The literature screening methodology followed PRISMA (Figure 1), detailing the databases used including PubMed, Web of Science, and Scopus, along with keywords “nanoparticles AND aromatic groups” and “inflammation AND nanocarriers” spanning 2005–2025. Studies included were preclinical/clinical research on aromatic‐functionalized nanomaterials and mechanistic analyses of biochemical interactions, while exclusions comprised non‐aromatic nanomaterials and purely computational studies without experimental validation.

During the pathogenesis of inflammatory bowel disease, notable pathological alterations are observed in the blood vessels at sites of inflammation. The disruption of tight junction proteins (TJPs) and gap junctions within vascular endothelial cells results in the formation of large intercellular gaps, thereby significantly enhancing vascular permeability (Bhat et al., 2019). Nanomaterials, with their unique physicochemical properties and size characteristics within the 1–100 nm range, exhibit significant advantages in targeted accumulation at inflammatory sites (Raj et al., 2018). When nanomaterials circulate through the bloodstream and reach inflammatory regions, they exhibit unique pharmacokinetic behaviors. In comparison to small molecules, nanomaterials possess an extended serum half-life, enabling prolonged circulation. Furthermore, unlike large molecules, nanomaterials can more readily penetrate the highly permeable blood vessels and accumulate in inflamed tissues, owing to their distinct size and properties (Zhang et al., 2015; Cui et al., 2021). Furthermore, impaired lymphatic drainage at the inflammatory sites leads to fluid stasis and obstruction of pathways critical for maintaining fluid balance and material metabolism (Moulari et al., 2014). Studies have shown that this targeting capability is closely associated with the pathological features of the inflammatory sites, such as increased vascular permeability and impaired lymphatic drainage (Aibani et al., 2021). The clearance of nanomaterials accumulated in inflamed tissues via the lymphatic system is impeded, resulting in an extended retention time. This prolonged retention facilitates the targeted accumulation of nanomaterials in areas affected by IBD (Ali et al., 2016; Ana Melero et al., 2017).

Immune factors play a central role in the pathogenesis of IBD. Under typical conditions, the intestinal immune system sustains immune tolerance towards commensal microorganisms while preserving its capacity to mount a defense against pathogenic agents (Mann and Li, 2014). In patients with inflammatory bowel disease (IBD), the intestinal immune system is characterized by hyperactivation. Specifically, innate immune cells, including macrophages and dendritic cells, demonstrate atypical functions in the recognition and response to gut microbiota (Koelink et al., 2020). These cells release large amounts of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which trigger an inflammatory cascade. On the other hand, adaptive immune cells, such as T lymphocytes, display dysregulated activity. The hyperactivation of T helper1 (Th1) and T helper17 (Th17) cells leads to the secretion of numerous inflammatory mediators (Guan and Zhang, 2017; Sun et al., 2020). Furthermore, the insufficient number and reduced function of regulatory T cells (Tregs) impair their ability to effectively suppress excessive immune responses, resulting in persistent inflammation of the intestinal mucosa (Imamura et al., 2018). Nanomaterials with Aromatic Functional Groups can interact with surface receptors on macrophages, activating specific signaling pathways that drive the conversion of M1 macrophages to M2 macrophages (Na et al., 2019). Furthermore, they can influence the metabolic state of macrophages to regulate their polarization. Studies have shown that nanomaterials with antioxidant properties can reduce oxidative stress in macrophages, inhibit the activity of key glycolytic enzymes like pyruvate kinase M2 (PKM2), and promote M2 polarization, leading to decreased production of pro-inflammatory factors (Regmi et al., 2019). In animal experiments, mice with colitis treated with such nanomaterials exhibited an increased proportion of M2 macrophages in the gut, resulting in alleviated inflammatory symptoms (Mohammadi et al., 2019).

