targeting

Inflammatory and tumor tissues often exhibit impaired mucosal barriers and reduced epithelial integrity, resulting in an enhanced permeability and retention (EPR) effect that promotes passive nanoparticle accumulation (Barua and Mitragotri, 2014; Matsumura and Maeda, 1986). In many tumors, vascular pore cutoffs range from 380 to 780 nm, allowing liposomes or viral vectors of 100–300 nm to preferentially localize at these sites via specific vascular channels (Hobbs et al., 1998). At the same time, reducing particle size to the nanoscale (10–200 nm) facilitates diffusion through the mucus mesh (Murgia et al., 2018). ANPs measuring 50–200 nm not only evade gastrointestinal clearance but also accumulate effectively in the permeable microenvironment of inflamed regions, such as the colon. Lamprecht et al. (2001) demonstrated this size-dependent targeting in a TNBS-induced colitis model: fluorescent particles of ∼100 nm showed the highest retention at sites of inflammation compared to larger or smaller counterparts.

5.2.2. pH-dependent targeting

pH differences along the gastrointestinal tract (e.g., gastric pH ∼2; ileal pH 6.8–8.0; colonic pH 5.3–7.5) provide a basis for designing pH-sensitive nanomedicines (Zeeshan et al., 2019). A local acidic environment is a common pathological feature of IBD and intestinal tumors. To exploit this, pH-responsive ANPs have been developed as an effective controlled-release strategy. Notably, albumin undergoes significant conformational changes with pH (transitions at pH 2.7, 4.3, 8.0, and 10.0). For example, at pH 7.4, albumin adopts a normal heart-like structure (N isoform), while at pH 3.5 it unfolds into a partially expanded cigar-like shape (F isoform) (Baler et al., 2014). When ANPs reach an acidic disease site, these conditions induce structural changes or nanoparticle dissociation, thereby triggering drug release. Huang et al. (2024) prepared ultra pH-sensitive HSA nanomedicines loaded with the photosensitizer Ce6 (HSA/CAT-PEPA@Ce6) via self-assembly (Fig. 3). These nanoparticles rapidly disassembled in the acidic tumor environment and, aided by positively charged monomers (through electrostatic adsorption), further penetrated tumor cells. The nanoparticles released a catalase (CAT) payload to generate oxygen, which in turn produced more reactive oxygen species upon light irradiation, achieving synergistic killing of tumor cells. Additionally, a pH- and redox-responsive albumin hydrogel demonstrated controlled drug release at physiological pH (7.4), but underwent rapid degradation and payload release in a reducing environment (e.g., 100 mM glutathione), highlighting its potential for targeted therapy in glutathione-rich cancer microenvironments (Raja et al., 2015). In IBS-D (diarrhea-predominant) patients, a decrease in colonic pH may similarly trigger drug release, thereby helping modulate intestinal motility and secretion.

Fig. 3.

Schematic diagram illustrating enhanced tumor penetration and alleviation of tumor hypoxia by HSA/CAT-PEPA@Ce6 for improved photodynamic therapy (Huang et al., 2024). Copyright 2024, adapted with permission from Huang et al. under the Creative Commons Attribution-Non Commercial License.

5.2.3. ROS-responsive targeting

Reactive oxygen species (ROS) in the gut arise both physiologically—from mitochondrial electron leakage and NADPH oxidase activity—and pathologically—from neutrophil respiratory bursts, dysbiosis, and ischemia–reperfusion injury (Aviello and Knaus, 2017). Excess ROS exacerbate IBD by inducing DNA damage, degrading tight-junction proteins, and triggering inflammatory cascades (Sies and Jones, 2020). Indeed, mucosal ROS levels in UC can be 10- to 100-fold higher than normal, making ROS an attractive biomarker for targeted therapy (Sedghi et al., 1993).

Albumin-based nanomedicines can be designed to release drugs in oxidative stress microenvironments using ROS-responsive components, such as polymers containing disulfide bonds or nitrophenyl ether groups (Chen et al., 2017; Jacob et al., 2020). Moreover, ANPs can exert antioxidant effects by scavenging free radicals and thereby alleviating inflammation. For example, GBP@HA nanoparticles scavenged over 60 % of ROS (e.g., PTIO•) and achieved radical scavenging rates of ∼70 % for certain reactive nitrogen species (e.g., DPPH•) and 98 % for ABTS• radicals at concentrations of 50–500 μg/mL (Zhao et al., 2024).

5.2.4. Enzyme-dependent targeting

In inflamed or pathological intestinal sites, specific enzymes are often overexpressed and can act as “switches” for targeted responses. ANPs can be engineered to be sensitive to such enzymes (e.g., matrix metalloproteinases MMP-2/9 (Xiong and Gao, 2017) or esterases (Wan et al., 2023) by incorporating enzyme-cleavable bonds or linkages, thereby achieving precise drug release upon enzymatic cleavage. For example, Xiong and Gao (2017) developed an HSA nanoparticle coupled with an MMP-specific substrate peptide, exploiting the high MMP-2/9 expression in the tumor microenvironment to trigger the release of chemotherapeutic drugs.

