Nanotechnology for drug delivery systems in colorectal cancer: Recent developments and future prospects

Abstract

Colorectal cancer (CRC) ranks as the third most prevalent malignancy globally, and has a rapidly rising incidence. The clinical utility of conventional therapies for CRC is limited by intrinsic tumor cell drug resistance, dose-limiting systemic toxicity, and a spectrum of treatment-related adverse effects. Nanoscale drug delivery systems have made it possible to precisely and efficiently deliver therapeutics, assisting it developing innovative strategies for management of CRC. Recent studies demonstrate that nanocarriers dramatically enhance anticancer drug efficacy, with tumor accumulation typically remaining below 1% of the injected dose, highlighting both their potential and current limitations. This review systematically summarizes recent studies on diverse nano-biomaterials, which are designed for controlled and targeted drug delivery in CRC. We highlight current advances in nanomedicine-based immunotherapy for CRC, focusing on targeting of immunosenescence to reprogram the immunosuppressive tumor microenvironment and improve immune checkpoint inhibitor effects. At last, we also discuss the challenges and future potential of translating these nanoplatforms into clinical practice. In summary, this review aims to provide a new perspective on the strategies for treating CRC using nanodrug delivery technology.

Key Words: Nanotechnology; Colorectal cancer; Drug delivery; Tumor microenvironment; Immune

Core Tip: This review systematically summarizes recent studies on diverse nano-biomaterials, which are designed for targeted and controlled drug delivery in colorectal cancer. We specifically highlight current advances in nanomedicine-based immunotherapy, focusing on targeting of immunosenescence to reprogram immunosuppression in the tumor microenvironment and improve immune checkpoint inhibitor effects. We further discuss the problems and potential of translating such nanoplatforms into clinical practice. In summary, the present work sheds new lights on those strategies for treating colorectal cancer using nanodrug delivery technology.

INTRODUCTION

Colorectal cancer (CRC) has the third highest prevalence among cancers and ranks second among factors inducing cancer-related mortality globally in 2022, and ~1.93 million new cases and 903859 fatalities were reported[1,2]. It typically originates in the intestinal mucosa and may progress to involve the intestinal wall and deeper muscular layers[3]. Because of factors including dietary habits, lifestyle changes, and population aging, the incidence of CRC has been increasing rapidly[4,5]. By 2040, newly diagnosed CRC cases are predicted to jump by around 63%, which would mean over 3.2 million people diagnosed annually[6-8]. CRC usually starts as polyps, and as genetic mutations build up over time, such benign polyps can turn into full-blown adenocarcinomas[9]. Standard treatments for CRC depend heavily on how far the disease has progressed and mostly include strategies like adjuvant or neoadjuvant therapies, surgery, radiotherapy, and chemotherapy[10]. But there are serious limits to what these approaches can achieve, such as cancer cells’ natural ability to resist drugs, toxic effects that come with higher doses, and various other treatment-related side effects[11]. So, it is needed to formulate a novel therapeutic strategy with improved efficacy and specificity. Nanoscale drug delivery systems (NDDSs) can help develop new anti-CRC treatments[12].

Over the past several decades, nanotechnology grow into a game-changing field, influencing everything from materials science to industrial applications[13,14]. Work in nanomedicine has led to novel biomaterials and therapies, not to mention major leaps forward in diagnosis and patient care[15]. Nanoparticles (NPs) are the real workhorses here[16], and they have made it possible to design nanomaterials that are especially good at detecting and treating CRC[17]. In fact, nanotechnology now plays a part in a wide range of CRC treatment strategies, including NP-based screening tests, customized drug delivery vehicles, and advanced treatment techniques[18].

NDDSs lie at the crossroads of nanotechnology and pharmacology, and they hold great promise for targeted diagnosis and treatment[19]. As nanotechnology continues to advance quickly, drug delivery systems (DDSs) have seen some impressive breakthroughs, bringing fresh hope to CRC treatment[20]. Lately, NPs sized between 25 nm and 500 nm have become more common for improving chemotherapeutic delivery[21]. Compared with traditional drug delivery, NDDSs have clearly boosted cellular uptake and made antitumor drugs work more predictably and effectively. All of this adds up to a much more precise and powerful way to target specific therapies in CRC[22-24]. Novel drug carriers, such as NPs[25], nanomicelles[26,27], hydrogel[28,29], and nanoemulsions[30] have been investigated for therapy of CRC.

Despite these advances, important barriers to clinical translation remain. Delivery efficiency to solid tumors is still low overall, tumor heterogeneity complicates treatment response, and the tumor microenvironment (TME) can limit therapeutic effectiveness. In CRC, these issues are especially important because most tumors are mismatch repair-proficient or microsatellite-stable and do not respond well to immune checkpoint blockade (ICB) alone. Recent reviews have summarized nanocarrier design, drug delivery mechanisms, and therapeutic applications in CRC. However, less attention has been paid to the role of immunosenescence in shaping therapeutic response and resistance.

In this review, we emphasize the critical role of NPs for DDSs in the treatment of CRC, and summarize recent studies on diverse nano-biomaterials, which are designed for targeted and controlled drug delivery to manage CRC. We highlight current advances in nanomedicine-based immunotherapy for CRC, focusing on targeting of immunosenescence to reprogram immunosuppression in the TME and improve immune checkpoint inhibitor (ICI) effects. Finally, we discuss the challenges and limitations and potential improvement in the near future.