It is well-known that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are significantly produced at the sites of colonic inflammation (Dang et al., 2020). The ROS and RNS, in conjunction with oxidative stress and redox regulation, has been shown to be pivotal in the pathophysiology of both experimental animal models and patients with IBD. ROS and RNS encompass hydroxyl radicals (OH), superoxide anions, nitric oxide (NO), and peroxynitrite (OONO⁻). Persistently elevated levels of NO have been associated with severe chronic inflammatory conditions, including IBD, sepsis, rheumatoid arthritis, and systemic lupus erythematosus (Stettner et al., 2018). Carbon nanotubes (CNTs), characterized by their distinctive tubular structures and substantial specific surface areas, are capable of interacting with reactive oxygen species (ROS) such as superoxide anions (O₂ ⁻). Specifically, the carbon atoms on the CNT surfaces can donate electrons to reduce O₂ ⁻ to oxygen and water, thereby alleviating oxidative damage to cells. Similarly, fullerenes, with their cage-like configurations, have the ability to trap ROS.

A substantial body of research has demonstrated a significant association between inflammatory bowel disease (IBD) and gut microbiota dysbiosis (Muhammad Shamoon and O’Brien, 2019; Ryan et al., 2020). Notably, this dysbiosis is characterized by a decreased prevalence of beneficial bacterial genera, including Bifidobacterium and Lactobacillus, alongside an increased relative abundance of pathogenic bacteria, such as Escherichia coli and members of the Enterobacteriaceae family (Hofer, 2014; Franzosa et al., 2019). This microbial imbalance can disrupt the function of the intestinal mucosal barrier, increase intestinal permeability, and facilitate the penetration of bacteria and their products into the submucosa of the intestine (Johansson et al., 2014; Rodriguez-Pineiro and Johansson, 2015). This, in turn, activates the immune system and triggers an inflammatory response (Hofer, 2014). Therefore, the use of nanomaterials to regulate the gut microbiota represents a promising therapeutic strategy for the treatment of IBD (Xiu Wang et al., 2024). Liu et al. designed colon-targeting adhesive hydrogel microspheres that degrade in the colon environment, releasing specific factors to optimize the composition of the gut microbiota (Liu et al., 2021).

Curcumin, a bioactive compound derived from turmeric (Curcuma longa), has garnered considerable interest in the domain of nanomedicine for the treatment of inflammatory bowel disease (IBD), owing to its distinctive aromatic functional groups and extensive range of biological activities (Beloqui et al., 2016; Karthikeyan et al., 2021). The molecular structure of curcumin is characterized by two benzene rings linked via an α,β-unsaturated carbonyl group, and includes various bioactive functional groups such as hydroxyl (-OH), methoxy (-OCH₃), and an α,β-unsaturated ketone (C=O) group. The presence of conjugated double bonds within the benzene rings enhances curcumin’s antioxidant capabilities, facilitating the scavenging of free radicals and the inhibition of ROS accumulation, which in turn mitigates oxidative damage to intestinal tissues (Guo et al., 2022). Curcumin exerts its anti-inflammatory effects through multiple mechanisms, including the regulation of M1/M2 macrophage polarization, inhibition of the TLR signaling pathway, suppression of NLRP3 inflammasome activation, modulation of the Treg/Th17 cell balance, and downregulation of NF-κB signaling pathway components, thereby inhibiting the release of pro-inflammatory cytokines and reducing oxidative stress levels (Liu et al., 2013; Hasanzadeh et al., 2020; Laurindo et al., 2023) (Figure 3). Despite its great pharmacological activities, curcumin is highly hydrophobic, which results in poor bioavailability. A simple way of solving the limiting factors of curcumin is to improve its bioavailability, protect it from degradation and meta bolism (Khezri et al., 2021). Various types of nanoparticles (NPs), such as polymer NPs, poly meric micelles, liposome/phospholipid, nano-/microemulsions, nanogels, solid lipid NPs, polymer conjugates, self-assemblies, and so on, are suitable for the delivery of an active form of curcumin (Hegde et al., 2023).