In the context of IBD, myeloperoxidase (MPO) released by activated neutrophils is markedly elevated in inflamed regions. Taking advantage of MPO's affinity for HSA, Tiruppathi et al. conjugated 5-aminosalicylic acid (5-ASA) to HSA nanoparticles. These MPO-responsive NPs accumulated selectively at inflamed sites and exhibited anti-inflammatory efficacy over 1000-fold greater than free 5-ASA (Tiruppathi et al., 2004a). By pairing the passive EPR effect with enzyme-triggered release, this strategy significantly enhances local drug concentration and treatment precision. More broadly, designing ANPs to respond to overexpressed enzymes in intestinal inflammation or tumors offers a powerful means to improve therapeutic index and minimize off-target exposure.

5.2.5. Microenvironment-responsive targeting

The tumor microenvironment (TME) in intestinal cancers is defined by hypoxia, chronic inflammation, immunosuppression, acidic pH, and elevated reducing agents—all of which can be harnessed for stimulus-responsive ANP delivery (Thakkar et al., 2020). Under hypoxia, HIF-1α activation increases gp60 receptor expression by 2–3-fold, enhancing endothelial transcytosis of albumin (Semenza, 2012). The mildly acidic milieu (pH ≈ 6.8) induces conformational shifts in albumin that strengthen its binding to SPARC in the tumor stroma (Sleep, 2015). High intracellular glutathione levels (2–10 mM) then cleave disulfide bonds within ANPs, triggering controlled drug release (Kratz, 2008). Furthermore, recombinant HSA can exploit native endocytic pathways to accumulate in tumor cells.

By integrating pH-, redox-, and enzyme-responsive elements into nanoparticle design, payloads are liberated specifically within the TME. For example, Wang et al. (2021) formulated atovaquone-loaded HSA nanoparticles (∼164.5 nm, ∼90 % encapsulation efficiency, ∼10 % drug loading) that alleviated tumor hypoxia and potentiated anti–PD-1 therapy. These HSA-ATO NPs exhibited robust tumor accumulation in a colorectal cancer patient-derived xenograft model, demonstrating the power of microenvironment-responsive targeting.

5.2.6. Active targeting via ligand-receptor interactions

ANPs can be actively targeted via surface modifications. For inflammatory conditions, one approach is to use albumin or attached ligands that have a high affinity for inflammation-associated molecules (e.g., myeloperoxidase released by neutrophils) or for receptors overexpressed on colonic epithelial cells and activated macrophages (e.g., CD44, mannose receptor, CD98, PepT1, F4/80). Among these, CD44 and the mannose receptor are the most extensively studied targets (Table 3), while others have been explored less frequently. Such ligand-directed modifications promote receptor-mediated endocytosis and enhance drug accumulation and cellular uptake at sites of inflammation (Hirata et al., 2010; Hua et al., 2015; Hua, 2014; Kumar et al., 2022; Tiruppathi et al., 2004b; Wang et al., 2014; Zheng et al., 2022). By binding to specific receptors on inflamed cells, ligand-decorated ANPs deliver drugs directly to the target area and achieve improved therapeutic effects. Receptor-mediated active targeting systems thus represent a promising therapeutic strategy for IBD (see Table 3). In tumors, cancer cells express albumin-binding receptors such as gp60 (Fig. 4). ANPs bind to gp60 on endothelial cells; this receptor is associated with caveolin-1 and leads to caveolae-mediated endocytosis. This process allows ANPs to transcytose across the endothelium and subsequently bind to SPARC (Secreted Protein Acidic and Rich in Cysteine), an albumin-binding protein overexpressed in many cancers. Through this gp60/SPARC pathway, ANPs achieve enhanced accumulation in tumor cells.

Table 3.

Representative receptor-targeted drug delivery systems for the treatment of IBD.