CURRENTLY APPROVED THERAPEUTICS FOR CRC

CRC is treated mainly according to disease stage. Currently available conventional options mainly consist of surgical procedures, radiotherapy, chemotherapy, targeted therapy, and immunotherapy[30-32]. Early diagnosis is beneficial to treatment efficacy. However, these therapies have shown limited success in improving survival of late-stage CRC patients. In addition to common surgical risks like major blood loss or infections, colectomy results in serious tissue injury, potentially leading to anastomotic leakage[33,34]. Radiotherapy also comes with a notable risk of inducing fecal or urinary incontinence[35,36]. After surgery, targeted therapy and immunotherapy are usually considered better options, but their poor bioavailability and high costs push many patients toward chemotherapy[37]. Chemotherapy is far less expensive, yet its effectiveness is seriously undercut by problems like drug resistance, low bioavailability, poor permeability and solubility, lacking target specificity, dose-related toxic effects, and serious adverse reactions[5]. So, there is a clear need for new approaches that can treat CRC more safely and effectively. One promising direction is the use of NDDSs to boost the performance of antitumor therapy while cutting down on systemic harm.

Nanotechnology has reshaped cancer treatment by advancing imaging techniques, diagnostic tools, and targeted DDSs. Some nanomaterials are found to improve cancer treatment outcomes by shuttling drugs directly to tumors[38-40]. DDSs stand out for longer circulation time, organ-specific targeting, and controlled release profiles[41]. They also offer a way to deal with drug resistance, especially multidrug resistance[42-44]. That means more drug builds up inside cancer cells, which can greatly enhance chemotherapeutic efficacy[45].

NDDSS

Advantages of nanocarriers for anticancer drug delivery

NDDSs are now a key part of modern DDSs. Typically, they work by encapsulating drugs or other active agents and guiding them into the desired target site[46]. There has been a lot of interest in using NDDSs for cancer treatment[47,48], mainly because they fit so many roles - delivering drugs to specific targets, controlling their release, and carrying DNA or RNA for gene therapy[49]. These nanocarriers have special physicochemical traits that affect how they bind to diverse therapeutics (chemotherapeutics, immunotherapies, radioisotopes, nucleic acids, proteins, and so on), making them useful in various biological settings. Relative to traditional anticancer drugs that aren’t attached to any carrier, NDDSs offer clear benefits. They can help drug accumulation within tumor tissues through enhanced permeability and retention effect; improve solubility, half-life, and bioavailability; help drugs cross biological barriers; enable combination regimens; and lower systemic toxicity. All these advantages add up to better efficacy ad higher specificity in cancer treatment[50,51]. The United States Food and Drug Administration (FDA) approved some nanomaterials for delivering drugs, like liposomes, polymeric substances, dendrimers, and inorganic materials. Currently, further sophisticated nanomaterials and diverse inorganic or organic materials are being developed and evaluated in clinical trials[52].

Nanocarrier properties

Physicochemical properties: The physicochemical characteristics of NPs, including their size, shape, and surface charge, elasticity, and surface modification, have been extensively explored, with their impacts on cancer drug delivery being thoroughly examined[53]. The inherent physicochemical properties of nanodrugs not only determine their in vivo fate (such as lymphatic drainage, tumor accumulation, cellular uptake, and intracellular transport) but also profoundly influence immune response type and intensity in CRC (Table 1)[54].

Table 1 Influences of nanoparticle physicochemical properties on immune modulation in colorectal cancer immunotherapy.

Physicochemical property	Parameter range	Immune-correlated effects in CRC	Ref.
Size	4-14 nm	M1 macrophage polarization through cellular uptake efficiency and lysosomal stress	[56]
	10-100 nm	Efficient lymphatic drainage and lymph node accumulation	[54]
	750-1000 nm	M1 macrophage polarization through membrane interaction	[56]
Shape	Spherical	Higher cellular internalization efficiency	[60]
	Spiky	Physical activation of innate immunity	[61]
Surface charge	Positive	Enhanced cellular uptake; increased immunogenicity	[62]
	Negative	Efficient lymph node accumulation; longer circulation	[63]
Elasticity	Soft	Activate Piezo1; reprogram TAMs	[64]
Surface funtionalization	PEGylation	Reprogram protein corona; extended circulation half-life	[68]
	Glycosylation	Promoted M1 polarization of macrophages through interaction with TLR4 receptors	[69]
	Cell membrane coating	Homologous targeting to CRC cells; immune evasion and enhanced tumor immunogenicity	[70,71]

CRC: Colorectal cancer; TAMs: Tumor-associated macrophages; PEG: Polyethylene glycol; TLR4: Toll-like receptor 4.

Size: NP size has an important effect on determining the circulation half-life, targeting efficiency, cellular uptake, and tumor penetration. NPs measuring 2-100 nm can regulate key pathways essential for fundamental cellular functions. To prevent clearance through the renal filtration barrier, NPs should exceed 10 nm in diameter. Thermodynamic models and experimental studies have demonstrated that NPs measuring ~50 nm achieve best cellular absorption. In contrast, NPs ≤ 20 nm show the most effective penetration into tumors[55]. Lymph nodes serve as the primary sites for immunotherapeutic drugs to regulate immune initiation and activation. NPs that are 10-100 nm in size can effectively reach the lymph nodes through lymphatic drainage and are more readily absorbed by immune cells via several absorption mechanisms. Large NPs with a diameter greater than 100 nm cannot be easily transferred to the lymphatic vessels and exhibit relatively low cellular uptake efficiency[54]. The interaction with membranes or receptors is a crucial process in the M1 polarization of macrophages induced by large NPs (750-1000 nm), which is contrary to the cell-uptake-dependent polarization induced by small NPs (4-14 nm)[56].

