Therapeutic Potential of Essential Oils and Their Bioactive Compounds Against Colon Cancer: Focus on Colon-Specific Micro- and Nanocarriers

Abstract

Colon cancer ranks among the most prevalent and lethal cancers worldwide. Lifestyle and dietary factors—such as high consumption of processed foods, red meat, and alcohol, coupled with sedentary behavior—are key contributors to its development. Despite the availability of standard treatments like surgery, chemotherapy, and radiotherapy, colon cancer remains a significant cause of cancer-related deaths. These conventional approaches are often limited by severe side effects, toxicity, recurrence, and the emergence of drug resistance, highlighting the urgent need for alternative therapeutic strategies. Essential oils are a potential cancer-treatment candidate owing to their diverse composition and favorable safety profile. Numerous studies have revealed essential oils’ promising cytotoxic, antioxidant, and anti-inflammatory effects, supporting their potential role in cancer prevention and treatment. Nevertheless, applying volatile oils to the colon faces several limitations, mainly due to their low bioavailability. Furthermore, conditions within the gastrointestinal tract also contribute to the reduced therapeutic efficacy of essential oils. Novel and promising strategies have been developed to overcome the limitations associated with the application of essential oils. The utilization of targeted drug delivery systems has improved the stability of essential oils and enhanced their therapeutic potential in colon cancer treatment. Moreover, even though essential oils cannot replace conventional chemotherapy, they can mitigate some of its adverse effects and improve the efficacy of associated chemotherapy drugs. This review explores the potential of essential oils and their bioactive compounds in colon cancer therapy and highlights current advancements in micro- and nanoencapsulation techniques for their targeted delivery to the colon.

1. Introduction

Colon cancer (CC) ranks as the third most common cancer globally, following breast and lung cancers, and holds the second-highest mortality rate among all malignancies [1]. By 2035, the number of deaths from rectal cancer is projected to rise by 60%, while fatalities from CC are expected to increase by 71.5% [2]. Although advancements in diagnostics, treatment options, and screening programs have been made, the rates of illness and death from CC remain significant [3]. There is a growing consensus that the most effective strategy for combating cancer lies in its prevention. One promising approach involves the long-term use of oral agents, a method known as chemoprevention. This strategy entails the use of pharmaceutical, nutritional, or biological substances to prevent, delay, or even reverse the development of cancer. CC, in particular, is considered a strong candidate for chemoprevention due to its extended premalignant phase, which offers a valuable window for early intervention [4]. Natural compounds derived from plants have been highlighted as potential chemopreventive agents, offering cancer-inhibiting properties with reduced toxicity compared to conventional synthetic drugs. Moreover, traditional cancer treatments often come with a range of adverse side effects for patients. Therefore, there is a pressing need to explore more effective and less harmful therapeutic approaches [2,5].

The use of natural products in treating various diseases has long been a foundational element of modern medicine. In the field of cancer therapy, natural compounds continue to play a critical role, with many therapeutic agents either derived directly from natural sources or inspired by them [6]. Essential oils (EOs), which are complex mixtures containing up to 300 distinct bioactive compounds, can be extracted from a variety of medicinal or aromatic plants [7]. Although research into their anticancer potential is relatively recent, EOs have already been shown to influence several molecular pathways, including the induction of apoptosis via both intrinsic and extrinsic mechanisms. While EOs are not a replacement for conventional chemotherapy, they offer notable benefits, such as alleviating some of chemotherapy’s side effects and enhancing the overall efficacy of cancer drugs, ultimately contributing to an improved quality of life for patients [2].

EOs have been widely shown to exhibit remarkable activity against cancer cells. Numerous EOs have been investigated across different experimental models in the search for novel therapies for CC, yielding highly encouraging results. These oils demonstrate a broad spectrum of bioactive properties, including cytotoxic, antiproliferative, and antimetastatic effects, which they exert through diverse mechanisms of action [4]. For example, linalool—a naturally occurring terpene alcohol found in various fruits, herbs, and EOs—is known for its antibacterial, anti-inflammatory, and antioxidant properties. Beyond these, linalool has demonstrated anticancer potential against several types of cancer, including prostate, colon, leukemia, and cervical cancers. Its anticancer activity is believed to be mediated through mechanisms such as the induction of apoptosis, generation of oxidative stress, cell cycle arrest, and modulation of the immune response [8].

Despite their potent anticancer properties, the clinical application of EOs remains limited due to several inherent limitations, including poor bioavailability, low solubility, chemical instability, high volatility, and sensitivity to environmental factors such as light and humidity [9]. In recent years, advancements in micro- and nanotechnology have opened new avenues for addressing these limitations. Innovative methods for encapsulating EOs into micro- and nanostructures are being developed, with ongoing efforts to identify suitable polymers and delivery carriers [10].

Micro- and nano-scale drug delivery systems have shown significant promise in enhancing the therapeutic potential of EOs against various tumor types. These delivery platforms offer numerous advantages, such as controlled and sustained release, increased permeability to tumor tissues, improved bioavailability and solubility, and ultimately enhanced anticancer efficacy [10,11].

In this context, the present review explores the chemical composition of EOs, their potential role in the prevention and treatment of CC, and the benefits and limitations of micro- and nanotechnology-based delivery systems. It also discusses the classification and properties of commonly used micro- and nanomaterials and highlights emerging colon-targeted carriers. Most importantly, the review emphasizes recent advances in micro- and nanosystems that have demonstrated promising capabilities in enhancing the anticancer activity of EOs across various cancer cell lines and tumor models [9,10,11,12].

2. Colon Cancer and Conventional Therapies

CC ranks as the second most frequently diagnosed cancer among women and the third among men. It represents about 10% of all annual cancer cases and related deaths. Global death rates from CC have increased, largely due to modern dietary patterns and lifestyles characterized by high meat and alcohol consumption and insufficient physical activity [13]. Several factors contribute to the development of CC. Research has shown that individuals face a higher risk of CC if they or their family members have a history of cancer, colon polyps, inflammatory bowel diseases, diabetes mellitus, or if they have undergone a cholecystectomy. Inflammatory bowel disease (IBD) is considered the third most significant risk factor for developing CC. IBD encompasses chronic, incurable conditions—primarily Crohn’s disease and ulcerative colitis—that disrupt the immune function of the gastrointestinal tract (GIT), resulting in persistent, uncontrolled inflammation [3].

CC typically begins as small, benign growths known as polyps that develop in the colon lining [14]. Over time, these can turn into malignant tumors capable of spreading to other parts of the body. The progression of CC is divided into four main stages. In the early stages (0 and 1), the abnormal cells are confined to the inner layers of the colon. By stage 2, the cancer penetrates the outer layers of the colon wall but has not yet spread to the lymph nodes; at this stage, these growths are often referred to as “adenomas.” In stage 3, the cancer reaches the lymph nodes and becomes known as “carcinoma.” Finally, in stage 4, the disease metastasizes and spreads to distant organs [15].

In the early stages, CC often progresses without obvious symptoms. Still, some individuals may experience subtle signs such as slight bleeding, tiredness, loss of appetite, anemia, unexplained weight loss, chronic constipation, or alternating constipation and diarrhea [2]. The mainstay of treatment is surgical removal of the tumor, which may be complemented by chemotherapy or radiotherapy—either separately or in combination—as part of adjuvant or neoadjuvant treatment plans. In recent years, targeted therapies and immunotherapies have become valuable options for managing more advanced, aggressive, or metastatic CC cases [16].