Receptor	Ligand	Carrier	Loading cargo	Delivery route	Characterization	Principal finding	Diseases	Reference
CD44	HA	GBP@HA NPs	EGCG	Oral	S: 441.93 ± 17.27 nm Z: −22.63 ± 3.62 mV PDI: 0.181	Regulating the Keap1-Nrf2 and NF-κB signaling pathways, as well as promoting Caspase-1 dependent pyroptosis	Inflammation	(Zhao et al., 2024)
	HA	TA/CUR-NPs	CUR	Oral	S: 220 nm Z: −28.8 mV	Prolonged colonic adhesion and increased uptake in Caco-2 cells	Inflammation	(Luo et al., 2020)
	HA	BSA·SH-Mag NPs	Mag	Oral	S: 403 ± 4 nm Z: −23.6 mV	HA conjugated via an amide reaction to target CD44+ receptors	Inflammation	(Li et al., 2024)
	HA	BSA-KPV/PLGA/PVA-chitosan	KPV	Oral	S: 272.3 nm Z: −5.3 mV PDI: 0.20 ± 0.06	HA-modified nanoparticles were selectively absorbed by Colon-26 cells and RAW264.7 macrophages	Cancer	(Xiao et al., 2017)
	HA	BSA-Ce6@MPN	EGCG	Injection	S: 219.62 ± 9.30 nm Z: −11.87 ± 0.31 mV	HA can specifically bind to the CD44 receptor overexpressed on the surface of CT26 cells	Cancer	(Liang et al., 2022)
Mannose receptor	Mannose	Man-BSA@Rb1 NPs	Rb1	Injection	S: 106 nm Z: −20.0 mV	Inhibiting NF-κB and MAPK signaling pathways in LPS-induced Raw264.7 cells	Inflammation	(Fu et al., 2022)
	Mannose	DOX@MAN-BSA	DOX	Injection	S: 150 nm Z: −15 mV	Internalized by colon tumor cells and M2 tumor-associated macrophages via mannose receptor-mediated endocytosis	Cancer	(Zeng et al., 2022)
	Mannose	eHSA	CA	Injection	S: 108.8 nm Z: −25.3 mV	Inhibiting Wnt signaling for CRC therapy	Cancer	(Yang et al., 2024)

Abbreviations: HA, hyaluronic acid; EGCG, Epigallo-catechin 3-gallate; S: Sizes; Z: Zeta-potentials; PDI: Polydispersity indexes; NF-κB, nuclear factor-κB; CUR, Curcumin; Mag, Magnolol; LPS, lipopolysaccharide; Man, Mannose; KPV: Lysine-proline-valine; PLGA, Poly(lactic-co-glycolic acid); PVA, Polyvinyl Alcohol; MAPK, mitogen-activated protein kinase; DOX, doxorubicin; CA, carnosic acid.

Fig. 4.

Schematic diagram of ANPs targeting tumor cells via the gp60 and SPARC pathways (Ji et al., 2024). Copyright 2024, adapted with permission from Ji et al. under the Creative Commons Attribution-Non Commercial License.

6. Advances in preclinical studies of drug-loaded ANPs for intestinal diseases

ANPs have emerged as a promising platform for the targeted treatment of intestinal diseases, owing to their favorable biocompatibility, stability, and ability to enhance site-specific drug delivery. Recent preclinical studies have explored ANP-based delivery systems in several prevalent intestinal conditions, demonstrating improved drug stability, targeted release, and therapeutic efficacy in disease models. In this chapter, we provide an overview of these advances, focusing on three common intestinal diseases: IBD, CRC, and other intestinal diseases. We discuss how drug-loaded ANPs can address the treatment challenges in each of these conditions, highlight representative preclinical findings, and outline the therapeutic potential of ANP-mediated strategies in intestinal disease management.

6.1. Inflammatory bowel disease

IBD, which includes Crohn's disease and ulcerative colitis, affects approximately 7 million individuals worldwide (Maddineni et al., 2024). It is characterized by chronic, relapsing inflammation of the intestinal mucosa, leading to epithelial damage, ulceration, and fibrotic remodeling (McDowell et al., 2025). Conventional treatments such as aminosalicylates, corticosteroids, immunosuppressants, and biologics, particularly anti-TNF agents, are often limited by poor targeting and systemic side effects (Cai et al., 2021; Peyrin-Biroulet et al., 2021).

Drug administration routes for IBD include oral, intravenous, and rectal delivery, each with unique pharmacokinetic profiles (Fig. 5). Oral delivery, while convenient, is hindered by the extreme pH variation in the gastrointestinal tract (pH 1.0–8.3), compromising drug stability (Zhang et al., 2017). To overcome this, researchers have developed ANP systems with pH-sensitive coatings (e.g., Eudragit® FS30D) or azo-reductase-responsive linkages for colon-specific release. Moreover, Zhang et al. (2023a) engineered a multistage albumin nanomedicine depots (MANDs) system that exhibited a high internalization rate (up to 99 %) in Caco-2 cells, confirming enhanced cellular uptake (Fig. 6A–C). In a DSS-induced colitis mouse model, MANDs significantly improved anti-inflammatory outcomes, as indicated by colon length, spleen weight, and colonic injury scores (Fig. 6D–F). Histological analyses further confirmed low organ toxicity (Fig. 6G). Similarly, He et al. (2023) developed an oral polyphenol armor ANP that synergistically inhibited intestinal inflammation in DSS-induced colitis mice via targeted TNF-α siRNA delivery and ROS scavenging. In vitro, these ANPs enhanced macrophage uptake and eliminated intracellular ROS, while in vivo they modulated gut microbiota composition and alleviated inflammation through gut-brain axis interactions. Intravenous delivery, while offering improved bioavailability, often leads to off-target hepatic accumulation and rapid renal clearance, especially for nanoparticles smaller than 10 nm (Liu et al., 2021a). Gou et al. (2018) demonstrated that intravenously delivered EGCG-loaded nanoparticles (EGCG-NPs) achieved a 1.4-fold higher accumulation in inflamed tissues compared to free EGCG, highlighting improved targeting efficiency and minimal organ toxicity. Rectal delivery facilitates localized drug administration with limited systemic exposure. For instance, curcumin-loaded albumin microspheres released 90 % of their drug payload at colonic pH 7.2 compared to only 15 % under acidic conditions, significantly alleviating symptoms in a DSS-induced colitis model (Beloqui et al., 2014).