Shape: NPs exhibit diverse morphologies, such as spherical, rod-like, clubbed, discoid, or nano-needle shapes. There is increasing evidence supporting that NP shape significantly influences their circulation, biodistribution, targeted delivery, and cellular uptake. Carbon nanotubes (CNTs), characterized by their cylindrical structure and great aspect ratio, can readily cross cell membrane, while rod-shaped NPs have a high number of accessible binding sites[57]. At present, spherical nanocarriers appear to be more widely utilized compared to their nonspherical counterparts, primarily due to difficulties associated with synthesis and testing[58,59]. Shape exerts a significant influence on the biodistribution of NPs and their interaction with immune cells. Spherical NPs exhibit high internalization efficiency by immune cells[60], whereas the spiky particles can activate the innate immunity[61].

Surface charge: Nanocarrier surface charge affects their stability and biodistribution. Positive charge has been shown to promote NP internalization rates and enhance their cellular uptake. Subsequent intracellular trafficking reveals that some positively-charged NPs can dissociate from lysosomes following internalization and show perinuclear localization, whereas negatively- or neutrally-charged NPs are more co-localized with lysosomes. Positively-charged NPs are likely absorbed by cells due to the enhanced electrostatic attraction between NPs and negatively charged cell membrane[62], but they also run the risk of setting off unwanted immune responses. On the other hand, negatively- or neutrally-charged NPs are preferable to drain freely to lymphatic vessels, then effectively reach the lymph nodes[54] and can stick around longer in the bloodstream[63]. In addition, nanomedicines with neutral or low negative charges may be more effective in targeting dendritic cells and macrophages.

Elasticity: Emerging research has also revealed the potential of elasticity as a key parameter for the immunoregulation of NPs. Tumor associated macrophages (TAMs) could be repolarized to M1 by the soft silica NPs. According to further mechanistic analysis, NP elasticity reprograms TAMs by activating the mechanically sensitive protein Piezo1[64].

Surface modification and ligand decoration: To achieve targeted interactions between NPs and cells, particle surfaces are commonly modified with ligands capable of recognizing distinct cellular structures. Core materials and ligands both influence NP surface hydrophobicity and cellular absorption. Modifying NPs with ligands can prolong circulation time, facilitate specific endocytosis, improve cellular uptake, and reduce cytotoxicity[65,66]. Particle size and the density of receptors or ligands[67] have been identified that can affect the multivalent binding of nanomaterials, and consequently influence the targeting ability of NPs. Surface modification has an important effect on regulating the interaction of NPs with immune system. PEGylation can enhance colloidal stability and prolongs circulation time. Uptake studies revealed that PEGylation-driven remodeling of protein corona on NPs influences macrophage recognition[68]. Glycosylation is also a common surface modification. The NPs with glucose-modification promoted M1 macrophage polarization and enhanced antitumor immunity through interaction with Toll-like receptor 4 (TLR4)-MD2 complex[69]. The cell membrane mimicking coating not only endows NPs with immune escape and homologous targeting capabilities but also integrates drug delivery and immunomodulatory functions through multiple modes[70,71].

Solubility: Hydrophilic NPs to encapsulate these drugs can improve drug solubility, thereby boosting drug bioavailability. Polyethylene glycol (PEG)-coated NPs can improve both stability and solubility[72,73].

Targeted drug delivery: NPs are engineered to target certain anatomical sites. To enhance drug delivery to tumor tissues or cells, NDDSs are functionalized with various specific ligands onto their surfaces, enabling selective recognition of tumor vasculature or malignant cells. They are capable of delivering their payloads via active or passive targeting mechanisms.

Passive targeting is NP accumulation inside or beyond the fenestrae of tumor blood vessels, which are characterized by their disordered and leaky structure. The extent of drug accumulation and effective delivery is determined by the capacity of the NDDSs in overcoming biological barriers as well as their intrinsic properties[74]. NPs’ capacity in specifically recognizing their target sites can be improved through targeting ligands, which are chemically bound onto NP surface. Such a strategy is called active targeting. This process involves specific binding of target cells with DDS, mediated by receptor–ligand interactions[75]. Active targeting is dependent on surface modifications using specific peptides, ligands[76], or coatings to enhance the identification and attachment to tumor cell surfaces[77]. In practice, the therapeutic success of these approaches depends on both carrier design and biological barriers in the TME. As an innovative nanovesicle delivery platform, camptothesome exhibits a high drug-loading capacity and strong stability. The research has confirmed that the utilization of cell-penetrating peptides can enhance the delivery efficiency of camptothesome and maximize its therapeutic index to improve the treatment of CRC[78].

Stimuli-responsive and triggered release systems: Drug release from different NPs is regulated by applying specific triggering mechanisms[79]. Stimulus-responsive NPs can retain their structural integrity during circulation and release the payload in response to certain external or internal stimuli[80,81] (Figure 1). These triggering factors can originate internally, such as variations in local temperature, pH levels, redox conditions, and enzymatic activity[82], or externally, including induced heating, ultrasound, magnetic fields, and light exposure[83]. At present, investigations are increasingly directed toward integrating internal and external stimuli for improving NDDS effectiveness.