Surgical intervention remains one of the most common treatment methods for patients with CC. However, a major drawback of surgical resection is the potential removal of healthy portions of the colon along with the tumor. Another treatment option is radiation therapy, which can lead to side effects such as fatigue, skin irritation, gastrointestinal discomfort, and, in some cases, bloody stools and infertility in both men and women [17]. Chemotherapy using synthetic anticancer drugs is also widely employed. These drugs aim to kill cancer cells by inhibiting their proliferation or halting cell division. While effective, they often cause side effects such as nausea, diarrhea, neuropathy, and mouth sores. Targeted therapies represent another strategy, focusing on the genes responsible for tumor growth [18]. These treatments work by blocking or deactivating cancer-causing genes, selectively inhibiting cancer cell growth and division while sparing healthy cells. Nonetheless, some patients experience rashes on the face and upper body [19]. Additionally, cancer immunotherapy has shown promise in improving survival rates among patients with advanced or metastatic cancers. However, its effectiveness in CC remains limited, with only about 12% of patients responding to this approach [20]. The effectiveness of immunotherapy varies significantly between patients, making it challenging to predict treatment outcomes. Additionally, immunotherapy can trigger immune-related adverse events that may affect vital organs. Identifying risk factors, such as individual patient characteristics, concurrent medications, and the specific type of cancer [21]. Another major limitation is the high cost of newer immunotherapy treatments, which makes them inaccessible to many patients. Given this context, there is a growing need to explore alternative strategies or combination therapies that can offer more effective outcomes in the treatment of CC [19].

Current cancer research is increasingly focused on developing novel therapeutic strategies and more effective chemotherapeutic agents. Notably, around 60% of cancer treatment drugs are derived from natural products [22]. Today, aromatic plants are recognized as valuable sources of therapeutic compounds, and it is anticipated that several new pharmaceuticals will be developed from these plants in the coming decade [23]. Medicinal plants in particular are a rich and reliable source of bioactive compounds (BACs), offering a sustainable and green approach to CC treatment. Compounds such as terpenoids, saponins, volatile oils, flavonoids, phenolics, quinones, and alkaloids have demonstrated strong cytotoxic effects against CC cells, often with fewer side effects and lower risk compared to conventional treatments. Plant-derived compounds are also known to support CC management by slowing tumor growth, alleviating the side effects of chemotherapy and radiation, and targeting cancer at the molecular level [24]. When used alongside conventional therapies, natural compounds can enhance treatment effectiveness by increasing the sensitivity of cancer cells to standard treatments, allowing for lower drug dosages, minimizing resistance, and reducing adverse side effects. This integrative approach holds significant promise as a valuable therapeutic strategy for managing the progression and metastasis of CC [1]. Although no dietary supplement can completely treat, cure, or prevent cancer, some therapies with BACs may help reduce the risk of developing it, relieve symptoms, and improve quality of life. Nature has long served as a rich reservoir of molecules for drug discovery and innovation. Over half of all anticancer drugs approved globally between 1940 and 2010 are either natural products or derived from them. Within the wide array of natural compounds, phytochemicals—especially EOs—have attracted significant attention due to their diverse and potent biological activities [25].

3. Essential Oils and Their Bioactive Compounds’ Potential for Colon Cancer Treatment

EOs are volatile blends of numerous compounds produced by aromatic plants as secondary metabolites, notable for their distinctive and potent scents. These oils typically contain a mixture of 20 to 60 different essential oil (EO) constituents, with terpenes being the most abundant. The components of EOs are categorized according to their chemical structures in terpene hydrocarbons, oxygenated terpenes, and other oxygenated compounds like phenols, esters, ketones, lactones, coumarins, monoterpene alcohols, and sesquiterpene alcohols [26]. EOs are often regarded as more potent than their constituents due to their synergistic interactions. The concentration of individual components in EOs can be affected by various microclimatic and environmental factors, including plant species, seasonal timing, geographic location, climate conditions, soil type, leaf maturity, and the method of extraction. Among these, seasonal changes are particularly significant, often playing a major role in altering the chemical composition of plant-derived EOs [27]. EOs can be extracted from plant materials using a variety of techniques, such as hydro-distillation, steam distillation, cold pressing, solvent extraction, as well as ultrasound and microwave-assisted methods. A distinctive characteristic of EOs is their vast chemical diversity and wide range of botanical sources. Globally, over 17,000 plant species are known to produce EOs, yet out of the more than 3000 identified EOs, only about 10% are produced on a commercial scale [9].

For centuries, EOs have been used in the treatment of various ailments, and their therapeutic use continues to grow in both whole-oil and isolated-compound forms. Recently, researchers have increasingly explored the anticancer properties of EOs, recognizing that their mechanisms of action differ from those of conventional cytotoxic drugs [28]. The complex and variable composition of EOs, along with the diverse nature of cancer types, makes it difficult to pinpoint a single, specific mechanism of action. Early studies primarily investigated the antioxidant and anti-inflammatory effects of EOs, proposing their potential role in cancer treatment. Notably, cancer cells typically exhibit moderately elevated levels of reactive oxygen species (ROS) compared to healthy cells. Additionally, chronic inflammation is recognized as a key feature in the development and progression of cancer [25]. EOs exhibit diverse bioactive properties, including cytotoxic, antiproliferative, and antimetastatic effects on cancer cells through multiple mechanisms of action. Numerous studies have shown the advantages of EOs and their ability to fight cancer cells via target systems (Figure 1). In the context of CC, the effects of EOs have been investigated through in vitro studies using various human CC cell lines, including HT-29, Caco-2, LoVo, Colo-205, SW480, and HCT-116. Among these, HCT-116 cells have been the most extensively studied, as they serve as a model for exploring the molecular mechanisms underlying tumor metastasis [4,29,30].

EOs can trigger programmed cell death in cancer cells through mechanisms such as apoptosis, necrosis, cell cycle arrest, and the disruption of key cellular organelles. These effects are typically accompanied by some critical events leading to cell death, such as increased membrane fluidity and changes in the pH gradient. The three primary classes of EO constituents—phenols, aldehydes, and alcohols—are believed to play central roles in these processes. For example, plant-derived isoprenoids have shown potential in reducing tumor cell size in cancer patients [31].

Oxidative stress is a defining feature of the tumor microenvironment, where the inhibition of the electron transport chain leads to the accumulation of ROS. This buildup can cause extensive damage to cellular components, including proteins, lipids, and nucleic acids such as deoxyribonucleic acid (DNA) [10]. Due to their already elevated baseline levels of oxidative stress, cancer cells are more vulnerable than normal cells to further increases in ROS. Consequently, they are highly susceptible to agents that promote ROS generation [32]. According to the literature, natural compounds found in EOs could be potent inducers of ROS, capable of disrupting critical cellular signaling pathways. Furthermore, EOs can stimulate the upregulation of both non-enzymatic antioxidants (like glutathione) and enzymatic antioxidants (such as superoxide dismutase, glutathione peroxidase, and catalase), which are essential for mitigating oxidative stress during tumor progression [10].