Fig. 5.

Delivery strategies and targeting mechanisms of NPs for intestinal inflammation in IBD (Zhang et al., 2017). (A) After oral or rectal administration, NPs reach the inflamed colonic mucosa via the epithelial route, mediated by particle size, surface charge, degradation rate, ligand–receptor interactions, and modulation of the gut microbiome. (B) After intravenous administration, NPs target the inflamed colon via the endothelial route, exploiting size-dependent distribution and ligand–receptor interactions, including selective homing of exosomes. DC, dendritic cells; MΦ, macrophages; PMN, polymorphonuclear leukocytes; ROS, reactive oxygen species. Copyright 2017, adapted with permission from Zhang et al. under the Creative Commons Attribution-Non Commercial License.

Fig. 6.

Oral administration of MANDs for the treatment of IBD (Zhang et al., 2023a). (A) Bright-field microscopic images of MANDs. (B) Caco-2 cells incubated with FITC-labeled MTX@HSA NPs for 1, 2, 4, and 8 h. (C) Flow cytometry analysis of Caco-2 cells incubated with FITC-labeled MTX@HSA NPs for the indicated times. (D and E) Colon length (D) and Spleen wight (E) were measured and analyzed (n = 6); (F) Colonic damage scores assessed by H&E staining (n = 6); (G) Representative H&E-stained colon sections from each group. Copyright 2023, adapted with permission from Zhang et al. under the Creative Commons Attribution-Non Commercial License.

Despite these advantages, challenges remain. Targeting efficiency varies between pH-sensitive and enzyme-responsive systems (Zhang et al., 2023a), and the acute DSS colitis model used in many studies does not fully replicate the chronic, fibrotic features of human IBD (Chassaing et al., 2014). Future research should prioritize humanized animal models and explore combination therapies with biologics (such as anti-TNF antibodies). Additionally, scalable manufacturing and batch consistency are critical for translating ANP-based IBD treatments into clinical use.

6.2. Colorectal cancer

CRC, a malignancy arising from colonic epithelial cells, ranks as the third most common cancer and the second leading cause of cancer-related deaths globally. Chronic inflammation, such as that seen in IBD, significantly increases CRC risk (Lucafò et al., 2021). In 2020 alone, CRC caused approximately 1.9 million new cases and 0.9 million deaths worldwide (Xi and Xu, 2021). Clinical symptoms typically appear in advanced stages and may include hematochezia, obstruction, and systemic manifestations (Duan et al., 2022a). Traditional chemotherapy drugs, including doxorubicin, suffer from limited tumor specificity and serious adverse effects such as cardiotoxicity and liver damage (Injac and Strukelj, 2008; Kim et al., 2017; Oleaga et al., 2016; Rivankar, 2014).

ANPs offer a solution through enhanced drug stability and tumor targeting. Albumin carriers such as HSA and BSA can evade clearance by the reticuloendothelial system and be functionalized for active targeting. A landmark example is Abraxane, an FDA-approved albumin-bound paclitaxel formulation (Ma and Mumper, 2013). Simultaneously, Wang et al. (2025) found that the combination of A4-Based ANPs with anti-CTLA4 antibodies can effectively reduce lung metastasis in colon cancer models by inhibiting endothelial microtubules. Nevertheless, achieving sufficient intratumoral drug accumulation remains a major challenge, particularly in tumors with poor vascular permeability, such as melanoma, pancreatic cancer, and CRC. In a CRC mouse model, Kinoshita et al. (2017) demonstrated that SNO-HSA dimers significantly enhanced the tumor targeting of nab-paclitaxel by strengthening the enhanced permeability and retention (EPR) effect, leading to a 2.5-fold increase in intratumoral PTX concentration and reduced systemic toxicity. This highlights the potential of ANPs for improving nanodrug delivery in poorly perfused tumors.