Figure 1 The most popular nano-drug delivery system designs. The ability of nanoparticles (NPs) to specifically recognize their target sites can be improved through the use of targeting ligands, which can be chemically conjugated to the NPs surface. Stimulus-responsive NPs are designed to remain their structural integrity during circulation and to release their payload when exposed to specific external or internal stimuli. A: Passive targeting is NP accumulation inside or beyond the fenestrae of tumor blood vessels; B: Active targeting involves specific binding of target cells with drug delivery systems, mediated by receptor-ligand interactions; C: The triggering factors of stimuli-responsive drug release can originate internally, such as variations in local temperature, pH levels, redox conditions, and enzymatic activity, or externally, including induced heating, ultrasound, magnetic fields, and light exposure.

NDDSS IN TARGETED THERAPY OF CRC

Promising role of nanotherapeutics in CRC

The application of NPs as drug carriers in colon-targeted therapies represents one emerging technique. NP properties exert a key effect on comprehensively understanding their interactions with biological systems[84]. Suitable characteristics can efficiently deliver NPs to targeted tissues and cells and maximally reduce adverse reactions through reduced drug accumulation in nontargeted areas of the body[85]. Currently, there are various organic and inorganic NPs, which vary in size, structure, and composition[50,86]. For CRC, such NPs are mainly given orally, intravenously or transrectally[87,88], providing a minimally invasive approach to drug delivery. Nanotherapeutics in CRC have potential in various fields, including chemotherapy, immunotherapy, radiotherapy, photothermal therapy (PTT), and targeted delivery using DNA/RNA (Figure 2).

Figure 2 Emerging potential of nanotherapeutic strategies in colorectal cancer management. Nanotherapeutics in colorectal cancer hold promising role in various fields, including chemotherapy, immunotherapy, radiotherapy, photothermal therapy, targeted delivery using DNA/RNA, and stem cell therapy. CRC: Colorectal cancer; PTT: Photothermal therapy; PDT: Photodynamic therapy.

Many types of materials have been designed for NPs, which can be synthesized using organic or inorganic materials. Quantum dots (QDs), gold NPs (AuNPs), magnetic NPs, and silica NPs are common inorganic NPs[89]. Inorganic NPs are typically synthesized from metallic elements, metal oxides, and nonmetallic materials such as carbon and silica. Organic NPs consist of natural or synthetic compounds, including polymer-based NPs (dendrimers, hydrogels, polymeric micelles) and lipid-based NPs (liposomes, nanoemulsions, solid lipid NPs)[90-92]. In the treatment of CRC, organic NPs like liposomes or polymer-based NDDSs have reached a mature stage of development, with several having already received approval from the FDA[20,93] (Table 2). In contrast to organic NPs, inorganic NPs possess distinctive characteristics such as outstanding photosensitivity, excellent electrical conductivity, superior optical properties, magnetic responsiveness, and thermal stability, and function as drug carriers and therapeutic agents[94] (Table 3). Their ease of synthesis, large surface area, and excellent mechanical and chemical stability highlight their distinct advantages, including enhanced quantum yield and increased drug-loading capacity[95]. Thanks to the above-mentioned merits, inorganic NPs like mesoporous silica NPs and CNTs are extensively utilized in specialized drug delivery carriers. Meanwhile, other inorganic materials like QDs, silver NPs (AgNPs), and AuNPs serve both as carriers and as effective therapeutics themselves. Their efficacy against cancer suggests they could also be useful for CRC treatment[96] (Table 4). So organic and inorganic NPs are not just chemically different; they also differ in how close they are to real-world clinical use and what functions they perform. Organic systems can be more established in clinical practice, whereas inorganic ones tend to offer a broader range of diagnostic and therapeutic options.

Table 2 Summary of organic nanomaterial-based in vitro and in vivo studies in colorectal cancer.

Nanoformulation	Compound/system	Model	Key findings	Ref.
Dendrimers	Au NR@PAMAM-GX1/FAM172A	In vitro (HCT-8, L929 cells) and in vivo (tumor-bearing mice)	Reduced cell viability to ~20% under laser irradiation; enabled combined gene and photothermal therapy	Ye et al[143], 2021
Dendrimers	G5-HP/CpG	In vitro (MC38 cells) and in vivo (tumor-bearing mice)	Induced tumor ablation and immunogenic cell death	Zhong et al[145], 2025
Liposomes	Metformin + 2-deoxyglucose-loaded liposomes	In vitro (CT26 cells) and in vivo (tumor-bearing mice)	Demonstrated efficacy in both localized and metastatic CRC models	Li et al[150], 2024
Liposomes	LBP-CD155 L nanovesicles	In vitro (HT-29 cells) and in vivo (tumor-bearing mice)	Enhanced therapeutic efficacy in CRC through immune modulation	Yan et al[151], 2025
Polymeric nanoparticles	EpCAM aptamer-functionalized 5-FU-loaded PLGA NPs (Ap-FU-NPs)	In vitro (HCT-116, CT-26, HEK-293 cells) and in vivo (tumor-bearing mice)	Showed targeted delivery and enhanced efficacy in EpCAM-overexpressing CRC cells	Yavari et al[155], 2023
Polymeric nanoparticles	Berberine-loaded PEG-PLGA NPs	In vitro (HCT-116 cells) and in vivo (tumor-bearing mice)	Improved tumor accumulation, sustained release, and enhanced anticancer activity	Shen et al[156], 2024

PAMAM: Polyamidoamine; CRC: Colorectal cancer; 5-FU: 5-fluorouracil; PLGA: Poly(lactic-co-glycolic acid); NPs: Nanoparticles; PEG: Polyethylene glycol; LBP: Lycium barbarum polysaccharides; CD155 L: CD155 gene in liposome.