The antimutagenic properties of EOs contribute significantly to cancer prevention by interfering with various stages of tumor initiation. These mechanisms include enhancing enzymatic detoxification of mutagens, blocking their entry into cells, inhibiting the metabolic activation of pro-mutagens, directly neutralizing mutagens, and scavenging free radicals [10]. Thymol, geraniol, and fennel EOs have shown notable antimutagenic effects, largely attributed to their strong antioxidant properties [4].

Numerous studies have shown that inflammation contributes significantly to tumor development. This is why preventing or reducing inflammation can halt the progression of precancerous conditions into malignant tumors. As a result, identifying new and effective strategies to counter inflammation-related carcinogenesis has become a central focus in cancer research [33]. The dual antioxidant and anti-inflammatory properties of EOs compounds are particularly relevant in CC, where chronic inflammation and oxidative stress are known to drive the neoplastic transformation and progression of CC cells [34].

Since EOs contain a variety of biologically active components with different effects, one type of oil can exhibit antifungal, antibacterial, antiseptic, cytotoxicity, anti-inflammatory, antimutagenic, antioxidant, anticancer, antiradical, and chemopreventive effects. Examples include the EO of Stachys germanica L. (Lamiaceae) [35,36], Tanacetum parthenium L. (Asteraceae) [37], Salvia miltiorrhiza and Salvia verticillata L. (Lamiaceae) [38], Carum carvi L. (Apiaceae) [39], Cymbopogon flexuosus (Poaceae), Laurus nobilis (Lauraceae), Melissa officinalis (Lamiaceae), Aristolochia mollissima (Aristolochiaceae), Cyperus rotundus (Cyperaceae), Lindera strychnifolia (Lauraceae), Salicornia europaea L. and Suaeda maritima L. (Chenopodiaceae) [40], Melaleuca alternifolia (Myrtaceae), Ocimum basilicum (Lamiaceae), Nigella sativa (Ranunculaceae) [41], Boswellia sacra (Burseraceae), Curcuma aromatica; Curcuma longa; Curcuma wenyujin (Zingiberaceae), Zanthoxylum rhoifolium (Rutaceae), Rosmarinus officinalis L. (Lamiaceae) [42], Juniperus excelsa M. Bieb and Juniperus sabina L. (Cupressaceae) [43], etc., and their main constituents. Several studies have shown the antitumor activity of certain biologically active components in Eos, such as 1,8-Cineole, allicin, Allyl Isothiocyanate, β-Bisabolene, camphene, Cinnamaldehyde, Iso-egomaketone, elemene, eugenol, farnesol, Furanodiene, geraniol, Hinokitiol, d-limonene, Linalool, Myrtenal, and Terpinen-4-Ol [41]. Therefore, EOs and their components hold potential as therapeutic agents and may be considered for use alongside conventional treatments.

Various EOs and their components have been evaluated in vitro and/or in vivo using the above-mentioned CC models, demonstrating notable antitumor activity.

Fan et al. (2015) tested the effect of carvacrol on CC cell lines such as HCT-116 and LoVo. It was found that carvacrol reduces cell proliferation and induces cell cycle arrest, alongside decreasing cell invasion and migration capabilities [29].

EO derived from blood oranges (Citrus sinensis) has demonstrated pro-apoptotic and anti-angiogenic effects in CC cells [44]. Similarly, the volatile oil extracted from Artemisia campestris L. exhibited notable antitumor activity against HT-29 CC cells, supporting its potential for further investigation as a candidate for chemoprevention and therapeutic development [4].

The study of Cianfaglione et al. (2017) evaluated the anticancer properties of Eryngium campestre L. and Eryngium amethystinum L., revealing IC₅₀ values ranging from 1.5 to 2.99 µg/mL for E. campestre and 1.65 to 5.32 µg/mL for E. amethystinum. These values were found to be comparable to those of the standard chemotherapeutic agent cisplatin [45].

Qi et al. (2018) found that geraniol exhibited strong cytotoxicity against the Colo-205 cell line [30], but did not induce apoptosis in Caco-2 cells. In the latter, it displayed a cytostatic effect by halting the cell cycle in the S phase, highlighting how the same compound can elicit varying responses depending on the CC cell model. Additionally, geraniol has shown anticancer potential by modulating polyamine metabolism—an emerging target in cancer therapy [46].

Chauhan et al. (2018) studied the cytotoxic effects of thymol on HCT-116 cells by promoting ROS generation, causing DNA damage, and triggering cell death via mitochondrial pathways [47]. Interestingly, at low concentrations, thymol, along with geraniol, nerolidol, and methyleugenol, exerted genoprotective effects in HT-29 cells by mitigating oxidative stress and DNA methylation damage [48]. These findings underscore the critical importance of effective dosing and bioavailability in the colon, as these compounds undergo intestinal absorption that may influence their local concentration and therapeutic potential.

Another study of Larbi et al. (2019) showed that EO from Brocchia cinerea (Delile) Vis. demonstrated a more selective anticancer effect in two human cancer cell lines—HCT-116 (CC) and HePG2 (liver cancer). Notably, it exhibited a significant inhibitory effect, reducing CC cell growth by 66.9% [49].

Cuminum cyminum L., a widely used spice from the Apiaceae family, is rich in diverse BACs, including alkaloids, flavonoids, and terpenoids. Among these, cinnamaldehyde stands out as the primary active constituent, contributing significantly to the plant’s pharmacological and clinical potential [50]. In animal studies, cumin supplementation demonstrated a protective effect against chemically induced CC in rats. Cinnamaldehyde, the main component of its EO, has been associated with notable antimicrobial, anticancer, and antimutagenic activities. Gas–mass spectrometry analysis of cumin seed extracts revealed the presence of several volatile constituents, including α-pinene, β-pinene, cuminaldehyde, and p-cymene [51].

The fruit rinds of Garcinia indica and Garcinia cambogia are natural sources of garcinol, a polyisoprenylated benzophenone with demonstrated anticancer properties. Extensive research involving cancer cell lines and animal models has highlighted garcinol’s potential in cancer therapy. It exerts strong anticancer effects by inducing both apoptosis and autophagy, and by enhancing the sensitivity of gastric cancer cells to chemotherapeutic agents. In CC, garcinol functions as a powerful suppressor of tumor progression by modulating key molecular pathways. It downregulates critical oncogenes and signaling molecules, thereby reducing tumor cell aggressiveness and invasiveness [52].

Eucalyptus camaldulensis, a fast-growing tree species from the Myrtaceae family, produces EO composed primarily of cineole, which accounts for about 60–80% of its content. In the study by Taheri et al. (2020), the EO of E. camaldulensis demonstrated notable cytotoxic effects against the CC cell line CaCo-2 in a manner dependent on both concentration and exposure time. The anticancer properties of this EO are likely linked to its ability to reduce free radical levels and promote apoptosis in these cancer cells [53].

Eugenia caryophyllata (clove), a member of the Myrtaceae family, has been used for various therapeutic applications, including antimicrobial, antioxidant, and anti-inflammatory purposes. Scientific studies have shown that clove contains 15–20% EO rich in phenolic compounds, which contribute to its diverse biological activities such as antibacterial, antioxidant, and antifungal effects. Clove EO has demonstrated antiproliferative activity against multiple cancer cell lines, including HTh-7 thyroid cancer, HT-29 and Caco-2 CC, HepG2 liver cancer, and MCF-7 breast cancer cells. Notably, the EO exhibited stronger anticancer effects than its primary constituent, eugenol, suggesting a possible synergistic interaction with other minor components [4].

