Ulcerative colitis (UC) is a chronic inflammatory condition that affects the colon and rectum. With a prevalence of 5 million cases in 2023, and a rising incidence worldwide, UC imposes a substantial burden on healthcare systems due to its chronic nature and frequent need for medical intervention [1]. UC is an immune-mediated disorder which typically manifests in patients as episodes of abdominal pain, bloody diarrhea, and urgency. The physical symptoms can impair patients' quality of life, contributing to psychological distress and social limitations. The chronic inflammatory nature of UC has also been linked to the development of colorectal and prostate cancers [2]. UC can manifest in people with genetic predisposition following environmental triggers and gut epithelial barrier defects, although the microbiota and a dysregulation in the immune response have also been implicated [3].

Therapeutic management of UC includes the use of topical and/or oral aminosalicylates (e.g., 5-ASA), oral corticosteroids, and immunosuppressants [3]. Moderate-to-severe cases of UC have also benefitted from the use of biologics. For example, tumor necrosis factor alpha (TNF-α) inhibitors, such as infliximab and adalimumab, are recommended for patients with steroid dependency and/or steroid refractory moderate-to-severe UC [4]. Although pharmacological agents can control UC symptoms and reduce the frequency of recurrence, they are linked to various adverse effects, particularly with long term use. Not to mention the increased treatment costs associated with new therapies such as biological agents. Importantly, UC has a heterogeneous etiology, which can lead to inadequate symptom control in some patients. Therefore, there is a pressing need for safer and more effective therapies that can target the disease with minimal side effects.

Plant-derived natural products have garnered great interest in recent years as complementary or alternative remedies for a variety of diseases. Plant polyphenols are especially known for their potent anti-inflammatory, antioxidant, and immunomodulatory properties, making them viable candidates for the management of inflammatory conditions such as UC [5]. Plant polyphenols can mitigate colonic inflammation by inhibiting the secretion of proinflammatory cytokines, reducing oxidative stress, and restoring the barrier properties of the intestinal epithelium [6,7]. In addition to their pharmacologic activity, plant-derived bioactive compounds have fewer side effects and a better safety profile compared to conventional therapies currently employed for UC management [8].

Grape seeds, a by-product of the wine industry, are a significant source of polyphenolic compounds, including flavonoids such as proanthocyanidins. This has led to the investigation of grape seed extracts (GSE) in various diseases such as diabetes, cardiovascular diseases, and cancer [9]. In animal models of colitis, GSE extracts showed protective and ameliorative effects due to their antioxidant and anti-inflammatory properties [10,11]. Despite the promising therapeutic benefits of GSE, like many other plant-derived bioactive compounds, their poor aqueous solubility and low oral bioavailability are major hurdles against their clinical translation potential [12]. Moreover, in the absence of a targeting mechanism, the active constituents of these extracts may not reach the colon intact due to the harsh environment of the gastrointestinal tract (GIT), limiting their efficacy.

Polymer-based nanocarriers have been extensively investigated for the delivery of hydrophobic drug molecules to enhance their solubility and stability and control their release. They can also be tailored for targeted delivery to specific sites such as the colon. We have recently described the extraction of polyphenols from the seeds of two Lebanese grape varieties: Asswad Karech (AS; red grape variety) and Obeidi (OB; white grape variety). The two GSE had a total phenol content (TPC) of more than 300 mg gallic acid equivalents (GAE) per gram of dry matter, with a high content of catechins, gallic acid, epicatechins, caffeic acid, syringic acid, and protocatechuic acid [13]. The extracts, particularly OB GSE, were characterized by high biocompatibility and excellent antioxidant and anti-inflammatory activities in vitro, and promoted wound healing in vivo. Moreover, OB GSE encapsulated in polymeric nanoparticles (NPs) demonstrated promising antiproliferative activity against B16F10 melanoma cells in vitro [14].

No previous studies have explored GSE in the form of a colon-targeted nanoformulation for the treatment or management of UC. Therefore, we hypothesized that we can unlock the full therapeutic potential of AS and OB GSE in UC management by designing a polymeric nanocarrier platform that can encapsulate the extracts and ensure colon-specific delivery. The nanocarrier was in the form of polymeric nanoparticles (NP) combining biodegradable poly(lactide-co-glycolide) (PLGA) and the pH-sensitive polymer Eudragit S100 (ES100). PLGA was employed to provide effective encapsulation and sustained release, and ES100 was chosen as it is commonly used by the pharmaceutical industry for colon-specific delivery of conventional solid dosage forms. To enhance site-specific uptake by the inflamed colon tissue, the NPs were surface-decorated with hyaluronic acid (HA) as a targeting ligand for CD44 receptors, which are known to be overexpressed by inflamed tissues. The NPs were developed, optimized, and investigated in terms of pH-dependent release, cellular uptake, and antioxidant activity in vitro, followed by evaluation of their in vivo therapeutic efficacy in a dextran sulfate sodium (DSS)-induced murine colitis model.