Nanomedicine Strategies in the Management of Inflammatory Bowel Disease and Colorectal Cancer

1. Introduction

1.1. The Gut Microbiota

The gut microbiome is a complex and dynamic system that originates from vertical transmission from the mother in the uterus, with full-term infants developing extensively colonised gut microbiome [1]. The gut receives a constant stream of microbes, which compete for resources and evade the host immune system to colonise the gut [2]. It is colonised by humongous populations of trillions of microorganisms, of which Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, Tenericutes, Actinobacteria, and Verrucomicrobia dominate [3]. The altering gut microbiome has great inter-person variability and undergoes extensive changes with age [4]. Many factors play a role in affecting its composition, including the host’s diet [5], genetics, and immune response [6]. The idea of a healthy gut microbiome is thus hard to define, with possible definitions being one with a stable microbiome community that can resist environmental stresses or a state where important metabolic pathways are preserved [7].

The gut microbiome plays an essential role in maintaining the health of the gastrointestinal tract (GIT). It maintains a thick mucus layer to prevent colonisation of the gut by foreign pathogens [8] and competes for both nutrients and attachment sites on the intestinal walls, preventing pathogen invasion [2,9]. It also promotes the production of antimicrobial molecules [10]. Another key role of the gut microbiome is immunomodulation, as the gut microbiome presents a vast amount of antigens to the immune cells of the mucosa. A fine balance is required to maintain between tolerating the gut microbiome and controlling bacterial microbiome overgrowth [2]. Apart from regulating the local immune response, the gut microbiome also influences the host’s systemic immune responses [10]. The gut is the largest reservoir the immune system actively samples antigens from, and its microbiome is suggested to influence the initiation, progression and severity of autoimmune diseases, including rheumatoid arthritis [11] (Figure 1).

1.2. Gut Dysbiosis

Gut dysbiosis has been described as the disruption of the symbiotic balance between the microbiota and host [12]. It is due to frequent changes to the environment or host related factors [13] that overpowers resistance and protective capabilities of the microbial system in the gut [14]. The host’s diet and antibiotic consumption are 2 major factors that contribute to gut dysbiosis. The gut microbiome is greatly affected by long-term dietary changes, with individuals from different communities having very different gut microbiomes [15]. Different proportions of carbohydrates, proteins, fats, food additives, and cooking methods exert different effects on the gut microbiome [5]. For example, animal-based diets result in a gut microbiome with more bile-tolerant bacteria such as Bacteroides, Alistipes and Biophilia [16,17], but decreases plant polysaccharide-fermenting Firmicutes including Roseburia, Eubacterium rectale, and Ruminococcus bromii [16]. Acute changes in diet can also affect the gut microbiome, with plain plant-based or animal-based diets for 5 days having a significant impact on microbial community structures [16]. Pathogens also trigger gut dysbiosis, where enteric pathogens have the greatest potential to cause microbial dysbiosis in mouse models [18], while foodborne viruses trigger local and systemic inflammation that alters microbial composition [19]. Alteration of the gut microbiome can also promote the growth of unfavourable microbiota that disrupt the intestinal barrier [20], allowing the entrance of hazardous chemicals and promoting systemic inflammation that can cause inflammatory bowel disease (IBD) [21].

The gut microbiome is also severely impacted by the administration of antibiotics, where broad-spectrum antibiotics can affect the abundance of 30% of the bacteria in the gut community, resulting in a marked decrease in taxonomic diversity and richness [22,23]. Antibiotics also alter the gut microbiota’s gene expression, protein activity, and overall metabolism [24,25]. For instance, it has been found that the use of beta-lactams in a host alters carbohydrate degradation and sugar metabolism to mimic that of an obese individual [26]. These antibiotic induced microbiota alterations can remain after long periods of time, ranging from months to years [27]. Notably, another study revealed that mice who were administered antibiotics suffered gut dysbiosis that eventually resulted in cognitive impairment [28]. Other causative factors of gut dysbiosis include host factors such as stress or infections [29].

2. Gut Dysbiosis in Pathogenesis of Diseases

Previous studies have shown that gut dysbiosis has profound implications on health and contributes to the pathogenesis of a range of diseases.

2.1. Gut Dysbiosis in Inflammatory Bowel Disease (IBD)

Gut dysbiosis has been found to play a key role in the pathogenesis of IBD [30], with patients exhibiting a reduced microbial population, functional diversity and microbiome stability [31]. The differing gut microbiota plays a key role in altering the metabolic pathways in the gut– though IBD patients only have a 2% difference in genus level clades, their metabolic pathways have a 12% difference when compared to a healthy individual [32]. Expression of genes related to oxidative stress and sulfate transport were found to be increased in IBD patients [32], and processes including bile acid modification and short chain fatty acid (SCFA) modification also altered in the intestinal microbiome of IBD patients [33,34,35] (Figure 1). These findings support that gut dysbiosis plays a role in the pathogenesis of IBD and is not merely an observed state as a result of the disease.

2.2. Gut Dysbiosis in Colorectal Cancer (CRC)

Changes in the gut microbiome also participate in the development of a substantial number of GIT malignancies [36,37], with links between gut dysbiosis and colorectal cancer (CRC) being found [38,39]. One mechanism involves the gut microbiome inducing genotoxic stress or producing metabolites that promote genetic and epigenetic alterations conducive to carcinogenesis [40]. Another pathway includes modulation of SCFA levels, which can influence global chromatin architecture and subsequently affect gene expression and transcriptional regulation [41]. Butyrate, a SCFA, can modulate the apoptosis, proliferation, and invasion of several cancer cell lines, facilitating aberrant hyperproliferation of colon epithelial cells in mice [42]. Overgrowth of specific bacteria also plays a role in CRC development. Fusobacterium nucleatum directly promotes carcinogenesis when it secretes adhesin FadA that binds to the extracellular domain of E-cadherin on epithelial cells. The adhesin complex is dysfunctional and is unable to bind to beta-catenin, causing beta-catenin to translocate to the nucleus. This upregulates mitogenic signalling, thereby increasing expression of transcription factors and growth stimulation of CRC cells [43]. Bacteroides fragilis secretes the B. fragilis toxin, which cleaves E-cadherin, a tumour suppressor protein. This results in enhanced nuclear Wnt/b-catenin signalling that increases colonic carcinoma cell proliferation and expression of the protooncogene, MYC [44] (Figure 1).

3. Current Therapeutic Strategies

3.1. IBD Treatment

The conventional pharmacological therapy for IBD primarily aims to achieve and sustain remission, as well as alleviate the secondary symptoms of the disease, rather than correct the root pathogenic mechanism [45,46]. Commonly used drugs include corticosteroids, aminosalicylates, and immunosuppressive agents [47], while metronidazole and broad-spectrum antibiotics may be found useful at times [46]. Specific drugs are preferred for various aims; steroids are selected for the short-term control of moderate to severe flare-ups but unsuitable for long-term use due to their many systemic adverse effects and inability to maintain remission. At the same time, immunosuppressants, such as azathioprine, are preferentially employed in long-term therapy due to their delayed onset of therapeutic action [46].