Carnosic acid (CA), a phenolic diterpenoid abundantly found in plants of the Lamiaceae family, has gained significant attention for its strong anticancer potential and low toxicity profile. Extensive in vitro and in vivo studies have identified a wide range of molecular targets influenced by CA, including enzymes, kinases, apoptotic regulators, transcription factors, growth factors, oncoproteins, tumor suppressor genes, and various receptors. These targets are associated with key processes such as cell proliferation, survival, angiogenesis, migration, and invasion, positioning CA as a promising agent for cancer prevention and therapy [54].

Barni et al. (2012) demonstrated that CA, derived from Rosmarinus officinalis, inhibited the proliferation of Caco-2 CC cells by inducing apoptosis and suppressing cell adhesion, migration, and proteolytic enzyme activity. These effects were likely mediated through the downregulation of COX-2 mRNA expression. The study suggested that CA may influence multiple signaling pathways involved in cancer cell growth and death, supporting its potential use as a chemopreventive or chemotherapeutic agent in CC [55].

Petrocelli et al. (2021) demonstrated that eugenol, an allylbenzene, and cinnamaldehyde, a phenylpropanoid, exhibit specific antitumor effects against CC cells within defined dosage and exposure timeframes. In their study, treatment with cinnamaldehyde and eugenol for 72 h induced apoptosis, necrosis, and cell cycle arrest in Caco-2 and SW-620 CC cell lines, while showing no cytotoxic effects on the normal colonic cell line NCM-460. These findings suggest that, when combined with targeted delivery to the colon, both compounds hold promise for CC prevention or therapy [34].

Research has indicated that plant-derived compounds tend to be less effective when used as isolated molecules. The concept of drug synergism—enhancing therapeutic impact through combination therapies—has gained significant interest. Co-administering conventional drugs with plant-derived BACs can enhance their cytotoxic effects against cancer cells or cell lines, improving overall treatment efficacy [24].

Drug resistance to existing therapies is the main reason for patient mortality. Overcoming this resistance is crucial to improving survival. Combining natural compounds with targeted therapies has shown promise in enhancing clinical efficacy while minimizing side effects. Bioactive natural compounds from EOs, for example, exhibit anticancer effects both in vitro and in vivo through various mechanisms [56]. When used alongside conventional treatments, these compounds can enhance therapeutic sensitivity, allow for lower drug dosages, reduce resistance, and mitigate adverse effects. This approach holds significant potential as a therapeutic strategy for managing the progression and metastasis of CC [1]. Certain specific EO components have been thoroughly investigated in vitro and in animal models, demonstrating notable anticancer properties when used in conjunction with chemotherapy drugs.

β-Elemene, a bioactive compound derived from plants of the Curcuma genus (Zingiberaceae family), has demonstrated significant anticancer properties. It is a sesquiterpene compound derived from turmeric that modulates the expression of several key molecules that play critical roles in tumor angiogenesis and metastasis [57]. According to Wang et al. (2022), β-elemene inhibited the proliferation of CC cells by inducing cell cycle arrest at the G2/M phase. It also triggered hallmark features of apoptosis, including nuclear chromatin condensation, externalization of phosphatidylserine on the cell membrane, and reduced mitochondrial membrane potential. In addition to its pro-apoptotic effects, β-elemene elevated intracellular ROS levels, suggesting a role in regulating metabolic stress pathways. In in vivo studies, β-elemene treatment led to a reduction in tumor volume and induced both apoptosis and autophagy in xenograft models using nude mice [58].

The study of Chen et al. (2020) comprehensively evaluated the role of β-elemene in inducing ferroptosis and enhancing the sensitivity of Kirsten rat sarcoma (KRAS)-mutant CC cells to cetuximab. In vitro experiments demonstrated that the combination of β-elemene and cetuximab triggered ferroptotic cell death in KRAS-mutant CC cell lines HCT116 and LoVo. In vivo results further confirmed that this combination inhibited tumor growth by promoting ferroptosis and reduced cancer cell migration through modulation of epithelial–mesenchymal transition. These findings highlight β-elemene as a potential ferroptosis inducer and suggest that its combined use with cetuximab may offer an effective therapeutic approach for CC patients harboring KRAS mutations [59].

Although EOs and their BACs exhibit remarkable biological properties, several challenges (Figure 2) hinder their widespread use in clinical settings and therapies.

The direct application of EOs in their free form is often limited by several critical factors. These include their low stability and vulnerability to degradation through volatilization and/or oxidation when exposed to environmental stressors such as oxygen, light, and temperature. EOs also exhibit poor water solubility and may interact unfavorably with food components or pharmaceutical compounds [60]. Oxygen exposure in particular has been shown to cause significant physicochemical and compositional changes in EOs, compromising their stability, quality, and functional properties. Temperature similarly affects EO stability, as higher temperatures tend to accelerate chemical reactions and degradation processes [61]. Light exposure can further exacerbate the instability of EOs, negatively influencing both their integrity and functional efficacy [62]. Another key limitation in EO application arises from its potential interactions with food constituents such as proteins, lipids, and other bioactive molecules. These interactions can diminish their effectiveness and hinder their practical use [63]. To address these challenges, innovative delivery systems—such as microencapsulation and nanoencapsulation—are being developed to enhance the stability, bioavailability, and overall effectiveness of EOs [60].

4. Encapsulation Strategies for Colon-Targeted Delivery of EOs and Their Bioactive Compounds: Advantages, Limitations, and Progress by Incorporating Essential Oils into Specific Colon-Targeted Drug Delivery Systems

Free EOs are typically administered orally by diluting them in milk, olive oil, or other vegetable oils. However, encapsulated EOs are more commonly used for oral intake, particularly in food supplements and functional foods [64]. It is believed that the biological effects of microencapsulated EOs differ from those of conventional EOs, owing to the influence of microencapsulation technology. Encapsulation of EOs or their isolated bioactive constituents allows for targeted and controlled release, protects the oils from degradation and loss, and helps to mask their often unpleasant taste and odor during consumption [65].

Encapsulation of EOs involves enclosing the oils within a uniform or composite matrix—often referred to as a shell, wall, or carrier material—at either the micro or nano size [60]. While the terms “nano” and “micro” generally refer to sizes ranging from 1 to 1000 nm and 1 to 1000 μm, respectively, in practice, nanoencapsulation typically produces capsules between 1 nm and several hundred nanometers in diameter, whereas microencapsulation results in capsules ranging from 1 μm to several hundred micrometers [66]. Encapsulating EOs has emerged as a preferred strategy to enhance their medical efficacy. The bioavailability of both the encapsulating matrix and the EO components is complex, requiring careful consideration of the stability of micro- or nanoencapsulated carriers within the GIT, as well as their potential to improve systemic absorption and therapeutic efficacy at the site of action [64,65].