Pharmacokinetic analysis following oral administration of nano-curcumin in murine models revealed an approximately 20-fold decrease in the required dosage compared to unformulated curcumin to attain similar concentrations in plasma and central nervous system (CNS) tissues (Szymusiak et al., 2016). Furthermore, the aromatic ring structure of curcumin facilitates its ability to chelate metal ions, which can be exploited to develop metal-polyphenol network nanocarriers, presenting potential strategies for improved drug targeting (Coelho et al., 2020).

Proanthocyanidins (PACs) constitute a class of polyphenolic compounds that are prevalent in various plant species. These compounds have been extensively characterized for their diverse biological and pharmacological properties, which encompass antioxidant, antibacterial, antiviral, anti-inflammatory, and anti-allergic activities. The molecular structure of PACs is distinguished by a conjugated system of multiple aromatic rings and phenolic hydroxyl groups, endowing them with potent antioxidant capabilities. In the context of IBD treatment, the antioxidant properties of PACs are of particular importance. Empirical studies have demonstrated that PACs are capable of scavenging ROS, mitigating oxidative stress-induced damage, and inhibiting the release of inflammatory mediators (Wang et al., 2022b). Proanthocyanidins, characterized by multiple phenolic hydroxyl groups within their molecular structure, exhibit heightened susceptibility to environmental factors including light, pH, and redox conditions (Luo et al., 2020). Their absorption predominantly occurs in the small intestine; however, this process is impeded by their substantial molecular weight and degree of polymerization (Tao et al., 2019). These characteristics contribute to the inherent instability and limited permeability of proanthocyanidins, thereby restricting the quantity of these compounds that enter the systemic circulation in their native or active form (Fernandez et al., 2016). To put it briefly, the application of proanthocyanidins is limited by their chemical instability and low bioavailability, even though they have desirable properties. To tackle the challenges of PC’s low oral bioavailability and instability, encapsulation methods have been adopted as a successful strategy to improve its shortcomings. A study explored the creation of proanthocyanidin-loaded chitosan nanoparticles (PC-CS-NPs) using ionotropic gelation. These nanoparticles, characterized by FTIR, XRD, and DLS, were under 300 nm in size, spherical, smooth, and uniform, as shown by SEM. In vitro tests revealed a sustained release of proanthocyanidins in different buffers. Additionally, PC-CS-NPs showed equal or superior effectiveness in scavenging DPPH and ABTS free radicals compared to native drugs (Ding et al., 2021). Sericin (SS), a biologically active polymer, demonstrates exceptional biocompatibility and bioactivity, indicating significant potential for drug delivery applications. Researchers have integrated proanthocyanidins (PACs) into sericin to develop SS/PAC composite materials, which synergize high antioxidant capacity with superior biocompatibility. The SS/PAC composites exhibit uniform dispersion in aqueous solutions, with an average particle diameter of approximately 136 nm, and achieve a substantial drug loading capacity of 1767 mg/g (Wang et al., 2022a). The SS/PAC demonstrated strong antioxidant properties and outstanding biocompatibility in both laboratory and living organism settings, and it could ease DSS-induced ulcerative colitis symptoms by managing oxidative stress, reducing inflammation, and repairing tissue damage. This strategy of combining proanthocyanidins with nano-carriers successfully addresses the potential stability and targeting challenges faced by PACs in biomedical applications, significantly enhancing their therapeutic efficacy (Figure 4).