Patients suffering from mild to moderate IBD are first treated with 5-aminosalicylic acid (5-ASA) before being given systemic glucocorticosteroids for more severe disease [48]. Azo-linked prodrugs of 5-ASA include sulfasalazine, olsalazine, and balsalazide, which are designed to deliver 5-ASA (mesalamine) specifically to the colon. These prodrugs remain intact through the upper GIT before being activated in the colon by azoreductase enzymes produced by colonic bacteria, cleaving the azo bond and releasing 5-ASA [46]. 5-ASA exerts its anti-inflammatory effects via the activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor highly expressed in colonic epithelial cells whose signalling is otherwise impaired in IBD [49]. Though 5-ASA is generally well tolerated, the most common adverse effects include diarrhoea, nausea/vomiting, headache, abdominal pain/dyspepsia, rash, fever, fatigue/weakness, arthralgia/myalgia [50].

The preferred corticosteroid therapy for IBD is prednisolone, whose administration can be done orally, rectally or in urgent emergencies, parenterally [46]. Glucocorticoids modulate immune responses by binding to glucocorticoid receptors, regulating pro-inflammatory genes and suppressing immune-controlling transcription factors like nuclear factor κB (NF-κB). They also exert rapid non-genomic effects on cell signalling and ultimately reduce immune cell activation, pro-inflammatory cytokine production and promote apoptosis in dendritic cells and T cells [48]. However, the numerous adverse effects of corticosteroids remain a concern, with long-term use impacting patients’ metabolic and endocrine functions. These include weight gain, change of fat distribution, hyperglycemia leading to diabetes, hypertension, reduced muscle and bone mass leading to osteoporosis and fractures, changes to skin with acne, cataract, glaucoma and depression [51]. There is also a pronounced risk of opportunistic infections when corticosteroids are prescribed concomitantly with other immunosuppressive drugs or biologics [52].

In patients with severe IBD or who are already steroid-resistant or dependent, immunosuppressants such as azathioprine and thiopurine derivative mercaptopurine are being used [53]. Azathioprine is a prodrug that is metabolised into mercaptopurine, which is further converted into 6-thioguanine nucleotides– the primary active compounds that suppress purine synthesis and inhibit cellular proliferation [46]. However, adverse effects are prominent, including allergic reactions consisting of fever or rash, or both, arthritis; leukopenia; pancreatitis; and nausea. In a study, they were severe enough that 27 of 302 patients had to be withdrawn from the trial [53].

Anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibodies such as Infliximab, can induce apoptosis in mucosal T cells [54], macrophages, and monocytes [55]. These antibodies are also able to modulate fibroblast function [56], decrease leukocyte migration [57], and induce mucosal regulatory macrophages [58]. However, the development of tolerance to these drugs [59] and increased frequency of serious infections are the downsides to this treatment [60]. Another antibody used is ustekinumab, a fully humanised antibody that blocks the p40 subunit of interleukin(IL)-12 and IL-23, showing consistent benefit over the placebo group treating CD and UC as both induction and maintenance therapy [61,62]. The rate of antidrug antibodies was found to be low, with the rates of adverse events occurring being similar between the group given ustekinumab and the placebo group [61].

Alternative therapies also include cholestyramine, sodium cromoglycate, bismuth, and arsenical salts, methotrexate and fish oils [46]. Though primarily established as a treatment methodology for recurrent and refractory Clostridium difficile infections, faecal microbiota transplantation (FMT) is also potentially indicated for IBD [63]. It is essentially stool transplantation, where stools from a healthy donor are transferred into another patient’s GIT to directly compensate for the gut dysbiosis present, and FMT via multiple infusions administered via the lower GIT appears very promising for IBD treatment [64].

3.2. CRC Treatment

Pre-cancerous and early-stage CRC can be removed by an endoscope, a safer and less invasive procedure than surgery [65]. For more advanced stages of CRC with liver metastases, surgical resection remains the only cure [66]. Lymph node dissection is also performed in surgery for staging and to determine the patient's prognosis [65]. While surgery is an important first line of defence, surgery has been shown to increase the mortality risk in some cancer patients by metastasis as it disrupts the integrity of the tumour [67]. Chemotherapy is used to treat CRC as well and can be used for neoadjuvant therapy, adjuvant chemotherapy, or chemotherapy for unresectable CRC [65]. Chemotherapeutic agents include cytotoxic drugs, molecular targeted drugs, and immune checkpoint inhibitors [65]. Traditional chemotherapy agents can also cause systemic effects such as nausea, vomiting, diarrhoea, and neuropathy due to their effect on other rapidly dividing cells in the body [67].

Over the past few decades, patients with CRC were treated homogeneously with the same standard chemotherapy drugs administered after surgical resection [68]. Precision medicine is set to change that, where factors including environmental, lifestyle, cancer staging, and biological characteristics will be evaluated, to identify which treatment approach will be most beneficial, improving treatment response and reducing the likelihood of side effects [69]. Drugs such as anti-vascular endothelial growth factor (VEGF) and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies [68] allow for a more targeted treatment with decreased systemic side effects. While the use of such drugs can avoid systemic side effects, they can potentially result in rash appearing in the upper body [67]. Radiotherapy is used too to treat locally advanced rectal cancer, as an adjuvant to therapy, or as palliative care to preserve patient quality of life [65].

4. Nanomedicine

Nanomedicine is an up-and-coming technology, and branch of evolving medicine that uses nanotechnology for disease prevention, monitoring and intervention through new modalities for imaging, diagnosis, treatment, repair and regeneration of biological systems [70]. Nanoparticles have unique chemical and physical properties that make them suitable for optical imaging, allowing for highly sensitive diagnostic tools with reduced degrees of invasiveness [71]. The high surface area to volume ratio of nanoparticles, combined with their ability to have surface modifications, enable them to deliver therapeutic agents to target sites more accurately, reducing unwanted side effects and thereby improving treatment efficacy [71]. Nanomedicine has revealed a promising future, with third-generation nanovectors bearing multi-functionality; externally are recognition units for nanoparticles to interact with target sites, while internally they are drug-loaded to deliver their desired therapeutic effect at the right place and time [72]. With its rapid development, nanomedicine has revealed great potential in becoming an asset to the healthcare industry by being able to overcome the limitations of traditional treatment methods. The different types of nanomedicine available and their uses in treating gut dysbiosis and its associated diseases will be discussed below.

5. Diagnostic Nanomedicine

5.1. Nanomedicine for Measuring Diagnostic Biomarkers

5.1.1. Biomarkers of Gut Dysbiosis

Nanomedicine has proven its usefulness in assisting in the detection of diagnostic biomarkers. Emerging indicators for gut microbiota health and function include indole and its derivatives, including tryptamine and indoxyl sulfate [73]. They carry out key functions in the gut, such as indole acting as an intracellular signalling molecule that enhances epithelial barrier function [74], promoting the growth of beneficial bacteria while inhibiting the growth of harmful bacteria [75]. High indoxyl sulfate levels are associated with reduced bacterial diversity and shifts in bacterial diversity and composition [76]. Due to their functional roles in maintaining a healthy gut, measuring systemic levels of indole and its related metabolites provides insight into the gut microbiota functional status [77]. Currently, indole levels are measured by mass spectrometry or high-performance liquid chromatography coupled with mass spectrometry [78,79,80] However, its potential as a point-of-care test has been limited due to the costly nature and extensive sample preparation required [81]. To combat this, a nanotip array has been proposed [77], which uses electrochemical sensing to provide a relatively low-cost alternative, requiring minimal sample preparation and also bears the potential for miniaturisation. The nanotip array provides a porous surface area for the attachment of selective capture molecules. Modification with silver (Ag) nanoparticles takes advantage of plasmonic effects to amplify electrical signals, allowing specific and sensitive quantification of indole, tryptamine, and indoxyl sulfate via cyclic voltammetry and differential pulse voltammetry. Given the nanotip’s ability to analyse serum and fecal extracts, it has become extremely attractive for point-of-care testing and bears potential for wide usage [77] (Figure 2A) (Table 1).