This encapsulation process shields EOs from harmful environmental conditions such as oxidation, evaporation, and degradation. Thanks to their reduced size and increased surface-area-to-volume ratio, microparticles (MPs) and nanoparticles (NPs) enhance the bioavailability of EOs and enable more efficient diffusion to target sites—for example, targeted delivery to the colon. Additionally, encapsulation requires smaller quantities of EOs, which helps to minimize potential toxicity and lower production costs [60,67]. Encapsulation serves to limit the interaction between the core substance and its surrounding environment, thereby reducing the evaporation or loss of core compounds. It also enhances the handling and stability of the encapsulated material, enables controlled release, minimizes unwanted odors and off-flavors, and promotes uniform dispersion of the active ingredient within food products [68]. One of the major challenges associated with plant-derived compounds, particularly EOs, is their limited bioavailability. EOs generally exhibit poor solubility in systemic fluids, which can cast doubt on their therapeutic potential. Moreover, many EOs are unstable in physiological conditions, hindering their ability to reach cancer cells at effective concentrations [24].

EO encapsulation requires the use of a wall or carrier material. A wide variety of substances can serve this purpose, including gums (sodium alginate), carbohydrates (starches, cellulose derivatives), chitosan, lipids (including stearic acid, waxes), polymethylmetacrylates, and proteins (albumin, casein), among others. Several techniques are employed for encapsulation, including spray drying (atomization), coacervation, nano-/microemulsions, nanoprecipitation, high pressure, homogenization, coatings, freeze-drying, in situ polymerization, supercritical fluid, and others [69].

The encapsulation approach enables controlled and sustained release of EOs over time, thereby improving their therapeutic performance. The primary objective is to develop advanced delivery systems that not only regulate the release of EOs but also enhance their physical stability, minimize off-target effects, reduce volatility, improve therapeutic activity, lower toxicity, and ultimately increase patient compliance and convenience [70]. Sustained-release formulations can help maintain EO concentrations within the therapeutic window for extended periods, thereby boosting treatment effectiveness [71]. Encapsulated EOs can be released through various mechanisms, such as mechanical stress, temperature fluctuations, diffusion from MPs and NPs, and stimuli-responsive triggers—including pH changes, nanocarrier biodegradation, or dissolution [9].

One potential challenge in using these compounds to prevent CC is ensuring their selective release into the colon at appropriate concentrations. This is complicated by the fact that, physiologically, they are quickly absorbed in the small intestine after ingestion and tend to have short half-lives in the bloodstream due to rapid liver metabolism [34]. Targeted delivery to the ileo-colon region is a highly effective strategy for the localized treatment of various bowel disorders, including ulcerative colitis, Crohn’s disease, and CC. Moreover, delivering sensitive compounds—such as proteins, peptides, and EOs—specifically to this region can significantly enhance their systemic bioavailability [72]. To achieve this, colon-specific drug delivery systems (CDDS) must be designed to protect EOs from degradation in the acidic environment of the stomach and the enzymatic activity of the small intestine, ensuring that release and absorption occur primarily upon reaching the colon [73]. Targeted drug delivery to the colon enhances drug concentration at the disease site, allowing for lower doses and consequently reducing side effects [74].

The GIT’s complex physiology—including variable pH levels, fluid volumes, and transit times—can significantly impact the performance of such systems. These factors vary both between and within individuals, and are further influenced by the presence of food and digestive enzymes, adding to the complexity [73]. Numerous studies have demonstrated that the colon is an effective site for the absorption of drugs and biologically active compounds, largely due to its lower enzymatic activity, which reduces the risk of degradation. Designing CDDS involves several challenges and limitations, as the oral dosage must go through the entire GIT before reaching its intended site of action. As a result, the primary objective of CDDS is to protect active substances from the harsh acidic environment of the stomach and enzymatic hydrolysis in the duodenum and jejunum [75]. Traditional oral dosage forms are largely ineffective for delivering substantial amounts of BACs to the colon, as these compounds are often absorbed or degraded in the upper segments of the GIT. Oral CDDS systems are designed to minimize or prevent drug release in the upper GIT, ensuring targeted delivery to the colorectal region for either local or systemic therapeutic effects. To achieve effective colon targeting, it is essential to consider the physiological conditions that influence drug delivery in this region. To overcome these barriers, several colon-targeting strategies have been developed, including pH-sensitive systems, time-dependent release mechanisms, microbiota-triggered delivery systems, and osmotically controlled CDDS [72,76,77], which will be discussed in greater detail in the following paragraphs. Some of them have been developed that exploit physiological conditions of the gastrointestinal tract, specifically the elevated luminal pH of the ileum and the enzymatic activity of the colonic microbiota. These microbial enzymes include pectinase, amylase, dextranase, glycosidase, and azoreductase [72]. The dynamic physiological conditions of the gastrointestinal tract, coupled with pathophysiological alterations at disease sites, pose significant challenges for the rational design of colon-targeted formulations. Such variability often compromises site-specific delivery, resulting in suboptimal in vivo performance. For instance, fluctuations in luminal pH, influenced by both intrinsic and extrinsic factors, can markedly reduce the reliability of pH-dependent systems, leading to premature drug release in the upper gastrointestinal tract or incomplete release at the target site [78]. Each approach for colon-targeted delivery offers unique benefits and limitations, but combining two or more strategies is a promising way to overcome individual drawbacks and enhance the overall efficiency of colon-targeted drug delivery [79].

What makes it possible to encapsulate and deliver EOs and their BACs directly to the colon? This is primarily enabled through the use of specialized polymers. Which polymers are specific for targeting the colon? The most widely employed are pH-sensitive polymers, followed by biodegradable polymers such as azopolymers, which remain stable throughout the gastric and small intestinal environments but undergo enzymatic cleavage in the colon through azoreduction mediated by azoreductase enzymes produced by the resident colonic microflora (e.g., azobacteria) [80].

Among pH-sensitive excipients, methacrylic acid copolymers (Eudragit^® series) are the most extensively utilized. Their dissolution profiles are pH-dependent: Eudragit^® L100 dissolves at pH 6.0, Eudragit^® S100 at pH 7.0, Eudragit^® L30D at pH 5.6, Eudragit^® FS30D at pH 6.8, and Eudragit^® L100-55 at pH 5.5 [81]. These polymers can be applied either individually or in combination to develop CDDS. Additional enteric pH-responsive polymers include polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate [82].

Another class of carriers comprises polysaccharide-based matrices, which resist degradation in the upper gastrointestinal tract but undergo enzymatic hydrolysis upon exposure to colonic microbiota. Representative polysaccharides for CDDS include amylose, guar gum, pectin, chitosan, inulin, cyclodextrins, chondroitin sulfate, dextrans, and locust bean gum [83].

Time-dependent systems provide an alternative targeting strategy by delaying drug release until the formulation reaches the colon [84]. While gastric emptying is highly variable, small intestinal transit is comparatively consistent, enabling the design of chronotherapeutic systems that resist gastric acidity and release the drug following a predetermined lag phase corresponding to orocecal transit [85].

In addition to conventional polymeric approaches, several patented delivery technologies—such as Phloral^® Technology, CODES^® Technology, and Opticore^® Technology—have been developed [86]. These systems integrate polymers with complementary mechanisms of action to enhance robustness and precision in colonic targeting.

4.1. Microencapsulation Approaches

Microencapsulation is described as the process of coating drugs or BACs within a homogeneous or heterogeneous matrix to form small capsules. This encapsulation protects the core material and can facilitate its controlled release [87].