Quercetin is a flavonoid compound extracted from plants, exhibiting excellent anti-inflammatory and antioxidant activities (Cui et al., 2022). Quercetin is a yellow, crystalline plant polyphenolic flavonoid, distinguished by its chemical composition of five hydroxyl groups and three benzene rings (Batiha et al., 2020; Aghababaei and Hadidi, 2023). This distinctive molecular structure underpins its wide range of biological activities and potential therapeutic applications. Quercetin exhibits numerous therapeutic effects, including antioxidant, anti-inflammatory, anti-apoptotic, and anti-aging properties, which are mediated through intricate mechanisms involving the modulation of various signaling pathways (Chen et al., 2018; Cui et al., 2022). In the realm of oncological therapeutics, quercetin is predominantly employed as an adjuvant treatment. Its co-administration with natural compounds, including curcumin, resveratrol, and green tea polyphenols, has been shown to markedly potentiate their anti-tumor efficacy (Joshi et al., 2023). Furthermore, quercetin enhances the sensitivity of cancer cells to chemotherapeutic agents and radiotherapy. For example, when combined with doxorubicin and cisplatin, quercetin allows for a reduction in the required dosage of these drugs, thereby minimizing side effects while preserving therapeutic efficacy (Xu et al., 2021). Notably, a mouse study has shown that quercetin also has the potential to alleviate inflammation (Schwingel et al., 2014; Dong et al., 2020). Quercetin’s anti-inflammatory effects are mediated through multiple mechanisms. It suppresses the activation of Toll-like receptor 4 (TLR4), thereby reducing the expression of inflammatory mediators and cytokines (Chen et al., 2018). Quercetin also inhibits the overexpression of adhesion molecules and chemokines, preventing inflammation. Additionally, it regulates immune responses by enhancing interferon-γ (IFN-γ) production in Th1 cells while reducing IL-4 levels in Th2 cells. Furthermore, quercetin reduces the levels of key inflammatory molecules, including COX-2, NF-κB, MAPK, and CRP, contributing to its anti-inflammatory activity (Haddad, 2002; Li et al., 2016).

Despite its promising therapeutic potential, quercetin’s poor solubility and low bioavailability have limited its clinical application (Moradi et al., 2020; Tomou et al., 2023; Zhang et al., 2023). To address this challenge, researchers have developed various nanosystems, such as nanoemulsions, liposomes, lipid nanoparticles, nanostructured lipid carriers (NLC), solid lipid nanoparticles (SLN), and mesoporous silica, to enhance its bioavailability and therapeutic efficacy (Chessa et al., 2011; Bose et al., 2013; Scalia et al., 2013; Sapino et al., 2015; Abel Lozano‐Perez et al., 2017). These systems are designed to enhance the absorption and distribution of quercetin, thereby optimizing its therapeutic efficacy. Beyond these nanosystems, researchers have engineered a vesicular delivery system encapsulated with chitosan/lecithin and loaded with quercetin. This system provides benefits in terms of stability, controlled release, and targeted delivery, further augmenting the therapeutic performance of quercetin (Kumari et al., 2010; Castangia et al., 2015).

Baicalein (3,3′,4′,5,6-pentahydroxyflavone) is a highly effective antioxidant prevalent in numerous plant species, with a notable concentration in the roots of Scutellaria baicalensis. It demonstrates a broad spectrum of physiological activities, encompassing neuroprotective, antioxidant, antibacterial, antiviral, antiallergic, anti-inflammatory, and antitumor properties (Gao et al., 2016; Wei et al., 2017). A study employing a murine model revealed that baicalein exhibits anti-inflammatory properties in macrophages stimulated by double-stranded RNA (dsRNA). This effect is mediated through the suppression of nitric oxide (NO), cytokines, chemokines, and growth factors production via the endoplasmic reticulum stress-CHOP/STAT signaling pathway (Raghavendra et al., 2016). Baicalein’s structure includes three adjacent phenolic hydroxyl groups, which facilitate the formation of intramolecular hydrogen bonds. This structural feature contributes to its low hydrophilicity and water solubility, ultimately resulting in poor oral bioavailability (Li et al., 2018; Pi et al., 2019). To address these limitations, various strategies have been reported to enhance the solubility, stability, and bioavailability of baicalein. The use of nano-liposomes is an effective method (Liu et al., 2016).

A notable advancement in this field involves the development of a highly efficient method for preparing glycyrrhizic acid–baicalein (GA-BE) nano-micelles. The nano-micelles produced using the optimal formulation were characterized via differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FT-IR), confirming that baicalein existed in a non-crystalline state within the micelles and that a conjugated aromatic system was present. This formulation increased the water solubility of baicalein by a factor of 4,600. In vitro drug release studies demonstrated that the nano-micelles exhibited a sustained-release effect, which could be partially controlled by adjusting the pH (You et al., 2021).