5.1.2. Biomarkers in CRC

More specific to CRC is a nanosensor array developed using monolayer-capped 5 nm gold nanoparticles (AuNPs), used as a breath sensor. It bears the capability to distinguish between the breaths of healthy and cancerous patients and even differentiate the types of cancers based on their specific volatile organic compounds (VOCs). This breath analysis method had an edge over breath analysis via gas chromatography linked to the mass spectrometry technique (GC-MS) due to its minimal preparation (pre-concentration or de-humidification) needed, quick and simple procedure, and insensitivity to external interrupting factors which could potentially alter the chemical composition of test subject’s breath, making it a technology that could have significant beneficial impact on cancer treatment [82] (Table 1).

5.2. Nanomedicine in Diagnostic Imaging

Nanotechnology has also proven its utility in radiography modalities through aiding in early diagnosis and improving prognosis of specific diseases.

5.2.1. Diagnostic Imaging of IBD

In IBD, the use of macrophages labelled with superparamagnetic iron oxide (SPIO) and indium (111) oxide (In₂O₃) nanoparticles enhanced magnetic resonance imaging (MRI) quality by visualising areas on the intestinal wall where signal was originally lost. The percentage of normalised enhancement at MRI correlated well with disease activity, revealing the utility and reliability of the incorporation of SPIO nanoparticles (SPIONs) in MRI -based techniques as a way to study and monitor IBD activity [83]. Another developing nanotechnology developed to target IBD is dextran coated cerium oxide nanoparticles (Dex-CeNP). Unlike iodine and barium-based contrast agents used in hospitals today, Dex-CeNP can enhance CT contrast generation and accumulate in inflammation sites, allowing for the localisation of colitis sites in mice models. They also carry the additional benefit of being able to protect cells against oxidative damage in vitro. Dex-CeNPs have shown potential to be transferred to human clinical use, given that 99.9% and 97.6% of nanoparticles were cleared within 24 hours in healthy and colitis mice respectively [84]. Additionally, the more moderate hypoxic state of patients with IBD compared to other diseases has posed a challenge for traditional hypoxia-activatable fluorescence probes. This has prompted the development of hypoxia-activatable and cytoplasmic protein-powered fluorescence cascade amplifiers (HCFA), which were successful in distinguishing the varying degrees of cellular hypoxia sensitively. This has also proven to be an edifying nanotechnology in the precise diagnosis and management of IBD [85] (Figure 2B) (Table 1).

5.2.2. Diagnostic Imaging of CRC

Diagnosing CRC has also been a beneficiary of the developments in nanotechnology. Near-infrared-emitting AuNPs have been found useful in investigating mechano-growth factor (MGF), an insulin-like growth factor (IGF)-1 isoform that is overexpressed in colon cancer tissues. Moreover, when compared to fluorescent dyes, AuNPs show stronger emission intensity and photostability, and are not cytotoxic like semiconductor quantum dots, making them a potential diagnostic agent [86]. Nanoparticles are also promising contrast agents for MRI, with SPIONs coated with a polymer demonstrating such potential [87]. Quantum dots have also been a growing platform for cancer research and can be used as an alternative to organic dyes. Some of their favourable properties include size-modulated absorbance and emission, high photostability, longer lifetime of excited state, and more [88]. Nanotechnology can also be used to detect circulating tumour cells, which are tumour cells shed from the primary tumour that drive cancer relapse. The concentration of such cells is normally in very low concentrations, making them difficult to detect and use to determine patient prognosis and chances of relapse. Poly(amidoamine) (PANAM) dendrimers were conjugated with various purified anti-Slex (aSlex) antibodies and were able to detect HT29 colon cancer cells with a maximum capture efficiency of 77.88% obtained within 1 hour of exposure. The nanoparticles were even able to detect HT29 cells when diluted with other cells commonly found in blood [89] (Figure 2C) (Table 1).

6. Therapeutic Nanomedicine

6.1. Nanomedicine in Drug Delivery

Nanoscale drug delivery systems (DDS) have been gaining much traction recently due to their ability to carry out targeted drug delivery, maximising efficacy while minimising undesired side effects. This can be attributed to the nanoscale of materials allowing for customisation of specific DDS properties, including drug release characteristics, dissolution, solubility, bioavailability and immunogenicity [90]. The utility of nanomedicine in drug delivery in the realm of treating gut dysbiosis and its associated diseases is discussed below.

6.1.1. Drug Delivery for IBD

Patients with IBD are found to have significantly heightened concentrations of reactive oxygen species (ROS) compared to normal mucosa, providing a potential target for DDS [91]. Based on this concept, a new nanoparticle prodrug named Bud-ATK-Tem (B-ATK-T) has been designed, which links budesonide together with tempol via aromatised thioketal. These thioketal bonds break down in the presence of excessive ROS at inflamed areas, allowing drug release from 55-100% based on the level of ROS present. In the mice model with dextran sulfate sodium induced colitis to model IBD, the B-ATK-T nanoparticle also reduced colon inflammation and weight loss, improved disease activity index while not exhibiting any toxicity to major organs [92] (Figure 3) (Table 2).

To overcome the problems of current first line therapy 5-ASA including high pill burden (2-4x dosing daily) and systemic adverse effects [93], a chitosan (Csn) bound ginger nanocarrier has been developed to enhance site-targeted drug delivery to inflamed mucosal linings in IBD. Csn is formed via the deacetylation of chitin, and has been recognised for its non-toxicity, biocompatibility and biodegradability. The drug carrier complex was able to entrap an estimated 50% of drug and was able to release the drug based on pH sensitivity, making itself a possible solution to overcome the current barriers of 5-ASA [94] (Figure 3) (Table 2).

The delivery of corticosteroids via nanoparticle DDS has also helped to reduce its systemic effects of immunosuppression, enabling their use as long term IBD treatment. For instance, the use of pH sensitive Eudragit L100–55 polymer microparticles loaded with prednisolone ensures that it is only released within the colon, and not in the upper GI tract where pH is acidic [95]. Tannic acid, a degradable mucoadhesive polyphenol, together with polymers, were formulated to form polyphenols and polymers self-assembled nanoparticle (PPNP), made to carry out targeted drug delivery to the colon. Esterase, whose levels are elevated in colon inflammation, can hydrolyse the polyphenols and enable drug release. Comparing the levels of dexamethasone released in the colon without and with esterase, its release increased from 30% to 62%, showing that the approach of incorporating polyphenol in corticosteroid therapy can potentially benefit IBD therapy [96] (Figure 3) (Table 2).

