Advances in oral treatment of inflammatory bowel disease using protein-based nanoparticle drug delivery systems

Abstract

Inflammatory bowel disease (IBD) comprises chronic autoimmune disorders with significant morbidity, highlighting the need for advanced, noninvasive, targeted therapies. Protein-based nanoparticle drug delivery systems (PNP-DDSs) have emerged as promising platforms to overcome limitations of conventional IBD therapies by improving drug stability and bioavailability while enabling colon-specific delivery. This review systematically classifies PNP-DDSs derived from natural proteins (albumin, gelatin, silk fibroin, and plant-derived proteins) and discusses their design principles along with strategies for intestinal targeting, including particle size and surface charge modulation, stimuli-responsive release (triggered by pH, reactive oxygen species, or enzymes), and active targeting. It highlights recent preclinical advances with oral PNP-DDSs delivering curcumin, resveratrol, 5-aminosalicylic acid, quercetin, and other anti-inflammatory agents, which demonstrate the therapeutic potential of these nanoplatforms in IBD models. Despite promising preclinical outcomes, clinical translation of PNP-DDSs remains challenging due to patient heterogeneity, manufacturing scale-up difficulties, and safety concerns. Future progress will require interdisciplinary innovation and optimization of multi‑stimuli-responsive designs for precise and safe clinical application of PNP-DDSs in IBD management.

Introduction

Inflammatory bowel disease (IBD) comprises a group of autoimmune disorders characterized by chronic intestinal inflammation. These conditions are marked by persistent inflammatory responses, disruption of the intestinal barrier, and an increased risk of developing colitis-associated neoplasms (Rubin et al. Citation2012; Francescone et al. Citation2015; Long Citation2024). Clinically, patients with IBD frequently experience gastrointestinal symptoms such as diarrhea, abdominal pain and weight loss, with some also presenting extraintestinal manifestations including arthritis, sclerosing cholangitis, and iritis (Rubin et al. Citation2012). Based on the anatomical site and pathological characteristics, IBD is primarily classified into Crohn’s disease (CD) and Ulcerative colitis (UC). CD can affect the entire gastrointestinal tract and is prone to complications like intestinal obstruction, whereas UC is generally confined to the colorectum, manifesting as hemorrhagic diarrhea and mucosal ulceration (Mowat et al. Citation2011; Rubin et al. Citation2012). Although IBD was once considered a predominantly Western disease, recent epidemiological data reveal a sharp increase in its incidence in newly industrialized regions such as South America, Asia and Africa, with the global prevalence now exceeding seven million cases. This globalization is attributed to various factors including environmental pollution, Westernized dietary patterns, antibiotic overuse, and dysbiosis of the intestinal microbiota (Ng et al. Citation2017; Ananthakrishnan et al. Citation2018).

Recent advancements in nano-drug delivery systems (NDDSs) have paved the way for novel therapeutic strategies for IBD (Patra et al. Citation2018). Nanoparticles (NPs), the core components of NDDSs, have been demonstrated to enhance drug bioavailability and prolong intestinal retention while reducing systemic toxicity owing to their high drug-loading capacity, controlled release properties, and improved targeting capabilities (Melo et al. Citation2018; Patra et al. Citation2018; Yang and Merlin Citation2019; Bhaskaran and Kumar Citation2021). Moreover, the capacity of NPs to modulate the gut microbiome and influence metabolic pathways further broadens their application in IBD management (Rajoka et al. Citation2021).

A variety of NDDSs, such as Poly(lactide-co-glycolide)/Eudragit S100 NPs (Makhlof et al. Citation2009), ε-polylysine-modified mesoporous silica (Nguyen et al. Citation2017), immunoliposomes (Harel et al. Citation2011), hydrogels (Xiao et al. Citation2014) and extracellular vesicles (Yang et al. Citation2010), are currently in preclinical development. Among these, protein-based nanoparticle drug delivery systems (PNP-DDSs) have garnered significant attention for oral IBD therapy due to the inherent advantages of natural proteins, including biodegradability, low immunogenicity, and efficient target modification capabilities (Lohcharoenkal et al. Citation2014; Jain et al. Citation2018; Zhang and Merlin Citation2018; Shah et al. Citation2020). In contrast to conventional routes, such as rectal or intravenous administration, oral PNP-DDSs can effectively circumvent drug inactivation by gastric acid and digestive enzymes. Furthermore, these systems can be engineered to target the colon specifically by modulating particle size, pH responsiveness, and surface charge. Such refinements not only improve patient compliance but also enhance therapeutic precision, thereby leading to more favorable treatment outcomes.

Compared to conventional polymeric or liposomal NDDSs, PNP-DDSs exhibit several distinctive strengths beyond their inherent biocompatibility. For example, they can achieve functional synergy: lactoferrin (LF), as a carrier, not only facilitates drug loading but also releases degradation products with additional therapeutic benefits (Li et al. Citation2024). The allosteric nature of protein structures enables the design of intelligent, stimuli-responsive release systems that promote precise drug delivery, even though proteins can be somewhat sensitive to degradation in the gastrointestinal environment (Liu et al. Citation2024). Furthermore, the active sites on amino acid residues allow for efficient drug binding, and surface groups are readily modifiable with targeting ligands, thereby enhancing delivery specificity and efficiency. While PNP-DDSs may face certain challenges, such as generally moderate drug-loading capacity, some degree of batch-to-batch variability due to the natural origin of proteins, and potentially higher production costs at scale, many of these limitations can be mitigated through advances in protein engineering, process optimization, and formulation technology. Overall, the unique multifunctional properties of PNP-DDSs continue to drive innovation and expand their potential in advanced drug delivery applications.

Currently, most reviews on PNP-DDSs emphasize their broad applications, with limited focus on oral therapies specifically for IBD. Likewise, existing reviews on oral IBD treatment, while discussing other nanosystems such as liposomes, rarely provide a systematic summary of PNPs as promising carriers. This gap indicates that the unique potential of PNPs remains underexplored and thus serves as the rationale for this review. Here, we systematically examine the classification and design principles of PNP-DDSs, including albumin-, gelatin-, and silk protein-based nanoparticles, and their intestinal targeting strategies. We further highlight recent advances in the oral administration of PNP-DDSs loaded with therapeutic agents such as curcumin (CUR) and 5-aminosalicylic acid (5-ASA) in animal models of IBD. Additionally, we discuss future challenges, including the need for personalized therapeutic approaches, the integration of multi-stimuli responsive systems, and the development of plant-derived protein carriers. The goal of this review is to provide a solid theoretical foundation for future innovations in the clinical treatment of IBD.

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Lin, Z., Zhao, Z., Lin, X., Yang, Z., Wang, L., Xi, R., & Long, D. (2025). Advances in oral treatment of inflammatory bowel disease using protein-based nanoparticle drug delivery systems. Drug Delivery, 32(1). https://doi.org/10.1080/10717544.2025.2544689

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