Table 3 Summary of inorganic nanomaterial-based in vitro and in vivo studies in colorectal cancer.

Nanoformulation	Compound/system	Model	Key findings	Ref.
QDs	Carbon quantum dots-silver heterostructure (CQD/Ag)	In vitro (HCT116 cells)	Exhibited potent anticancer activity via Akt signaling with minimal toxicity to normal cells	Mishra et al[110], 2023
QDs	QD-P (PLAC-1-targeted quantum dots)	In vitro (HCT-29, HCT-116, LS-180 cells)	Demonstrated theranostic potential for detection and targeted treatment of PLAC-1-positive CRC cells	Haider et al[112], 2023
IONPs	5-FU-loaded IONPs with magnetic hyperthermia	In vivo (HT-29 tumor-bearing mice)	Showed significant tumor inhibition when combined with magnetic hyperthermia	Dabaghi et al[116], 2021
IONPs	5-FU-loaded IONPs	In vitro (Caco-2 cells)	Optimized formulation (IONP:5-FU = 1.5:1) showed highest antitumor activity	Predoi et al[117], 2023
IONPs	Oleic acid-modified superparamagnetic IONPs and PLL (OPPL nanodrug)	In vitro and in vivo (CRC models)	Enhanced tumor accumulation, increased cytotoxicity, and suppressed tumor growth	Li et al[118], 2024
CNTs	ADP@SWNT/TNFα	In vitro (HCT116 cells) and in vivo (tumor-bearing mice)	Suppressed tumor growth and metastasis; activity enhanced under near-infrared irradiation	Chen et al[125], 2022
CNTs	CNTs combined with 5-FU, tacrine, and ethionamide	In vitro (HT-29 cells)	Improved anticancer activity of both chemotherapeutic and repurposed drugs	Abreu et al[127], 2023
AuNPs	Cetuximab-conjugated AuNPs	In vitro (HT-29 cells)	Enhanced cytotoxicity and altered phenotypic behavior of CRC cells	El Hallal et al[136], 2021
AgNPs	Citrate-coated (AgNP-cit) and EG6OH-coated (AgNP-EG6OH)	In vitro (LoVo and HT-29 cells)	EG6OH-coated AgNPs showed minimal toxicity toward CRC cells and primary colonocytes	Barbalinardo et al[139], 2025

QDs: Quantum dots; Akt: Protein kinase B; CRC: Colorectal cancer; IONPs: Iron oxide nanoparticles; CNTs: Carbon nanotubes; AuNPs: Gold nanoparticles; AgNPs: Silver nanoparticles; 5-FU: 5-fluorouracil; PLAC-1: Placenta-specific protein 1.

Table 4 Comparative summary of major nanocarriers used in colorectal cancer drug delivery.

Nanocarrier class	Representative examples	Key properties	Main advantages in CRC	Main limitations	Typical applications in CRC
Polymeric nanoparticles	PLGA, PEG-PLGA, polymeric micelles, polymersomes, nanospheres	Biodegradable, tunable size and surface chemistry, controlled drug release	Good biocompatibility, sustained release, flexible ligand modification, suitable for small molecules and nucleic acids	Possible burst release, formulation complexity, scale-up challenges	Chemotherapy delivery, gene/miRNA delivery, combination therapy, targeted delivery
Dendrimers	PAMAM, poly(propyleneimine), poly(L-lysine) dendrimers	Highly branched 3D architecture, multiple surface groups, high loading capacity	Precise surface functionalization, strong drug/gene conjugation potential, useful for multifunctional systems	Potential toxicity at higher generations, synthesis cost, limited large-scale translation	Targeted chemotherapy, gene delivery, photothermal and photoimmunotherapy
Liposomes	Conventional liposomes, PEGylated liposomes, liposomal nanovaccines	Phospholipid bilayer vesicles with aqueous core, biocompatible, able to carry hydrophilic and hydrophobic cargo	Strong translational maturity, reduced systemic toxicity, good encapsulation flexibility, suitable for immunomodulators	Stability issues, leakage during storage, RES clearance if not optimized	Chemotherapy, metabolic therapy, immunotherapy, vaccine delivery
Nanoemulsions/Lipid nanoparticles	Nanoemulsions, solid lipid nanoparticles, lipid-based nanocarriers	Lipid-rich structure, good solubilization of hydrophobic drugs, oral-delivery potential	Improved bioavailability, useful for colon-targeted and mucosal delivery, relatively low toxicity	Physical instability, limited drug-loading for some agents, formulation sensitivity	Oral delivery, colon-specific release, hydrophobic drug delivery
Quantum dots	Carbon quantum dots, graphene oxide quantum dots, peptide-functionalized QDs	Strong fluorescence, tunable optical properties, nanoscale imaging capability	Theranostic potential, real-time tracking, combined imaging and treatment	Concern about long-term toxicity and clinical translation, especially for non-carbon systems	Imaging, biomarker-targeted detection, theranostics
Iron oxide nanoparticles	Superparamagnetic iron oxide nanoparticles, 5-FU-loaded IONPs, Fe3O4 nanocatalysts	Magnetic responsiveness, imaging capability, possible hyperthermia effects	Useful for image-guided therapy, magnetic targeting, hyperthermia, ferroptosis-related strategies	Need careful control of biodistribution and safety, variable tumor penetration	MRI contrast, magnetic hyperthermia, targeted chemotherapy, sonodynamic/chemodynamic therapy
Gold nanoparticles	AuNPs, antibody-conjugated AuNPs, drug-loaded AuNPs	High surface area, optical responsiveness, good surface functionalization	Useful for targeted delivery, photothermal therapy, receptor-specific systems, signal amplification	Cost, long-term accumulation concerns, translational standardization issues	Chemotherapy enhancement, receptor-targeted therapy, photothermal therapy
Silver nanoparticles	Citrate-coated AgNPs, surface-functionalized AgNPs	Reactive surface, antimicrobial and cytotoxic properties	Potential anticancer activity and carrier function	Greater concern about toxicity and off-target effects, less mature translational profile	Experimental cytotoxic systems, drug delivery carriers
CNTs	SWCNTs, MWCNTs, functionalized CNTs	High aspect ratio, large surface area, strong mechanical and thermal properties	Excellent loading capacity, membrane penetration, useful for photothermal and gene delivery strategies	Biopersistence and safety concerns, regulatory challenges	Drug delivery, gene delivery, photothermal therapy, combination therapy
Hydrogels/nanogel-associated systems	Thermosensitive hydrogels, injectable hydrogels, nanocomposite hydrogels	High water content, local depot effect, controlled release	Strong potential for local delivery, postoperative recurrence prevention, prolonged release	Limited systemic use, formulation-dependent stability, translation still emerging	Local drug delivery, postoperative CRC control, combination immunotherapy