6.1.2. Drug Delivery for CRC

Nano-targeted DDS have also gained popularity among research in cancer pharmacology. Nanoparticles can accumulate in tumour cells due to the enhanced permeability and retention (EPR) effect, where the leaky tumour vasculature results in increased permeability to nanoparticles [97]. Cancer cells also rely on glycolysis instead of the Krebs cycle to produce ATP, known as the Warburg effect, causing the tumour environment to be acidic due to the lactic acid formed as the tumour cells undergo anaerobic respiration [97]. These specific tumour environments allow for the drugs to be released in the tumour site, minimising systemic toxicity associated with cancer drugs [98]. Bufadienolides nanocrystals decorated by Csn quaternary ammonium salt could protect bufadienolides from damage in the acidic environment of the stomach, increasing drug delivery the tumour sites in the colon and increasing its therapeutic effect [99].

Nanoparticles can also be modified and functionalised with specific ligands that enhance their ability to target and bind to CRC cells, thereby improving their uptake by these cells. An epidermal growth factor (EGF) modified poly (lactic-co-glycolic acid) (PLGA) nanoparticle was loaded with 5-fluorouracil (5-FU) and perfluorocarbon (PFC) for a targeted treatment for CRC [100]. The presence of EGF allowed the nanoparticles to interact strongly with cancer cells that expressed EGFR, as the cancer cells could take up the cells via EGF receptor-mediated endocytosis. Nanoparticles with EGF had a more pronounced tumour suppression of SW260 colon cancer cell line and also induced apoptosis in more colon cancer cells [100]. Epithelial cell adhesion molecule (EpCAM) is another target for drug delivery, as it is a dominant surface antigen in human colon carcinoma [101]. Polyethylene glycol (PEG) dendrimers with EpCAM aptamer were able to deliver celastrol, an anticancer agent, to induce apoptosis in SW260 colon cancer cells in vitro and in mice [101]. This targeted DDS was able to reduce local and systemic toxicity in xenograft and mice and zebrafish models, providing a promising treatment that can reduce side effects to the patients [101] (Figure 4) (Table 2).

Beyond targeting the cancer cells themselves, scientists have begun looking into treating cancer stem cells (CSCs). CSCs are a subset of cancer cells with increased renewal capacity and ability to recapitulate the heterogeneity found in primary tumours, playing an essential role in the growth and metastasis of tumours [102]. In view of improving targeted chemotherapy to these cells, there has been a development of a biocompatible tumour-cell-exocytosed exosome-biomimetic porous silicon nanoparticle (PSiNPs). These nanoparticles loaded with DOX have exhibited enhanced tumour accumulation, tumour penetration and cross-reactive cellular uptake by both bulk cancer cells and CSC. Notably, killing activity was demonstrated across several tumour models, including subcutaneous transplantation, orthotopic and advanced metastatic tumour models, demonstrating its potential as a drug carrier to improve anticancer therapy [103] (Figure 4) (Table 2).

6.2. Nanomedicine in Targeted Therapies

6.2.1. Hyperthermia Treatment for CRC

Hyperthermia treatment at 43ºC for 60 minutes can inactivate tumour cells [104]. The highest impact on tumour cells is observed when heating and delivering chemotherapeutic drugs are applied simultaneously in the same area [105], with hyperthermia increasing the effectiveness of 5-FU in disrupting DNA synthesis and repair [106]. Csn-coated magnetic nanoparticles (MNPs) with 5-FU were injected into human colon cancer xenograft in mice before the tumour was exposed to an alternating magnetic field. The thermo-chemotherapeutic treatment resulted in distinct tumour regression, much more evident than magnetic hypothermia or 5-FU alone [104]. 5-FU loaded onto PLGA encapsulating iron oxide nanoparticles has also been found to have increased cytotoxic activity on human colon cancer HT-29 cell lines when exposed to hyperthermia. The nanoparticles combined with hyperthermia treatment were found to have a cytotoxicity of 97.3% compared to 75.5% when 5-FU was given alone. As such, this allows for a lower concentration of 5-FU to be given, reducing the effects of systemic toxicity [107] (Figure 4) (Table 2).

6.2.2. Magnetic Drug Targeting for CRC

MNPs have several advantages over nonmagnetic nanoparticles, as drug release can be controlled via specific magnetic field stimulation, thus improving drug stability and bioavailability. They can also be localised and targeted to specific tissues, minimising unwanted side effects on other tissue sites [108]. SPIONs can aggregate to tumour sites upon exposure to a magnetic field, reducing uncontrolled aggregation in other tissue or in the bloodstream. Docetaxel, a drug that is not systemically used due to its hydrophobic nature, was encapsulated into the oil core of polymeric SPIONs. The nanoparticles were found to have an efficient cell-killing effect on the CT26 cell line in the in vitro cytotoxicity study. Only the magnetically targeted groups were found to have significantly smaller tumour volume compared to that of control treatments [109]. SPIONs were also aggregated with mAb198.3, an antibody that is able to stain and recognise CRC samples from surgically resected samples. The SPIONs linked to mAb198.3 significantly reduced tumour growth compared to the control and the nanoparticles without mAb198.3. A similar tumour size was found for the SPIONs linked to mAb198.3 compared to just using free mAb198.3, despite a 300 fold lower concentration used when the antibodies were linked to SPIONs. Erythrocytes too were engineered to contain the SPIONs and tumour reduction was noted at an earlier time than when SPIONs were used without erythrocytes [110] (Figure 4) (Table 2).

EGFR-targeted monoclonal antibodies like cetuximab have improved survival rates in patients, but their effectiveness has been limited by the KRAS activating mutations that confer resistance in approximately 25% of advanced CRC cases [111]. MNPs can induce oxidative stress by depleting glutathione and inducing ROS production [112]. This ROS-dependent apoptosis is found to enhance existing CRC treatment given drug-resistant late-stage cases. Combining Cetuximab and MNPs showed that approximately 31% of SW-480 CRC tumour cells exhibited signs of apoptosis, higher than the 10% observed when Cetuximab was used alone. This synergistic action led to a significant increase in ROS production, suggesting that intracellular ROS production did lead to the cytotoxic effect observed and holds promise of combining Cetuximab and MNPs to treat cancer [111] (Figure 4) (Table 2).

6.2.3. Photothermal Therapy (PTT) for CRC

Photothermal therapy (PTT) is an emerging and promising strategy in cancer treatment. It involves the use of photothermal agents (PTAs) which convert light energy–typically in the near-infrared (NIR) region–into heat energy, inducing localised thermal injury to tumour tissues and ultimately leading to cancer cell death. An advantage of PTT over conventional cancer therapies is its highly effective and noninvasive nature [113], but challenge still lies in the systemic distribution of PTAs in the body which leads to non-precision exposure and damage to normal tissues surrounding the tumours [114]. Nanotechnology has significantly advanced in the field of PTT. Apart from facilitating cancer diagnosis and treatment monitoring through improved imaging capabilities, nanoparticles have also demonstrated strong absorption in the NIR region alongside accurate targeting of cancer cells for improved specificity, making them highly suitable candidates for PTT applications [115]. Commonly used nanoparticles include metal (gold, iron oxide, Ag etc.) nanoparticles, polymer nanoparticles and carbon nanoparticles.