Recent advances include sirolimus-loaded ANPs (ABI-009, Aadi Bioscience) and BSA/si-Nodal nanocomplexes, which have shown potent antitumor activity in CRC models, including inhibition of metastasis (Wu et al., 2023). Figs. 7A–C present the preparation process, size distribution (204.2 nm), and zeta potential (−46.13 mV) of the BSA-NP/siRNA complexes, highlighting their well-defined physicochemical characteristics. In vivo tumor imaging (Fig. 7D), tumor volume analysis (Fig. 7E), and fluorescence imaging of lung metastases (Fig. 7F) further confirmed that the BSA-NP/si-Nodal nanocomplexes effectively suppressed tumor progression while minimizing systemic toxicity. Moreover, photothermal therapeutic strategies such as HSA-IR825 nanoparticles, developed by Chen et al. (2014), integrate imaging and targeted therapy to enhance treatment precision for CRC. Likewise, Liang et al. (2022) reported that hyaluronic acid (HA)-EGCG-modified metal–phenolic network (MPN) nanoreactors, targeting CD44 receptors, induced ferroptosis and photodynamic synergy, achieving a 12-fold reduction in tumor volume in CT26-bearing mice compared with controls, with minimal off-target toxicity.

Fig. 7.

(A) Schematic representation of the preparation of BSA-NP/si-Nodal nanocomplexes. (B and C) Hydrodynamic size (B) and zeta potential (C) distributions of BSA-NP/si-Nodal complexes measured by dynamic light scattering. (D and E) Representative images of mouse tumors (D) and IHC-stained tissue sections (E). (F) Fluorescence images of nude mice with lung metastases and quantitative analysis of fluorescence intensity (Wu et al., 2023). Copyright 2023, adapted with permission from Wu et al. under the Creative Commons Attribution-Non Commercial License.

These findings underscore the strong translational potential of ANPs in malignant intestinal diseases. Compared to IBD therapy, where ANPs primarily facilitate colon-specific drug delivery and reduce systemic side effects (Zhang et al., 2023a; Zhang et al., 2017), CRC-focused applications aim to improve tumor penetration and overcome chemoresistance. However, challenges such as tumor heterogeneity and limited intratumoral diffusion persist (Ma and Mumper, 2013; Wu et al., 2023). To address these issues, multifunctional ANPs with pH-, enzyme-, and redox-responsiveness are being developed to improve tumor accumulation and therapeutic precision (Kuang et al., 2023). Future progress will require not only technological refinements but also clinical trials targeting refractory IBD and metastatic CRC, alongside the standardization of large-scale production processes, to enable successful clinical translation of ANP-based therapies.

6.3. Other intestinal diseases

ANP-based delivery systems offer excellent biocompatibility, intestinal targeting, and drug-loading versatility for various intestinal therapy. ANPs have shown promise in treating conditions such as IBS, infectious enteropathies, and intestinal barrier dysfunction. By binding to intestinal epithelial receptors (such as the neonatal Fc receptor, FcRn, or SPARC) and by enhancing drug penetration of the intestinal mucosal barrier, ANPs can efficiently concentrate therapeutic agents at lesion sites, thereby improving drug absorption. Supporting this approach, Xie et al. (2020) demonstrated that graphdiyne-modified BSA nanoparticles (GDY-BSA NPs) provided significant radioprotective effects in a radiation-induced diarrhea model. Under whole-body X-ray irradiation, when the survival rate of mice in the untreated group dropped to 30 %, the GDY-BSA NP-treated group maintained a 90 % survival rate. These nanoparticles markedly reduced the severity of diarrhea, prevented weight loss, and mitigated histopathological damage in intestinal tissues, highlighting their strong potential as gastrointestinal radioprotectants.

Although ANP platforms have not yet reached clinical application for these conditions, the preclinical evidence supports their potential for future translation. However, mechanistic studies remain limited. Research into infectious enteropathies, for instance, has primarily focused on antibiotic-loaded ANPs, with relatively little exploration of antiviral or antiparasitic formulations (Hussain et al., 2018; Pisani et al., 2024).

Currently, the exploration of ANPs in these diseases is still in its early stages—reflecting high potential but low maturity. The relatively modest market size for these conditions may dampen industry enthusiasm for investment, underscoring the need for policy incentives and academic–industry collaboration. In the years ahead, research should prioritize the development of combination-loaded ANPs tailored to diverse intestinal pathologies, along with detailed mechanistic studies and long-term efficacy assessments.

7. Toxictity analysis of ANPs

Assessing nanodrug toxicity primarily involves evaluating cell viability, organ-specific toxicity, and biological survival. ANPs, as natural nanocarriers, exhibit inherently low cytotoxicity and can effectively mitigate off-target effects when loaded with chemotherapeutics such as methotrexate or paclitaxel. Notably, ANPs also enhance drug cytotoxicity against multidrug-resistant tumor cells. Gad et al. (2018) demonstrated that docetaxel-loaded HSA nanoparticles showed superior cytotoxic effects against multidrug-resistant NCI/ADR-RES cells compared to free docetaxel within 4 h, highlighting their intracellular sustained-release capability (Gad et al., 2018).