CRC: Colorectal cancer; PLGA: Poly(lactic-co-glycolic acid); PEG: Polyethylene glycol; miRNA: MicroRNA; PAMAM: Polyamidoamine; QDs: Quantum dots; IONPs: Iron oxide nanoparticles; MRI: Magnetic resonance imaging; AuNPs: Gold nanoparticles; AgNPs: Silver nanoparticles; SWCNTs: Single-walled carbon nanotubes; MWCNTs: Multi-walled carbon nanotubes; RES: Reticuloendothelial system; CNTs: Carbon nanotubes.

Nanotechnology in ICB therapy: ICB has done remarkably well against CRC, but it still faces problems like side effects, drug resistance, and physiobiological barriers. To get around these issues, researchers have built a number of nanoplatforms aimed at making ICB work better for CRC. These nanoplatforms improve ICB efficacy in a few key ways: They deliver ICIs directly to tumors, boost the tumor’s own immunogenicity, and remodel the TME[97]. By using nanocarriers that are modified with targeted ligands for programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (like aptamers or antibodies), ICIs can be selectively concentrated in tumor tissues. That means higher local drug concentrations and fewer systemic immune-related adverse reactions.

Reversing immunosenescence to overcome ICI resistance: Immunotherapy, especially ICIs, has revolutionized CRC therapy, but the therapeutic effect is restricted by intrinsic or acquired resistance, largely attributed to immunosenescence in the TME. More than 95% of patients with CRC exhibit proficient mismatch repair status and their tumors are classified as immunologically cold, rendering them largely unresponsive to ICB[98]. Immunosenescence refers to the gradual decline of immune function that comes with aging or chronic inflammation. As a result, immune surveillance weakens and the body becomes less effective on clearing cancer cells. Since CRC patients are getting older, immunosenescence has become a major factor influencing tumor development, disease progression, and therapeutic efficacy. Immunosenescence displays the typical signs of impaired T-cell function, higher inhibitory checkpoint levels (like PD-1 and cytotoxic T-lymphocyte-associated protein 4), and defective antigen-presenting cells. All these create a suppressive loop that dampens ICI activity. Regulatory T cell expansion and exhausted CD8+ T cell accumulation foster the immunosuppressive TME promoting CRC immune escape[99]. In addition, senescent immune cells produce various proinflammatory factors, chemokines, growth factors, extracellular matrix components, and proteases - jointly termed the senescence-associated secretory phenotype (SASP). The extracellular matrix is secreted by cancer-associated fibroblasts, and serves as a reservoir for immunosuppressive cytokines. Aging tumor cells enhance the up-regulated levels, differentiation and recruitment of regulatory T cells, TAMs, and myeloid-derived suppressor cells through SASP, thereby exacerbating the immunosuppressive microenvironment[100]. SASP factors can induce epithelial-to-mesenchymal transition within tumor cells; a process strongly associated with enhanced therapeutic resistance and metastatic potential. Emerging research indicates that immunosenescence significantly promotes tumor progression and induces ICI resistance[101].

A combined strategy that targets both immunosenescence and immune checkpoints could be an important way to overcome ICI resistance in CRC. Nanocarriers offer an efficient means to achieve this synergy (Figure 3). On the one hand, they can precisely deliver immunosenescence-reversing agents (e.g., TLR agonists, cytokines, and senolytics) to TME, thereby reversing the SASP. For instance, NPs that encapsulate TLR7/8 agonist are the effective immunostimulatory adjuvant in antibody-based cancer immunotherapy through activating natural killer cells[102]. TLR7/8 agonists activate TLR7/8 via myeloid differentiation factor 88, which serves as a bridge for interleukin-1 receptor-associated kinase proteins. Subsequently, interleukin-1 receptor-associated kinase can activate nuclear factor kappa B and interferon regulatory factor 3/7, thereby promoting the transcription of pro-inflammatory cytokines and interferon genes. The immune stimulation leads to the subsequent activation of dendritic cells, macrophages, and T cells[103]. Galacto-conjugated NPs with senolytics (navitoclax) can be specifically activated by senescence-associated lysosomal β-galactosidase and can selectively induce senescent cell apoptosis to reduce tumor growth[104]. On the other hand, nanocarriers can simultaneously deliver ICIs to block abnormally activated immune checkpoint pathways, disrupting the vicious cycle of immunosenescence-high checkpoint expression. Multifunctional nanocrystals remodel TME through enhancing activation of CD8+ T cells and natural killer cells and decreasing myeloid-derived suppressor cells, thus eliminating primary and metastatic tumors without significant adverse reactions when combined with programmed death ligand-1 (PD-L1) blockade[105]. The epigenetic nanoagonist can combat PD-L1-resistant tumors through orchestrating coordinated, multilevel T cell immune responses[106]. These findings suggest that nanotechnology may do more than improve drug delivery. It also assists in turning a TME that is immunologically resistant into one that responds better to treatment.