AuNPs are able to convert light energy in the NIR region to heat energy effectively making it suitable for PTT as NIR is able to penetrate tissue optimally [116]. AuNPs have good biocompatibility and can be functionalised with targeting ligands. PEG-ylated nanoshells with gold were able to significantly reduce rapid tumour growth when tumours were irradiated with NIR light in CT26 CRC tumour xenografts in murine models [117]. AuNPs can also be functionalised with an A33 antibody that binds to the surface antigen A33 that is overexpressed in colon cancer, providing a more targeted PTT approach [118]. Gold nanorods were also able to prolong the lifespan of mice bearing CT26 CRC xenografts, and the gold nanorods were found to accumulate mainly in tumours with no confirmed toxicity to other organs [119] (Figure 4) (Table 2)

Carbon nanotubes are also able to convert NIR light energy to heat, making them a suitable candidate to be used for PTT [116]. Carbon nanotubes can be functionalised with nanocomposite polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU) and can reduce the viability of HT29 CRC cells by 95% upon irradiation with NIR light [120]. Carbon nanotubes can also be conjugated with folic acid onto the surface, as the folic acid receptor is overexpressed in CRC. Cell viability was also found to be greatly reduced in HTC116 and RKO CRC cells after irradiation with NIR light [121]. The combination of PTT with immunotherapy has been explored with the development of GNC-Gal@CMaP nanocomposites. They consist of hollow gold nanocages (GNCs) loaded with galunisertib, a transforming growth factor (TGF)-β inhibitor, and surface-functionalized with anti-programmed cell death ligand-1 (PD-L1) antibodies. The study showed that GNC-Gal@CMaP selectively accumulated in tumours, was able to eliminate the primary tumour mass under NIR light irradiation and inhibited distant metastases, demonstrating the abscopal effect [122] (Figure 4) (Table 2).

A multifunctional endoscope-based interventional system has also been developed, consisting of both bioelectronics and nanoparticles. These nanoparticles are engineered to carry both phototherapeutic and chemotherapeutic agents, which can be precisely delivered and locally activated via light stimulation. This system offers optical fluorescence-based mapping, radio frequency-based ablation and site-specific photo/chemotherapy, forming the basis of a minimally invasive treatment strategy for CRC [123] (Table 2).

6.3. Nanotechnology and the Gut Microbiota

Nanoformulations of probiotics, prebiotics and synbiotics are emerging as powerful tools for optimising gut health treatments [124].

6.3.1. Nano-Prebiotics

Prebiotics are non-digestible food ingredients that selectively stimulate activity of beneficial bacteria in the colon. Prebiotics can be used as a vehicle for improved delivery of nanomedicine. Pectin (Pcn) is a biocompatible polysaccharide that is reputed for its biodegradability, biocompatibility and non-toxicity [125]. Csn is also a biopolymer that has received attention due to its biocompatibility, antimicrobial [126], mucoadhesive and absorption-enhancing properties [127]. Together, they were both used as a prebiotic shell around a PLGA core loaded with sulfasalazine. This design exhibited pH-responsive characteristics for protecting anti-inflammatory drugs in the upper GIT, and also demonstrated a specific colonic delivery property triggered by pectinase which degraded the Pcn/Csn shell, whose enzymatic product revealed notable prebiotic properties [128]. High molecular weight insulin nanoparticles were also shown to improve drug delivery, with no toxicity detected in peripheral blood mononuclear cells at concentrations < 200 μg/mL [129] (Table 2). Other nano-prebiotics such as phthalyl dextran nanoparticles have also shown antimicrobial effects [130] (Figure 5). Altogether, nano-prebiotics offer a promising solution for targeted therapy and microbial modulation in the gut.

6.3.2. Nano-Probiotics

Probiotics are live microorganisms (eg. bacteria, yeast) that offer health benefits to the gut microbiome when consumed. Nanotechnology has contributed to the development of strategies to preserve probiotic viability and functionality in food systems. A recent study developed modified poly(L-glutamic acid) (PG) films incorporating varying levels of poly(L-lysine) (PL), resulting in a dual-function active packaging material, capable of acting as a microbioreactor which enabled continued gamma-aminobutyric acid (GABA) production by the probiotic during the shelf life of the packaged food and also bearing antimicrobial activity, preventing the growth of foodborne pathogenic bacteria [131] (Figure 5) (Table 2).

Nano-probiotics have demonstrated utility in their anticancer properties. Synthesized Ag/Lactobacillus rhamnosus GG nanoparticles (Ag-LNPs) were assessed against CRC cell lines and significantly decreased the viability of these cell lines from 7.8-1000 μg/ml, possibly due to the activation of ROS which led to cell damage and death [132]. Probiotic bacteria Lactobacillus casei was also used to synthesize copper oxide nanoparticles (CuONPs) which exerted cytotoxic effects by suppressing growth, increasing oxidative stress and inducing apoptosis on cancer cells, alongside antimicrobial effects on gram positive and negative bacteria [133] (Table 2). Other nanotechnologies that have shown anti-cancer properties include selenium nanoparticles synthesised by Lactobacillus casei [134,135], dead nano-sized Lactobacillus plantarum (LP) [136] and AuNPs synthesised by novel probiotic Lactobacillus kimchicus [137] (Figure 5). These findings highlight how nano-probiotics can go beyond conventional supplementation into potent bioactive agents for gut health intervention by maintaining microbial viability, enhancing therapeutic properties and even offer anticancer properties in the gut.

6.3.4. Nano-Synbiotics

Synbiotics are combinations of probiotics and prebiotics that work synergistically to improve host health. Nano prebiotics [eg. phthalyl pullulan nanoparticles (PPNs)] has been developed to enhance the antimicrobial action of probiotics (LP), and together, were tested as synbiotics for their therapeutic effect on dysbiosis-induced models. Results demonstrated that antimicrobial activity of the PPN-internalised LP was significantly higher than that of untreated LP or pullulan alone, and groups that underwent synbiotic treatment also had the greatest gain in body weight and longest colons [138]. This suggests weight gain as part of recovery with little to no supplement, and ability to reverse colon shortening, an occurrence due to intestinal inflammation. Additionally, synbiotic treatment also lowered endotoxin and permeability levels, reduced coliform bacteria while boosting lactic acid bacteria, and restored microbiome diversity to a more balanced state [138] (Figure 5) (Table 2).

Nano emulsion systems have also been developed to enhance the bioavailability and maintain the viability of probiotics. One example is the formulation of a synbiotic nanoemulsion incorporating whey protein concentrate, inulin, Gum Arabic, and Enterococcus faecium in the aqueous phase, with coconut oil as the oil phase. The study showed that the droplet size increased up to 500 nm after 60 days of storage, while the viability of the probiotic organism remained promising [139] (Figure 5) (Table 2).