ANPs preferentially target inflamed or tumor tissues, enhancing local drug accumulation and reducing systemic toxicity. Histopathological evaluations are valuable indicators of organ toxicity. For example, Kushwah et al. (2018) reported minimal organ toxicity through biodistribution studies using coumarin-6-loaded AA-GEM-BSA nanoparticles (Kushwah et al., 2018). Furthermore, ANPs significantly extend survival in disease models; experiments by Taheri et al. (2012) demonstrated that biotin-modified HSA nanoparticles prolonged survival to 47.5 ± 0.43 days in tumor-bearing mice, significantly exceeding the 30 ± 0.96 days observed with free methotrexate (Taheri et al., 2012).

Despite these promising attributes, ANPs' nanoscale dimensions may pose unique toxicological challenges (Fischer and Chan, 2007). For instance, residual glutaraldehyde from crosslinking processes can compromise cellular viability (Meng et al., 2022). Consequently, alternative, lower-toxicity crosslinkers (e.g., tannic acid, ascorbic acid, citric acid, sorbitol, and glucose) have been explored to mitigate these concerns, although further refinement is necessary (Amighi et al., 2020; Weiner et al., 2011). Additionally, albumin, although inherently nontoxic, may amplify drug-related toxicity under certain conditions. In a rat model of aspirin poisoning, for instance, combining albumin with lactated Ringer's solution exacerbated toxicity (Harb et al., 2024). Moreover, interactions between albumin and blood proteins may reduce nanoparticle delivery efficiency to tumors (Saha et al., 2019). Thus, ANP safety profiles depend significantly on nanoparticle preparation methods, drug-albumin compatibility, and in vivo interactions. Future research should prioritize developing safer crosslinking strategies and more precise targeting approaches to further enhance the clinical safety and therapeutic efficacy of ANP-based nanomedicines.

8. Clinical potential of drug-loaded ANPs in intestinal disease therapy

By virtue of its unique structure and abundant surface functional groups, albumin can interact specifically with a broad range of molecules. This property provides an ideal basis for numerous modifications, making albumin a preferred nanocarrier system. Albumin-based nanocry stallization approaches have been widely applied in diagnostics and personalized medicine, and several albumin formulations have been successfully marketed (Table 4). Abraxane, the world's first albumin-bound paclitaxel formulation, has achieved promising clinical outcomes by reducing PTX toxicity, increasing drug loading (up to 49 %), and minimizing allergic reactions. Clinical trials have demonstrated that Abraxane is highly effective in cancer patients with severe hypersensitivity reactions and does not induce immune tolerance; however, its efficacy in treating CRC remains unsatisfactory (Fader and Rose, 2009).

Table 4.

Albumin drug delivery system for the treatment of intestinal diseases.