Figure 3 Nanodrug-mediated synergy of immune checkpoint inhibitors and immunosenescence targeting. Nanocarriers-mediated delivery of immune checkpoint inhibitors and immunosenescence modulators (Toll-like receptor 7/8 agonists) to reprogram the immunosuppressive tumor microenvironment. TCR: T cell receptor; MHCI: Class I major histocompatibility complex; PD-1: Programmed cell death protein 1; PD-L1/2: Programmed death ligand-1/2; TLR7/8: Toll-like receptor 7/8; MyD88: Myeloid differentiation factor 88; IRAK: Interleukin-1 receptor-associated kinase; NF-κB: Nuclear factor kappa B; IRF3/7: Interferon regulatory factor 3/7; DCs: Dendritic cells; Treg: Regulatory T cell; MDSCs: Myeloid-derived suppressor cells; TAM: Tumor-associated macrophage; NK: Natural killer; TME: Tumor microenvironment.

Multimodal combination therapy: When multiple therapeutics are delivered together within a single NDDS, the approach has shown real promise for improving CRC treatment outcomes and for triggering immunogenic cell death. A peptide-grafted polymer-based nanorobot simultaneously blocking the PD-1/PD-L1 pathway while mechanically breaking tumor cell membrane effectively overcomes the immune escape mechanism in proficient mismatch repair-type CRC, offering a safe and promising strategy for clinical management of immunologically cold tumors[98]. A co-delivery nanoplatform for cascade combined immunotherapy and chemotherapy against CRC overcomes immune escape and off-target effects[107]. These multimodal approaches are particularly attractive in CRC because of the complex and heterogeneous barriers that limit the success of monotherapy.

Application of NDDSs in treatment of CRC

Inorganic NPs: QDs - QDs are nanoscale semiconductor crystals, measuring 1-15 nm, that are recognized for their remarkable optical properties[108]. QDs exhibit a range of favorable properties as DDSs, such as their simple and efficient synthesis, ability to be conjugated with various drugs, adjustable physicochemical attributes, and special optical characteristics facilitating real-time tracking and post-administration monitoring[109]. QDs are well-suited for targeting CRC due to their high electrical conductivity, superior mechanical strength, effective thermal conductivity, favorable optical behavior, and distinct fluorescence emission/excitation capabilities[110].

Carbon QDs have garnered significant research interest as candidate components to diagnose and treat tumor; largely attributed to their tunable fluorescence emission and excitation properties. The carbon QD/Ag heterostructure demonstrated no cytotoxic effects on normal cells and displayed potent anticancer activity through the protein kinase B signaling pathway[110]. In contrast to this study, another study not only explored the role of peptide-functionalized graphene oxide QDs in the treatment but also analyzed their value in the diagnosis of CRC. Placenta-specific protein 1 is markedly upregulated within CRC and is a promising biomarker with potential applications in diagnosis and targeted therapy[111]. QD-P has been developed as the promising theranostic agent to detect and target placenta-specific protein 1-expressing colon cancer cells[112]. Further research is still required to elucidate the mechanisms of cytotoxicity and genotoxicity of QD-P on CRC cells. All in all, the main advantage of QDs is that they can be used for imaging and therapy simultaneously. But whether they’re actually useful in clinical practice depends on keeping that dual function without causing toxicity problems. Moreover, there are still relatively few studies on the application of QDs in the immunotherapy of CRC at present.

Iron oxide NPs (IONPs): IONPs serve as efficient nanoplatforms. Their unique magnetic and biological traits give them a notable ability to deliver great drug payloads in a targeted way[113]. Multifunctional magnetic NPs are getting more attention for their wide usefulness, especially as contrast agents used for magnetic resonance imaging[114]. One thing that sets IONPs apart is that they’re biodegradable, which means they are eliminated out of the body efficiently when they are used[115]. IONPs have diverse applications, including molecular imaging, targeted drug delivery, and hyperthermic therapy.

Regarding the application of IONPs in the chemotherapy of CRC, when used in combination with magnetic hyperthermia or loaded with 5-fluorouracil (5-FU), IONPs showed strong tumor suppression in CRC mouse models[116]. The same study found that a nano-formulation (IONP-to-5-FU ratio, 1.5:1) worked best against tumors. A decrease in minichromosome maintenance complex component 2 expression was detected within Caco-2 cells following exposure to 5-FU-loaded IONPs[117]. The synthesis methods and characterization techniques of IONPs vary between the two studies. Establishing a unified efficacy evaluation standard in subsequent research would facilitate a more effective comparison of the efficacy of IONPs across different studies. Oleic-acid-modified superparamagnetic IONPs have been shown to effectively trigger tumor ferroptosis and overcome Fusobacterium nucleatum (Fn)-induced chemoresistance in CRC[118]. The dual antibacterial and chemotherapeutic nanodrugs proposed in this study offer a promising strategy for the management of refractory Fn-infected CRC. The tumor-targeting biomimetic sonosensitizer-conjugated Fe₃O₄ nanocatalysts were capable of significantly enhancing CT26 cell apoptosis and markedly inhibiting tumor growth in mice[119]. This study uniquely demonstrates the application of IONPs in the combined chemodynamic-sonodynamic therapy for CRC. Collectively, these findings indicate that IONPs are especially valuable when integrating imaging, magnetic responsiveness, and therapeutic delivery in a single platform.