Encapsulation technologies have also been explored to enhance the tolerance and stability of probiotic bacteria. A study developed an oral synbiotic supplement using alginate beads incorporated with varying concentrations of inulin to protect three probiotic strains: Pediococcus acidilactici, Lactobacillus reuteri, and Lactobacillus salivarius. Notably, encapsulation did not affect the antimicrobial or probiotic properties of the strains. Inulin-enhanced beads improved bacterial survival in acidic conditions, while beads containing 5% inulin offered the greatest protection against bile salts [140]. This study highlights the potential of emerging nanotechnologies in improving the delivery and efficacy of probiotics in the gut (Figure 5) (Table 2). These studies collectively point to nano-synbiotics as a powerful therapeutic approach to combat gut dysbiosis through enhanced delivery, viability and functional outcomes.

6.3.5. Nanoparticles with Antioxidant and Anti-Inflammatory Effects (IBD)

Tantalum (Ta), a medical metal element known for its superb physicochemical properties, has been used for the treatment of many diseases, but yet to be explored deeply in IBD. Modification with chondroitin sulfate has resulted in the formation of TACS (Ta2C modified with chondroitin sulfate), evaluated to be a highly targeted therapy nanomedicine for IBD. Its main mechanism of action is mitochondrial protection, oxidative stress elimination, inhibition of macrophage M1 polarisation, among others [141] (Figure 6) (Table 2).

Another therapeutic strategy being explored is a nanomedicine that treats IBD by targeting multiple proinflammatory factors that contribute to its pathogenesis. Specific to this study, researchers reasoned that the neutralisation of cell-free DNA (cfDNA) could modulate the imbalanced immune response in IBD [142]. This is because cfDNA released by damaged cells activated toll like receptor (TLR)-9 mediated proinflammatory signalling in immune cells and contributed to the extent and timespan of inflammation [143]. A nanoparticulate, polyethylenimine-mesoporous organosilica nanoparticles (MON-PEI), was developed via conjugating DNA binding polyethylenimine to antioxidative diselenide-bridged mesoporous organosilica nanoparticles (MON), which bears cfDNA-scavenging, antioxidative and anti-inflammatory properties. It also effectively decreased cfDNA-induced TLR9-MyD88-NF-κB signaling and proinflammatory macrophage activation in treating inflammation, and has an additional benefit of lower dose frequency with better safety profile compared to mesalazine due to its preferential accumulation in diseased areas [142] (Figure 6) (Table 2).

Another approach is capitalising on physiological anti-inflammatory molecules, an example being the gut hormone glucagon like peptide-1 (GLP-1). In order to overcome its limitation of a short half-life due to degradation by enzymes such as dipeptidyl peptidase IV (DPP-4), GLP-1 in sterically stabilised phospholipid micelles (GLP-1-SSM) was developed. GLP-1-SSM treatment was able to lessen colonic inflammation and associated diarrhoea in mouse colitis models via decreasing the expression IL-1β, a pro-inflammatory cytokine, increasing goblet cells and preserving the architecture of the intestinal epithelium [144] (Figure 6) (Table 2). These results show the potential of GLP-1 nanomedicine in acting as IBD treatment.

Mimicking the body’s natural enzymes can also be a way to combat ROS. In this system, the free radical scavenger tempol, which acts as a superoxide dismutase (SOD) mimic, is loaded into a β-cyclodextrin-derived material (OxbCD) that also mimics catalase activity. These components were then assembled into stable nanoparticles with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE)-PEG. Upon entering inflamed areas with high levels of ROS, nanoparticles release tempol, reducing both inflammatory cytokines and disease index. It is significant to note that this nanoparticle treatment performed more effectively than free tempol and tempol-loaded PLGA nanoparticles [92] (Figure 6) (Table 2).

6.3.6. Nanomedicine for Microbiome Modulation

• In IBD

Traditional approaches to treating IBD focus mainly on suppressing the immune response via immunosuppressant drugs. However, such a strategy causes systemic side effects and is unable to treat the disrupted intestinal barriers or restore the underlying gut dysbiosis. The development of hyaluronic acid-bilirubin nanomedicine (HABN) aims to improve this by accumulating in the inflamed colon and restoring the epithelium barriers in murine models of acute colitis [145]. HABN was also able to regulate gut microbiomes, increasing their diversity and richness. This is due to hyaluronic acid’s ability to regulate macrophages and induce antimicrobial peptides and CD4 T regulatory cells. Bilirubin has strong ROS scavenging, anti-oxidant, and cytoprotective properties that allow HABN to aggregate to colon inflammation. Mice undergoing HABN treatment were able to achieve full body weight recovery, maintain colon length, reduce colon damage, and increase beneficial bacteria in IBD such as Akkermansia muciniphila, Clostridium and Lactobacillus [145] (Figure 6) (Table 2).

Ag nanoparticles conjugated with a selective wall-binding domain targeting Fusobacteriaceae were found to eliminate these bacteria– known to be overabundant in IBD patients– and thereby reduce intestinal inflammation [146]. Zinc oxide nanoparticles have also been found to reduce the population of Lactobacillus and alter their production of SCFA, a key process that is implicated in the pathogenesis of IBD [146] (Figure 6) (Table 2).

• In CRC

Traditional methods to modulate the gut microbiome have shown promise in enhancing cancer treatment but damage the commensal gut microbiome [147]. The ability to modify the surface of nanoparticles allows them to target specific bacteria, resulting in a controlled killing of cancer-causing microbes with minimal effect on the rest of the gut microbiome [147]. A bacteriophage was found to eliminate a cancer-causing bacterium, F. nucleatum. The bacteriophage was functionalised to nanoparticles and was able to reduce F. nucleatum load with minimal inhibition to other bacteria strains, preserving strains such as Clostridium butycirum, that are useful in suppressing the growth of colon cancer [147] (Figure 7) (Table 2).

Figure 7. Nanotherapeutics in colorectal cancer include microbiome modulation.

Figure 7. Nanotherapeutics in colorectal cancer include microbiome modulation.

Table 2. Summary of nanomedicine based therapeutic approaches for IBD and CRC.