Name of disease	Loaded drugs	Delivery system	Characterization	Preparation method	Mode of administration	Design strategies	Therapeutic outcomes	Bibliography
IBD	5-ASA	5-ASA-HAS NPs	S: 190 nm Z: −11.8 mV PDI: 0.35	Desolvation	Oral administration	Active-targeting	Repair damaged intestinal mucosa, alleviate symptoms	(Iwao et al., 2018)
	BUD, Vanco, GM-CSF	HEP-HSA NPs	S: 250–350 nm Z: −38 ∼ −42 mV PDI < 0.02	Desolvation	Rectal administration	Electrostatic interaction	Inhibit microvascular thromboses and Reduce proinflammatory cytokines/signaling molecules	(Zhang et al., 2020)
	CUR	TA/CUR-NPs	S: 220.4 ± 4.3 nm Z: −28.80 ± 0.40 mV PDI: 0.102 ± 0.018	Improved desolvation	Oral administration	pH-dependent and Enzyme-dependent	Suppress the expression levels of pro-inflammatory cytokines	(Luo et al., 2020)
	EGCG	EGCG-NPs	S: 202.9 nm Z: −13.2 mV PDI: 0.101	Self-assembling	Intravenous injection	pH-dependent and GSH-dependent	Enhanced EPR effect	(Gou et al., 2018)
	KPV	BSA-KPV/PLGA/PVA-chitosan	S: 272.3 nm Z: −5.3 mV PDI: 0.20 ± 0.06	Improved desolvation	Oral administration	Active-targeting	Prevent mucosa damage and downregulate TNF-α, alleviate colitis symptoms	(Xiao et al., 2017)
	MTX	MTX@HSA NPs/MANDs	S: 30 ± 3.2 nm Z: 37 mV	Microfluidics	Oral administration	pH-dependent	Evades stomach acid, inhibit the synthesis of DNA and RNA and suppress the proliferation of inflammatory cells	(Zhang et al., 2023a)
	Se	Se@Albumin NPs	S: 96 ± 7.5 nm Z: −37.3 mV	Self-assembly	Intravenous injection	Active-targeting	Maintain intestinal flora balance, alleviate colitis symptoms	(Deng et al., 2021)
	Tof	Tof@BSA-Chs-CP	S: 308.5 ± 4.8 nm Z: −22.4 ± 0.7 mV PDI: 0.065 ± 0.033	Desolvation	Oral administration	Active-targeting	Modulating the expression of pro-inflammatory cytokines and immune regulatory factors, alleviate colitis symptoms	(Wu et al., 2025)
	Tof	–	S: 250.6 ± 42.1 nm	Self-assembly	Oral administration	ROS-responsive and Active-targeting	Remodulate immune microenvironment, alleviate colitis symptoms	(Li et al., 2023)
CRC	Cetuximab	HSA-cetuximab nanoparticles	S: 241.5 ± 14.7 nm PDI: 0.068 ± 0.063	Desolvation	–	Active-targeting	Enhanced EPR effect	(Löw et al., 2011)
	DOX	MSNP-BR-BSA	S: 210 nm Z: −12.2 mV	Self-assembly	–	Enzyme-dependent	Inhibits tumor cell growth, defense against colon cancer	(Srivastava et al., 2017)
	DOX	DOX-HSA	S: 112 nm	Desolvation	Intravenous injection	Active-targeting	Inhibits tumor cell growth and enhanced EPR effect	(Kimura et al., 2019)
	DOX, TRAIL	TRAIL/Dox HSA NPs	S: 60–120 nm Z: −35 ∼ −22 mV	Nab™ technology	Intravenous injection	Apoptosis synergy	Apoptotic synergy	(Thao et al., 2016b)
	DTX	Apt-NPs-DTX	S: 62 nm Z: −31.2 mV	self-assembly	Intravenous injection	Active-targeting	Bind with nucleolin	(Yu et al., 2020)
	EGCG	BSA-Ce6@MPN	S:219.62 ± 9.30 nm Z:-11.87 ± 0.31 mV	Self-assembly	Intravenous injection	Active targeting and ROS-responsive	Generating ROS to induce apoptosis and tissue damage	(Liang et al., 2022)
	FITC	FITC-HSA	S: 146.0 ± 2.1 nm PDI: 0.1 ± 0.01	Desolvation	Oral administration	Active-targeting	Enhanced EPR effect	(Hashem et al., 2018)
	5-Fu	BLDH/5FU-ABX	S: 168.3 ± 2.0 nm Z: −14.0 mV PDI: 0.181	Self-assembly	Intravenous injection	pH-dependent and Charged-dependent	Exhibited synergetic inhibition of tumor proliferation and induction of cell apoptosis	(Li et al., 2021)
	5-FU	5-FU-rHSA-PEG-NPs	S: 65.7 ± 7.2 nm Z: 25.8 ± 3.5 mV PDI < 0.05	Covalent coupling method	Intravenous injection	Active-targeting	Inhibits tumor cell growth and enhanced EPR effect	(Sharma et al., 2017)
	OXA	Nps-BSA-OXA	S: 163.2 ± 6.3 nm Z: −27 mV PDI < 0.3	Desolvation	Intravenous injection	Active-targeting	Interfere with replication of DNA and transcription leading to cell death	(Wilson et al., 2024)
	PTX	SNO-HSA Dimer	S: 20 nm	Nab™ technology	Intravenous injection	ERF and Active-targeting	Enhance EPR and improve tumor microenvironment	(Kinoshita et al., 2017)

Abbreviations: S: Sizes; Z: Zeta-potentials; PDI: Polydispersity indexes; 5-ASA: 5-Aminosalicylic acid; BUD: budesonide; GM-CSF, granulocyte macrophage colony-stimulating factor; HEP, Heparin; CUR, Curcumin; TA, Tannic Acid; KPV: Lysine-proline-valine; PLGA, Poly(lactic-co-glycolic acid); PVA, Polyvinyl Alcohol; Vano: vancomycin; TNF-α: tumor necrosis factor-α; MTX, methotrexate; MANDs, Multistage albumin nanomedicine depots; Tof: Tofacitinib; ERP effect: permeability and retention effect; DOX: doxorubicin; MSNP: mesoporous silica nanoparticles; BR: Bilirubin; TRAIL, TNF-α-related apoptosis-inducing ligands; NPs: nanoparticles; DTX: docetaxel; Apt: aptamer; EGCG, Epigallo-catechin 3-gallate; Ce6: Chlorin e6; MPN: metal-phenolic network; GSH: glutathione; ROS: reactive oxygen species; FITC: fluorescein isothiocyanate; 5-FU, 5-Fluorouracil; BLDH: albumin-stabilized layered double hydroxide; ABX: Abraxane; PEG: Polyethylene glycol; OXA, oxaliplatin; PTX: paclitaxel; SNO: S-nitrosated;.

To further improve therapeutic efficacy against CRC, Kinoshita et al. prepared an SNO-HSA dimer intended to augment the tumor's enhanced permeability and retention (EPR) effect, thereby increasing drug accumulation and efficacy at the tumor site (Kinoshita et al., 2017). In addition, Li et al. encapsulated a Janus kinase (JAK) inhibitor in reactive oxygen species (ROS)-responsive HSA nanoparticles and modified them with an anti-MAdCAM-1 antibody. This design significantly enhanced targeting to inflamed intestinal regions (Li et al., 2023). Both in vivo and ex vivo experiments confirmed that this nanomedicine produced favorable therapeutic effects in a DSS-induced acute colitis mouse model. It is noteworthy that current ANP-based therapies for IBS are relatively limited. This scarcity likely arises because most research on ANPs as drug carriers has focused on oncology, and their application in digestive diseases like IBS remains in an exploratory stage.