This technique was initially developed to shield active ingredients from environmental and external factors. Microencapsulaton approach holds significant importance in the pharmaceutical field for several key reasons: it protects bioactive ingredients from environmental factors such as heat, humidity, air, and light; it helps preserve their bioactivity; it improves ease of handling; it enables controlled release under specific conditions; it masks unpleasant tastes and odors; and it allows for precise dosing, especially when working with small quantities of active compounds [88]. In oil microencapsulation, emulsification is a crucial step in which BACs are typically dispersed within an aqueous solution. The process typically begins with emulsifying or dispersing the oils in an aqueous solution containing a wall material that also serves as an emulsifier. This forms an emulsion, which is the basis for obtaining the final microstructures. Nevertheless, the primary purpose of encapsulating an active ingredient is to achieve controlled release, as already said [89]. Over time, however, the ability to achieve controlled release has become a key focus in the advancement of encapsulation technologies. These techniques are generally categorized into chemical, physicochemical, or mechanical methods. Some of the most widely used approaches for protecting lipid-based compounds include coacervation, spray drying, liposome formation, fluid bed spray coating, and emulsification followed by solvent evaporation or extraction [88]. Microencapsulated structures can be classified into two types: microcapsules or microspheres. This division refers to polymers and methods used in the process of microencapsulation. Common wall materials used in microencapsulation include carbohydrates (such as starches, cellulose, and chitosan), gums (like sodium alginate and carrageenan), lipids (including waxes, oils, and fats), and proteins (such as casein and peptides) [87].

Microspheres can be obtained in a range of sizes, from micrometers to millimeters. Their small size provides a larger surface area, giving them an advantage in drug delivery [90]. Most micro-scale carriers designed for colon-targeted therapy fall within a size range of 10–300 μm. Their enhanced therapeutic effectiveness is largely due to reduced EOs absorption in the small intestine and slower transit through the colon, aided by the streaming effect [91]. As already mentioned, by integrating various controlled release strategies—such as polymeric or swellable matrices, enzymatic degradation of the carrier, and pH-responsive coatings—these systems can enhance colon-specific EOs delivery. However, this complexity also brings a heightened risk of incomplete EOs release, particularly due to individual variations in gastrointestinal physiology [92].

4.2. Nanoencapsulation Approaches

Nanoencapsulation technology presents both a significant challenge and a promising opportunity for the delivery of EOs. Due to their subcellular dimensions, nanocarriers can enhance the bioactivity of EOs by enabling deeper tissue penetration and facilitating cellular uptake. Additionally, they offer the ability to control and modulate the release of active compounds at the targeted site [93]. The size and shape of NPs play a crucial role in the effective delivery and penetration of the bioactive compound. NPs can be engineered in various forms, such as spheres, nanotubes, nanorods, nanoflowers, nanostars, and nanoprisms, to enhance therapeutic outcomes. Among these, spherical NPs have demonstrated superior penetration into cancer cells. Research shows that NPs ranging from 10 to 400 nm can effectively pass through cancer cell membranes, while larger NPs—over 500 nm—can still enter cells via endocytosis [19]. Various EO delivery strategies have been used for cancer therapy, including the use of polymeric nanocarriers (dendrimers, micelles, and nanofibers), metallic nanocarriers (magnetic and gold NPs), and carbon-based nanocarriers (multi-wall carbon nanotubes and graphene), as well as lipid-based systems such as liposomes, solid lipid NPs (SLNs), and nanoemulsions (NEs) [10]. Among these, NEs are the most straightforward and cost-effective to formulate and handle [94]. NEs are created by mixing two immiscible liquids to form a heterogeneous system in which the dispersed droplets are smaller than 1000 nm [9]. NEs offer numerous benefits according to their unique properties, such as a high surface area and small droplet size, including enhanced solubility and bioavailability, improved stability, increased dispersibility of hydrophobic drugs, and better sustainability [95]. Unlike traditional emulsions, which typically appear milky, NEs are generally translucent [96]. Some studies have shown that liposomes have become increasingly prominent as carriers for antitumor drugs or BACs. Despite their potential, only a limited number of liposomal drug formulations have successfully reached the market, highlighting the significant challenges in translating liposome technology from laboratory research to clinical practice [97]. One of the most critical issues is the stability of liposomes, which directly impacts drug loading, permeability, and release rates during formulation, storage, and metabolism [98]. Their inherent physical and chemical instability poses a major barrier to clinical application. The liposomal membrane, composed of dynamic phospholipid bilayers, is prone to constant transmembrane movement, which can cause particle aggregation, sedimentation, and ultimately lead to structural instability. Chemically, liposomes are vulnerable to degradation through phospholipid oxidation and hydrolysis, two primary factors contributing to their instability [99]. Additionally, finding suitable sterilization methods for liposomal formulations remains a significant technical challenge in their development for medical use. SLNs were introduced in the 1990s as a novel system for encapsulating lipophilic drugs, offering an alternative to traditional lipid-based carriers like emulsions and liposomes [25]. SLNs provide several key advantages, including excellent physical stability, high drug loading capacity, controlled drug release, and the potential for surface modification to enable both passive and active targeting of cells [100]. Being biocompatible, non-toxic, and suitable for large-scale production makes them especially attractive for pharmaceutical applications. Furthermore, incorporating liquid lipids—such as EOs—into the solid lipid matrix leads to the formation of nanostructured lipid carriers [101]. This modification enhances the system’s stability, drug loading efficiency, and encapsulation capacity while minimizing drug expulsion during storage [25].

In healthy tissues, NPs are generally unable to enter or accumulate within cells because of the intact cell membrane, tight cell junctions, and efficient lymphatic drainage [102]. However, tumor cells disrupt the normal physiological environment as they grow and invade the surrounding tissue. This disruption leads to several abnormal changes, including damage to cell membranes, development of hypoxic (low oxygen) regions, initiation of new blood vessel growth (angiogenesis), increased tissue permeability, and impaired lymphatic drainage [103]. These changes create a unique tumor microenvironment that NPs can exploit. By taking advantage of the enhanced permeability and retention (EPR) effect in tumors, NPs can more effectively and passively deliver their therapeutic cargo to cancer cells [10]. Nanoparticle-based drug formulations typically require lower doses than conventional therapies. Additionally, NPs tend to be taken up by macrophages at sites of inflammation in the colon, which helps retain the drug at the target site for an extended period [79].

Nano-scaled drug delivery systems face several challenges in reaching their target site. However, one of the key advantages of NPs as drug delivery systems is their ability to release drugs in a controlled, pH-dependent manner. This feature helps maintain drug stability as they pass through varying pH environments in the GIT [104]. Additionally, encapsulating active compounds within nanocarriers protects them from enzymatic degradation by intestinal microbiota, which could otherwise bind to and break down bioactive molecules, reducing their pharmacological effectiveness [105]. Their surface properties can be customized—such as by adjusting their charge—to target specific conditions like colonic diseases. For instance, polycationic NPs can bind to inflamed intestinal tissues, while polyanionic NPs can interact with positively charged molecules such as cytokines found in CC [79]. It has been shown that negatively charged NPs with a diameter of 200 nm or smaller can more effectively cross the intestinal mucosal barrier [106].