Application	Disease	Nanotechnology Used	Mechanism	Advantages	Stage	Reference
Drug delivery	IBD	B-ATK-T nanoparticle prodrug linked with budesonide	Thioketal bonds that link budesonide with tempol break down in areas where there is excessive ROS	Precise delivery of higher drug dosage to affected areas, less systemic side effects, reduced colon inflammation and weight loss	Preclinical	[92]
		Csn bound ginger nanocarrier linked with 5-ASA	Drug carrier complex that releases drug in colon based on pH sensitivity	Enhanced site-targeted drug delivery, decreased pill burden and systemic side effects		[94]
		Eudragit polymer microparticles containing prednisolone	Drug carrier complex that releases drug in colon based on pH sensitivity	Higher drug dosage to diseased areas, reduced systemic immunosuppressive effects		[95]
		PPNP loaded with dexamethasone	The inflamed colon's higher esterase levels hydrolyse phenols allowing targeted drug release	Higher drug dosage to diseased areas, reduced systemic immunosuppressive effects		[96]
	CRC	EGF modified PLGA nanoparticles loaded with 5-FU and PFC	Nanoparticles interact directly with cancer cells that express EGFR	More effective tumour suppression, more induced apoptosis for cancer cell death		[100]
		PEG dendrimer nanoparticles with EpCAM aptamer loaded with Celastrol	EpCAM aptamer on nanoparticles target cancer cells	Reduced local and systemic toxicity, improving precision		[101]
		PSiNPs loaded with DOX	Enhanced tumour accumulation and penetration in cancer cells and CSCs	Improved chemotherapy efficacy		[103]
Hyperthermia treatment	CRC	Csn-coated MNPs with 5-FU	Hyperthermia combined with chemotherapy increased tumour regression	Improved chemotherapy efficacy		[104]
		5-FU loaded onto PLGA encapsulating iron oxide nanoparticles	Increased cytotoxic activity on human colon cancer cells	Decreased dosage required allowing reduced systemic toxicity		[107]
Magnetic drug targeting	CRC	Docetaxel encapsulated with oil core polymeric SPIONs	Local magnetic field promotes nanoparticle aggregation in tumour site to deliver chemotherapeutics	Efficient cell-killing effect, precise delivery, decreased systemic side effects		[109]
		SPIONs aggregated with mAb198.3	mAb198.3 is able to stain and recognise CRC samples	Significant reduction in tumour growth		[110]
		MNPs combined with Cetuximab	MNPs can induce oxidative stress, overcoming cancer cells resistant to Cetuximab	Promising treatment to overcome Cetuximab resistant CRC		[111,112]
PTT	CRC	AuNPs functionalised with A33 antibody	Act as PTAs that absorb NIR region light to promote cancer cell death, A33 antibody functionalised to target CRC cells, good accumulation in tumours	More targeted PTT with no toxicity to other organs		[117,118,119]
		Carbon nanotubes functionalised with nanocomposite POSS-PCU	Functionalisation allows carbon nanotubes to aggregate in CRC tumours, allowing for effective decreases in CRC cell lines	More targeted PTT approach due to functionalising with antibodies		[120,121]
		GNC-Gal@CMaP nanocomposites loaded with galunisertib, surface-functionalized with anti-PD-L1 antibodies	Accumulates in tumour cells selectively, improving PTT efficacy	More targeted PTT approach due to functionalising with antibodies, could eliminate primary tumour while inhibiting metastases		[122]
		Multifunctional endoscope-based interventional system	Fluorescence-based mapping, radio frequency-based ablation and site-specific photo/chemotherapy	Novel minimally invasive treatment strategy for CRC		[123]
Nanoprebiotics	IBD	Pcn and Csn prebiotic shell surrounding PLGA core loaded with sulfasalazine	pH-responsive prebiotic shell to protect drug from acidic environment for enhanced drug delivery, prebiotic properties	Improved drug concentration in target sites		[128]
		High molecular weight insulin nanoparticles	Improved drug delivery	No toxicity detected in peripheries		[129]
Nanoprobiotics	General dysbiosis	Modified PG films incorporating varying levels of PL	Active packaging material, continues GABA production by probiotic, antimicrobial properties	Preserves probiotic viability and functionality during shelf-life		[131]
	CRC	Ag-LNPs	Activation of ROS in CRC cell lines causing cell death	Decreased viability of CRC cell lines		[132]
		CuONPs synthesised with Lactobacillus casei	Suppresses growth of cancer cells, increases oxidative stress and induces apoptosis in cancer cells, antimicrobial effects	Cytotoxic effects on CRC cell lines		[133]
Nanosynbiotics	IBD	PPNs and LP	Enhances probiotic function, lowers endotoxin and permeability levels, restores microbiome diversity and balance	Enhanced antimicrobial action, decreased dysbiosis		[138]
		Nanoemulsion incorporating whey protein concentrate, inulin, Gum Arabic, and Enterococcus faecium, coconut oil	Enhance bioavailability and maintain viability of probiotics	Increased efficacy of probiotics		[139]
		Alginate beads incorporated with inulin to protect probiotic strains Pediococcus acidilactici, Lactobacillus reuteri, and Lactobacillus salivarius	Improved probiotic survival, maintained antimicrobial and probiotic properties	Improved probiotic efficacy in the gut		[140]
Anti-oxidant and anti-inflammatory nanoparticles	IBD	TACS	Mitochondrial protection, oxidative stress elimination, inhibition of macrophage M1 polarisation	Reduction of IBD inflammation		[141]
		MON-PEI	Has cfDNA-scavenging, antioxidative, anti-inflammatory peroerties, targets multiple proinflammatory factors	Has lower dose frequency, better safety profile than mesalazine		[144]
		GLP-1-SSM	Decreases expression of IL-1β, increases goblet cells and preserves intestinal epithelium architecture	Able to lessen colonic inflammation and associated diarrhoea		[145]
		DSPE-PEG assembled with tempol and OxbCD	Releases tempol in areas with high levels of ROS, reducing inflammatory cytokines and disease index	Enhanced anti-inflammatory activity compared to free tempol and tempol-loaded PLGA nanoparticles		[92]
Microbiome Modulation	IBD	HABN	Accumulates in inflamed colon, restore epithelium barriers in colitis, regulates gut microbiome	Directly targets underlying gut dysbiosis and restores disrupted intestinal barriers		[145]
		Ag nanoparticles targeting Fusobacteriaceae	Selective wall binding domain to target Fusobacteriaceae directly	Addresses underlying dysbiosis that underlies pathology of IBD		[146]
		Zinc oxide nanoparticles	Reduce population of Lactobacillus and alter production of SCFA	Minimises processes implicated in IBD pathogenesis		[146]
	CRC	Bacteriophage targeting F. nucleatum functionalised to nanoparticles	Eliminates cancer-causing F. nucleatum, while preserving other strains that suppress CRC growth	Controlled killing of cancer-causing microbes with minimal effect on other gut microbiome		[147]

Table 2. Summary of nanomedicine based therapeutic approaches for IBD and CRC.