9. Challenges and future perspectives of drug-loaded ANPs for intestinal disease therapy

ANPs have emerged as highly promising drug carriers due to their excellent biocompatibility, intrinsic stability, and easily modifiable surface functional groups, which facilitate precise targeted delivery (Chen et al., 2014; Yoo et al., 2019). Nevertheless, the clinical application of ANPs in treating intestinal diseases still faces multiple significant challenges. Specifically, the harsh gastrointestinal environment, characterized by extreme pH variations, digestive enzymes, and complex microbiota interactions, can potentially compromise the structural integrity and stability of ANPs (Jahanban-Esfahlan et al., 2016). Furthermore, comprehensive validation of long-term safety, including potential chronic toxicity and metabolic fate, remains insufficiently explored.

We believe that a crucial step toward clinical translation involves addressing standardization and scalability challenges. Current ANP production methods, such as Nab™ technology, typically require specialized equipment, stringent process conditions, and high operational costs, limiting large-scale and cost-effective manufacturing (Min et al., 2015). Rigorous quality control and reproducibility across batches also remain significant hurdles. Additionally, most marketed ANP-based therapeutics are administered through injection, with few oral formulations available, thereby reducing patient compliance. The reliance on HSA derived from blood donations further raises ethical concerns and potential shortages in raw material supplies (Cho et al., 2024).

Moving forward, we advocate for the strategic integration of ANPs with advanced therapeutic modalities (e.g., biologics or corticosteroids) to enhance clinical efficacy and personalization. For example, combining ANPs with immune checkpoint inhibitors holds considerable promise in augmenting therapeutic outcomes within complex tumor microenvironments (Zhang et al., 2024). Additionally, incorporating real-time imaging techniques, such as fluorescence or magnetic resonance imaging, into ANP systems could facilitate precise monitoring and dynamic evaluation of drug distribution and therapeutic effectiveness in vivo (Duan et al., 2023). Stimuli-responsive materials capable of controlled and site-specific drug release at pathological lesions represent another critical advancement area that deserves further exploration (Wei et al., 2017).

From our perspective, achieving successful translation from bench to bedside will require concerted interdisciplinary collaboration aimed at refining material design, reducing manufacturing costs, and streamlining global regulatory frameworks. It remains essential to develop comprehensive toxicological assessments, particularly addressing the long-term biodistribution, biodegradation, and biocompatibility of ANPs (Bas et al., 2021). Moreover, addressing formulation challenges for oral delivery would significantly enhance patient acceptance and market penetration.

In conclusion, ANP-based drug delivery systems exhibit considerable potential in overcoming limitations associated with conventional therapies for intestinal diseases, such as IBD, CRC, and IBS. This review has highlighted the unique strengths of ANPs, especially their robust biocompatibility, stability, and versatile surface modifiability, and summarized various preparation methods, targeted delivery mechanisms, controlled release strategies, and significant preclinical and clinical advances. Despite landmark successes such as Abraxane, persistent challenges, including nanoparticle stability in harsh gastrointestinal conditions, targeted delivery efficiency, long-term safety validation, and scalable production processes, still need to be comprehensively addressed. We strongly recommend that future research efforts prioritize nanoparticle optimization for enhanced mucus penetration and site-specific targeting, extensive long-term safety evaluations, and refinement of production technologies to reduce costs. With sustained innovation and collaborative interdisciplinary research, next-generation ANPs are poised to offer more precise, effective, and patient-friendly therapies, significantly advancing the treatment landscape of intestinal diseases.

Funding

This work was supported by the Academician Foundation Program of Chongqing (cstb2023yszx-jcx0003), the Venture and Innovation Support Program for Chongqing Overseas Returnees (cx2024003), the Fundamental Research Funds for the Central Universities (SWU-KF25005), the Chongqing Natural Science Foundation (CSTB2023NSCQ-MSX0506), the Opening fund of State Key Laboratory of Resource Insects (SKLRI-ORP202502), the Chongqing GraduateStudent Research Innovation Project (CYS25197) and the Southwest University Municipal Training Program of Innovation and Entrepreneurship for Undergraduates (X202410635267).

CRediT authorship contribution statement

Xianrui Lin: Writing – original draft. Lin Wang: Methodology. Zhihao Lin: Methodology. Zhenlin Yang: Investigation. Ziheng Zhao: Formal analysis. Yuanyuan Wen: Conceptualization. Rui Xi: Methodology. Dingpei Long: Writing – review & editing, Project administration, Funding acquisition.

Declaration of competing interest

The authors declare no conflict of interest in this work.

Data availability

Data will be made available on request.