4.3. Comparison Between Micro- and Nano-Scaled Colon-Targeted Delivery Systems

Microparticles (MPs) in particular tend to exhibit mucoadhesive properties, allowing them to adhere to the intestinal mucosal surface, though their absorption across the epithelial barrier remains limited. Studies have reported the accumulation of MPs in the rectal mucosa of patients, whereas NPs were detected only in minimal amounts at that site. In contrast, NPs can penetrate the systemic circulation, enabling them to exert systemic effects [73]. Compared to MPs, NPs offer a significantly larger surface area and greater flexibility for surface modification, which enhances their ability to deliver antitumor drugs to targeted sites while reducing the risk of opsonization. Moreover, NPs improve drug diffusion and accumulation within tumor cells by leveraging the EPR effect [75]. Most nanomedicines typically exhibit a low drug-loading capacity (less than 10%), which poses challenges for clinical translation. Consequently, there is growing interest in nanomedicines with drug loadings exceeding 10% [9]. One of the key features of NPs is their biocompatibility and high bioavailability, making them appropriate for drug delivery in cancer therapy. A major challenge in current cancer treatment is efficiently delivering drugs into cancerous cells—a task that is difficult for larger molecules. To penetrate the cancer cells, the carrier structure must be small, and NPs offer an advantage due to their nano-scale size, which allows easier cellular entry [19]. However, smaller particles may penetrate more deeply into the tissue, passing beyond the epithelium into the submucosa, where they tend to remain for longer periods. Previous studies have demonstrated that accumulated NPs in the colon can remain in cancerous regions for several days. A sustained release over this period appears beneficial for establishing a reservoir of EOs at the target site [91].

Ultimately, both micro- and nanoencapsulation techniques can significantly improve the physicochemical properties and stability of EOs by enhancing their water dispersibility, reducing volatility, and protecting them from environmental degradation [107]. Furthermore, nano- and micro-particulate carriers offer considerable promise for improving both colonic targeting and mucosal uptake. Therefore, this review focuses precisely on them as an alternative strategy for delivering EOs and their BACs to the colon. Consequently, formulation strategies incorporating particle size reduction are increasingly recognized as advantageous for enhancing the therapeutic efficacy of CDDS [108]. Figure 3 represents a comparison between micro- and nano-scaled carriers.

Developing EOs micro- and nano-scale delivery systems for colon targeting, using various strategies, presents a promising approach for colon-specific therapy by enabling controlled EOs release and enhanced therapeutic outcomes. However, the release of EOs should not be considered the ultimate goal of these delivery systems. Since the colon naturally tends to expel metabolites rather than absorb them, further research is needed, focusing especially on the uptake of specific BACs within the colonic environment [90].

5. Advanced Micro- and Nano-Delivery Systems for Colon-Specific Targeting of Essential Oils and Their Bioactive Compounds

As already noted, micro- and nanotechnology-based strategies have great potential for delivering EOs or their BACs directly to the colon, maximizing their therapeutic benefits while minimizing systemic side effects. These advanced approaches exploit the unique characteristics of polymers and the preparation method to encapsulate EOs, protect them from degradation, and provide targeted release in the colon with the potential to treat or prevent CC. Many studies have demonstrated the incorporation of EOs or their bioactive components into micro- and nanostructures, some of which are presented in Figure 4 and described below.

Zhai et al. (2022) developed polyethylene glycol (PEG)ylated β-elemene (from Curcuma, Zingiberaceae) liposomes and evaluated them for antitumor activity [109]. Rodenak-Kladniew et al. (2023) explored the encapsulation of EOs derived from Clinopodium nepeta and Lippia alba into SLNs. Their study aimed to improve the anticancer efficacy of these EOs by incorporating them into biocompatible lipid-based carriers [25]. Waad A. Al-Otaibi (2022) developed an NE containing EO derived from Teucrium polium [32]. Parvez et al. (2022) prepared nerolidol-loaded SLNs by the emulsion solvent evaporation method [110]. Poyatos-Racionero, E et al. (2021) prepared lactose-gated mesoporous silica MPs loaded with cinnamaldehyde [111]. Josef Jampilekk et al. (2022) formulated cuminaldehyde-loaded SLNs [95]. Rassu et al. (2014) developed alginate and soy protein isolate-based microspheres with thymol [112]. Berraaouan et al. (2023) formulated calcium alginate and calcium alginate/montmorillonite hybrid microcapsules with Romarinus officinalis EO [113]. Turasan et al. (2015) used the freeze-drying encapsulation technique for microencapsulation of rosemary EO with two coating materials—maltodextrin and whey protein—in different coating ratios [114]. Alshahrani et al. (2022) synthesized gold NPs loaded with Rosmarinus officinalis EO [115]. Szentmiklósi et al. (2024) encapsulated Lavandula officinalis EO into gum arabic and gelatin type A microcapsules [116]. Alencar et al. (2022) encapsulated Cymbopogon citratus EO into microcapsules [117]. Szentmiklósi et al. (2024) loaded Achillea millefolium EO into microcapsules [118]. Dima et al. (2014) synthesized microspheres with Pimenta dioica EO [119]. Wang et al. (2024) formulated gelatin–sodium alginate-based microcapsules loaded with Origanum vulgare EO [120]. Alirezaei et al. (2022) encapsulated Artemisia vulgaris L. EO into Poly(lactic-co-glycolic acid)-based NPs modified with chitosan-folic acid [121]. Keshavarz et al. (2024) investigated the apoptotic and antiproliferative effects of thymol-loaded nanoliposomes [122]. Nosrat et al. (2022) encapsulated Ferula gummosa EO into an NE [123]. Abadi et al. (2022) prepared an NE system containing the EOs of clove (Syzygium aromaticum L.) [124]. Khatamian et al. (2019) developed an NE containing carvi EO and evaluated its anticancer effects on HT-29 human CC cells, focusing on its ability to induce apoptosis. Their findings showed that the nanoformulations significantly reduced the viability of HT-29 cells, suggesting selective toxicity. Moreover, treatment with the NEs led to a marked upregulation of caspase-3 expression, indicating strong pro-apoptotic activity in the cancer cells. Khatamian et al. proved that an NE of carvi oil enhanced its anticancer effect against human CC cells [125].

The research conducted by Wijewantha et al. (2023) focuses on the preparation of enzyme-responsive NPs encapsulating eugenol (eNPs–EUG), aiming to develop novel antimetastatic therapies. Eugenol (2-methoxy-4-(2-propenyl)phenol), a natural phenolic compound primarily found in clove oil (Syzygium aromaticum L., Myrtaceae), has long been used in traditional Asian medicine for its antimicrobial, antioxidant, anti-inflammatory, antiseptic, and analgesic properties. More recently, it has gained attention for its pro-apoptotic and antiproliferative effects against various cancers, including CC. However, eugenol’s clinical utility is hindered by its rapid metabolism, quick excretion, and toxic effects on normal cells at high doses. To overcome these limitations, Wijewantha and colleagues engineered “smart” eNPs–EUG, designed to deliver high concentrations of the drug directly to tumor cells while minimizing exposure to healthy tissues. Their findings show that eugenol triggers apoptosis in CC cells across different tumor grades in a dose- and time-dependent fashion. Moreover, it effectively suppresses cancer cell migration, invasion, and the population of CC stem cells—key drivers of metastasis and chemoresistance. These engineered NPs demonstrated selective uptake by cancer cells with rapid internalization, while showing minimal interaction with healthy colon epithelial cells. Overall, eNPs–EUG significantly enhances the therapeutic impact of eugenol [126].