Application	Disease	Nanotechnology Used	Mechanism	Advantages	Stage	Reference
Drug delivery	IBD	B-ATK-T nanoparticle prodrug linked with budesonide	Thioketal bonds that link budesonide with tempol break down in areas where there is excessive ROS	Precise delivery of higher drug dosage to affected areas, less systemic side effects, reduced colon inflammation and weight loss	Preclinical	[92]
		Csn bound ginger nanocarrier linked with 5-ASA	Drug carrier complex that releases drug in colon based on pH sensitivity	Enhanced site-targeted drug delivery, decreased pill burden and systemic side effects		[94]
		Eudragit polymer microparticles containing prednisolone	Drug carrier complex that releases drug in colon based on pH sensitivity	Higher drug dosage to diseased areas, reduced systemic immunosuppressive effects		[95]
		PPNP loaded with dexamethasone	The inflamed colon's higher esterase levels hydrolyse phenols allowing targeted drug release	Higher drug dosage to diseased areas, reduced systemic immunosuppressive effects		[96]
	CRC	EGF modified PLGA nanoparticles loaded with 5-FU and PFC	Nanoparticles interact directly with cancer cells that express EGFR	More effective tumour suppression, more induced apoptosis for cancer cell death		[100]
		PEG dendrimer nanoparticles with EpCAM aptamer loaded with Celastrol	EpCAM aptamer on nanoparticles target cancer cells	Reduced local and systemic toxicity, improving precision		[101]
		PSiNPs loaded with DOX	Enhanced tumour accumulation and penetration in cancer cells and CSCs	Improved chemotherapy efficacy		[103]
Hyperthermia treatment	CRC	Csn-coated MNPs with 5-FU	Hyperthermia combined with chemotherapy increased tumour regression	Improved chemotherapy efficacy		[104]
		5-FU loaded onto PLGA encapsulating iron oxide nanoparticles	Increased cytotoxic activity on human colon cancer cells	Decreased dosage required allowing reduced systemic toxicity		[107]
Magnetic drug targeting	CRC	Docetaxel encapsulated with oil core polymeric SPIONs	Local magnetic field promotes nanoparticle aggregation in tumour site to deliver chemotherapeutics	Efficient cell-killing effect, precise delivery, decreased systemic side effects		[109]
		SPIONs aggregated with mAb198.3	mAb198.3 is able to stain and recognise CRC samples	Significant reduction in tumour growth		[110]
		MNPs combined with Cetuximab	MNPs can induce oxidative stress, overcoming cancer cells resistant to Cetuximab	Promising treatment to overcome Cetuximab resistant CRC		[111,112]
PTT	CRC	AuNPs functionalised with A33 antibody	Act as PTAs that absorb NIR region light to promote cancer cell death, A33 antibody functionalised to target CRC cells, good accumulation in tumours	More targeted PTT with no toxicity to other organs		[117,118,119]
		Carbon nanotubes functionalised with nanocomposite POSS-PCU	Functionalisation allows carbon nanotubes to aggregate in CRC tumours, allowing for effective decreases in CRC cell lines	More targeted PTT approach due to functionalising with antibodies		[120,121]
		GNC-Gal@CMaP nanocomposites loaded with galunisertib, surface-functionalized with anti-PD-L1 antibodies	Accumulates in tumour cells selectively, improving PTT efficacy	More targeted PTT approach due to functionalising with antibodies, could eliminate primary tumour while inhibiting metastases		[122]
		Multifunctional endoscope-based interventional system	Fluorescence-based mapping, radio frequency-based ablation and site-specific photo/chemotherapy	Novel minimally invasive treatment strategy for CRC		[123]
Nanoprebiotics	IBD	Pcn and Csn prebiotic shell surrounding PLGA core loaded with sulfasalazine	pH-responsive prebiotic shell to protect drug from acidic environment for enhanced drug delivery, prebiotic properties	Improved drug concentration in target sites		[128]
		High molecular weight insulin nanoparticles	Improved drug delivery	No toxicity detected in peripheries		[129]
Nanoprobiotics	General dysbiosis	Modified PG films incorporating varying levels of PL	Active packaging material, continues GABA production by probiotic, antimicrobial properties	Preserves probiotic viability and functionality during shelf-life		[131]
	CRC	Ag-LNPs	Activation of ROS in CRC cell lines causing cell death	Decreased viability of CRC cell lines		[132]
		CuONPs synthesised with Lactobacillus casei	Suppresses growth of cancer cells, increases oxidative stress and induces apoptosis in cancer cells, antimicrobial effects	Cytotoxic effects on CRC cell lines		[133]
Nanosynbiotics	IBD	PPNs and LP	Enhances probiotic function, lowers endotoxin and permeability levels, restores microbiome diversity and balance	Enhanced antimicrobial action, decreased dysbiosis		[138]
		Nanoemulsion incorporating whey protein concentrate, inulin, Gum Arabic, and Enterococcus faecium, coconut oil	Enhance bioavailability and maintain viability of probiotics	Increased efficacy of probiotics		[139]
		Alginate beads incorporated with inulin to protect probiotic strains Pediococcus acidilactici, Lactobacillus reuteri, and Lactobacillus salivarius	Improved probiotic survival, maintained antimicrobial and probiotic properties	Improved probiotic efficacy in the gut		[140]
Anti-oxidant and anti-inflammatory nanoparticles	IBD	TACS	Mitochondrial protection, oxidative stress elimination, inhibition of macrophage M1 polarisation	Reduction of IBD inflammation		[141]
		MON-PEI	Has cfDNA-scavenging, antioxidative, anti-inflammatory peroerties, targets multiple proinflammatory factors	Has lower dose frequency, better safety profile than mesalazine		[144]
		GLP-1-SSM	Decreases expression of IL-1β, increases goblet cells and preserves intestinal epithelium architecture	Able to lessen colonic inflammation and associated diarrhoea		[145]
		DSPE-PEG assembled with tempol and OxbCD	Releases tempol in areas with high levels of ROS, reducing inflammatory cytokines and disease index	Enhanced anti-inflammatory activity compared to free tempol and tempol-loaded PLGA nanoparticles		[92]
Microbiome Modulation	IBD	HABN	Accumulates in inflamed colon, restore epithelium barriers in colitis, regulates gut microbiome	Directly targets underlying gut dysbiosis and restores disrupted intestinal barriers		[145]
		Ag nanoparticles targeting Fusobacteriaceae	Selective wall binding domain to target Fusobacteriaceae directly	Addresses underlying dysbiosis that underlies pathology of IBD		[146]
		Zinc oxide nanoparticles	Reduce population of Lactobacillus and alter production of SCFA	Minimises processes implicated in IBD pathogenesis		[146]
	CRC	Bacteriophage targeting F. nucleatum functionalised to nanoparticles	Eliminates cancer-causing F. nucleatum, while preserving other strains that suppress CRC growth	Controlled killing of cancer-causing microbes with minimal effect on other gut microbiome		[147]

7. Challenges and Future Directions

While nanotechnology has shown much promise in animal models with its unique and useful physical and chemical properties, current clinical trials and regulations prove to be major obstacles to translate this technology into clinical practice. Some of the major challenges include difficulties with reproducible manufacturing and scale-up, inadequate characterisation tools, instability in vivo, safety concerns and a limited understanding of disease variability and patient selection [148]. Moreover, regulatory agencies such as the US Food and Drug Administration and European Medicines Agency require extensive safety and efficacy evaluations for nanotechnology, yet there is a lack of standardised protocol to determine the safety of nanomaterials [149]. Concerns have also been expressed over the potential long-term toxicity of nanoparticles, due to their tendency to accumulate in organs such as the liver and spleen [149]. Furthermore, the GIT’s complex environment characterised by fluctuating pH, enzymatic activity and mucus layers, have also posed significant barriers for effective drug delivery [149], further complicating the transition of nanomedicine from lab research to clinical application. In essence, more extensive research, clinical trials and standardised protocols are necessary to accelerate the integration of nanomedicine into routine clinical practice (Figure 8).

8. Conclusion

It is evident that gut dysbiosis plays a key role in the pathogenesis of IBD and CRC and should be treated to prevent implications in both the gut and other parts of the body. In this regard, nanomedicine has emerged as a transformative frontier. By enabling targeted drug delivery with controlled release, nanotechnological approaches offer the potential to overcome current limitations of conventional therapies to improve patient outcomes. The ongoing advancements in nanomedicine across many treatment modalities hold much promise for future clinical application.