6. Advanced Drug Delivery Systems’ Potential to Improve the Outcomes of CC Treatment

6.1. Cytotoxicity Evaluation of Novel EO’s Drug Delivery Strategies in CC Cell Lines

Salihu et al. (2025) investigated the cytotoxic activity of Thymus capitatus and Origanum vulgare EOs against MCF7, DU145, and HT-29 cancer cell lines, both in their free form and after encapsulation in NEs produced via high-pressure homogenization. The researchers successfully developed stable NEs characterized by high encapsulation efficiency, minimal phase separation, and small droplet sizes. For the HT-29 CC cells, treatment with T. capitatus NE and O. vulgare NE reduced cell viability to approximately 28% and 26%, respectively, with highly significant effects (p < 0.001). Overall, encapsulated oils demonstrated superior cytotoxicity compared to their unencapsulated form. Notably, T. capitatus NE showed stronger anticancer activity than O. vulgare NE, highlighting its greater potential as a cytotoxic agent [127].

Saffari et al. (2023) explored the anticancer potential of an NE formulated with Rosa damascena EO NE. The prepared NE exhibited IC₅₀ values of 3.31 µg/mL against HCT116 colon cancer cells and 4.6 µg/mL against HeLa cervical cancer cells, indicating greater sensitivity of CC cells compared to HeLa cells [128].

Almnhavy (2020) investigated the development of poly(lactic acid)-based NPs loaded with Trachyspermum ammi seed EO. The NPs were prepared using evaporation and ultrasound-assisted emulsification techniques. Experimental findings revealed that prepared NPs induced apoptosis in HT-29 colon cancer cells, as evidenced by the upregulation of pro-apoptotic genes (Caspase-9 and BAX), downregulation of the anti-apoptotic gene (BCL-2), and flow cytometry analysis showing increased apoptosis with higher doses. Furthermore, the prepared NPs demonstrated a significant dose- and time-dependent cytotoxic effect on HT-29 cells. The anticancer effects of the prepared NPs were attributed to three main mechanisms: reduction in oxidative stress, induction of apoptosis, and inhibition of angiogenesis [129]. This study proved the advantages of the presented EO-loaded nanocarrier as a successful targeted agent against CC cell lines.

In the study by Moghimipour et al. (2023), thymol was successfully encapsulated into solid lipid nanoparticles (SLNs). The resulting SLNs have a mean particle size of 145 nm and an encapsulation efficiency % of 63%. In vitro release experiments demonstrated a sustained release profile of thymol from the SLNs. Moreover, thymol-loaded SLNs (Th-SLNs) exhibited significantly higher cytotoxicity in the HT29 CC cell line compared with free thymol and blank SLNs (p < 0.05). The IC₅₀ values obtained for free thymol, SLNs, and Th-SLNs were 39.22 ± 0.9, 94.87 ± 1.1, and 7.88 ± 0.7 µM, respectively. The findings suggest that Th-SLNs are more effectively internalized by cancer cells than free thymol, likely due to differences in cellular uptake mechanisms. The enhanced efficiency of Th-SLNs may be attributed to the active endocytosis of SLNs, which facilitates greater intracellular delivery of thymol [130].

Overall, these results highlight the potential of SLNs as a promising nanocarrier system to enhance the therapeutic efficacy of thymol and other essential oil constituents in CC treatment.

6.2. Effect of Advanced Combinations of EOs and Cytotoxic Agents in the Treatment of CC

Advanced drug delivery systems offer significant promise in cancer therapy, as they can incorporate multiple anticancer agents with distinct mechanisms of action.

Similarly, Alkhatib et al. (2021) investigated the incorporation of epirubicin (EPI) into an NE formulated with algae and cinnamon oils via ultrasonication. The apoptotic potential of this formulation was evaluated in HCT116 human CC cells. Findings demonstrated that NE treatment markedly increased intracellular ROS generation and induced higher levels of late apoptosis compared to cells treated with EPI alone. Moreover, the prepared NE suppressed the invasive capacity of HCT116 cells to approximately 33%, in contrast to the 56% reduction observed with EPI treatment. Based on the antiproliferation assay, the IC₅₀ value of EPI was reported to be 8.6-fold lower than that of the prepared NE. Collectively, these results indicate that the nanoformulation enhanced the antitumor efficacy of EPI, highlighting its potential as a novel nanotherapeutic strategy [131].

As already mentioned, Al-Otaibi et al. (2022) developed and optimized an NE of Teucrium polium L. EO and evaluated its ability to enhance the sensitivity of CC cells (HCT116 wild-type and HT-29 mutant-type) to Oxaliplatin. The combined treatment with NE of Oxaliplatin and T. polium demonstrated a synergistic effect, with combination index values of 0.94 for HCT116 and 0.88 for HT-29 cells. Microscopy and flow cytometry analyses confirmed that co-treatment induced a higher proportion of apoptotic cells compared to monotherapy. Mechanistically, the combination promoted apoptosis in both wild-type and mutant p53 CC cells through ROS-mediated mitochondrial pathways. Overall, these results indicate that NEs of Oxaliplatin and T. polium may represent a promising therapeutic approach for CC management [32].

The enhanced activity of NE strategies is likely attributed to their nano-scale size, which facilitates greater cellular penetration and promotes improved accumulation at the target site [131]. The findings suggest that encapsulating EOs in NEs not only enhances their biological efficacy but also improves stability, supporting their potential application in therapeutic strategies [127]. In addition, novel drug delivery systems can be designed with imaging functions, enabling non-invasive tracking of drug biodistribution, tumor localization, and therapeutic response. Such innovations hold promise for advancing personalized medicine and optimizing treatment strategies in CC [132].

7. Future Directions

EOs have long been utilized in medicine for their anti-inflammatory, antioxidant, and anticancer properties. Their BACs represent a valuable source of anticancer agents and plant-based therapeutics. The current technological focus is on developing intelligent EOs microcapsules capable of multiple reactions and containing distinct compartments that can simultaneously respond to diverse external stimuli (for example, pH- or time-responsive stimuli). Moreover, enhancing the retention of EOs and their BACs within microcapsules—particularly under environmentally triggered conditions—remains a critical challenge. Future research should explore innovative approaches to achieve sustained release and improved retention of EOs and their BACs within these systems [133]. With continued research, EOs hold promise for incorporation into pharmaceutical formulations, and several are already in various stages of clinical trials. Preliminary studies suggest that whole EOs often exhibit greater effectiveness than their isolated components. However, their full therapeutic potential remains underexplored, largely due to challenges such as the lack of targeted delivery mechanisms. As research into the anticancer applications of EOs is still in its early phases, further investigation—including well-designed clinical trials and the development of advanced, organ-specific delivery systems—is essential to enhance their efficacy in cancer treatment [41].

8. Conclusions

EOs contain a wide array of diversified BACs, including terpenoids, monoterpenes, sesquiterpenes, and other aromatic constituents, and have shown great promise for anticancer therapeutic applications. However, their clinical potential is hindered by challenges such as low stability, poor bioavailability, high volatility, and lack of targeted delivery. This review provides a comparison of micro- and nanocarriers loaded with EOs or their BACs, highlighting their potential as a promising strategy for CC prevention and treatment. However, preclinical research on EOs as anticancer agents remains limited, and many EOs still require thorough safety and toxicity evaluations before advancing to clinical trials. As previously noted, numerous EO-based micro- and nanoformulations have shown promising anticancer activity in vitro; however, substantial progress is still needed before these traditional compounds from folk medicine can be successfully registered and utilized as approved anticancer drugs.