CNTs: CNTs, which belong to the family of carbon allotropes, are cylindrical nanostructures composed of rolled graphene layers, characterized by diameters < 1 μm and lengths extending to several micrometers[120]. CNTs come with some unique physicochemical traits - they have a needle-like shape, a huge surface area, high chemostability, and high thermal conductivity. Those traits make them promising for gene therapy, immunotherapy, and as carriers in DDSs[121]. Structurally, CNTs have hexagonal structures made from small tubular carbon atoms[122]. Depending on how many carbon layers they have, they are grouped into single-walled, double-walled, multi-walled, and functionalized types[123].

Single-walled carbon nanotubes comprise one graphene layer rolled into a cylinder. Functionalized SWCNT/II-NCC hybrids are even active relative to capecitabine[124]. In terms of the application of CNTs for the PTT of CRC, ADP@SWNT/TNFa was able to inhibit tumor development and metastasis, and its anticancer effect was even stronger upon NIR irradiation[125]. Regarding the application of CNTs in the chemotherapy of CRC, another antitumor study verified that gemcitabine-loaded, hyaluronic acid-conjugated PEGylated multi-walled CNTs (GEM/HA-PEG-MWCNTs) dramatically reduced tumor volume and elevated survival rates, without causing major body weight loss[126]. Meanwhile, both 5-FU and tacrine worked better when given together with CNTs[127]. The shortcoming of the two studies is that it is necessary to enhance these formulations to reduce toxicity and improve targeting in terms of endosomal escape and drug loading efficiency. All these results highlight the potential of CNTs, though questions about long-term safety and clinical acceptance should be solved before they can be widely used. There are relatively few studies on the specific responses of CNTs to different molecular subtypes of CRC, which may serve as a breakthrough point for future research.

AuNPs: AuNPs have a distinctive wine-red color and antioxidant effects. Their size is within 1-1000 nm. Thanks to their stable structure, large surface area, superb optical traits, and low toxicity, they are suitable for local hyperthermia and targeted drug delivery into cancer tissues[128,129]. Because of the above excellent features, AuNPs are being studied and used in phase 1 and 2 clinical studies for cancer treatment[130].

In CRC, AuNPs are utilized as straight-up carriers and as effective agents that enhance treatment response. For example, AuNPs made cisplatin delivery more effective and improved tumor growth inhibition through helping to decompress blood vessels inside CRC tumors[131]. Anti-epidermal growth factor receptor-coated functionalized AuNPs are promising - they can deliver 5-FU directly to CRC cells, which could turn into a new therapeutic strategy[132]. The synthesized 5-FU/glutathione-AuNPs formulation interfered with cell cycle progression and exhibited a twofold higher anticancer efficacy than free 5-FU[133]. The antitumor efficacy of chemotherapeutic agents may be significantly improved through conjugation of oxaliplatin’s effective component onto AuNPs[134]. Similar to the combination of AuNPs and chemotherapy drugs for the treatment of CRC, AuNPs are also a potential strategy in CRC therapies for combined with targeted therapy. Cetuximab-AuNPs promoted epidermal growth factor receptor endocytosis, resulting in more pronounced suppression on cell growth and accelerated apoptosis, in comparison with AuNPs or cetuximab[135]. Cetuximab-conjugated AuNPs affected cytotoxicity and phenotypic evolution of CRC cells[136]. The mechanism of cell death induction and cytotoxic effects mediated by GNP-cetuximab still needs to be studied in vivo. Overall, AuNPs appear especially attractive for combination strategies that merge drug delivery with optical or receptor-targeted effects.

AgNPs: AgNPs have been used to address the growing challenges posed by drug-resistant microorganisms. AgNPs were evaluated in colon cancer cells, demonstrating a significant reduction in cancer cell viability[137]. AgNPs are extensively used as nanocarriers for delivering anticancer agents to tumor tissues[138]. AgNPs-EG6OH exhibited no substantial toxicity toward HT-29 cells or primary colonocytes[139]. Although these findings are promising, the therapeutic role of AgNPs in CRC is less mature than that of other inorganic platforms, and their safety profile still requires careful evaluation.

Organic NPs: Dendrimers refer to 3D, spherical macromolecules possessing a heavily branched structure. Thanks to their biodegradable backbones, they have become quite promising in nanopharmaceutical applications. Among the many nanomaterials available, dendrimers are one of the most widely used - especially in CRC chemotherapy, where they help improve drug solubility, stability, and overall bioavailability. Their heavily branched polymer structure makes it easy to attach or encapsulate therapeutics[140]. Functionalized dendrimers can boost the chemotherapeutic efficacy of CRC agents and reduce their systemic toxic effects. This is why dendrimers are seen as smart nanocarriers for CRC chemotherapy. Of all the types out there, polyamidoamine (PAMAM), poly(propyleneimine), and poly(L-lysine) dendrimers are studied most for delivering anticancer drugs[141].

What really makes dendrimers useful is the flexibility that we can get with surface chemistry and how much cargo they can carry. For instance, sialyl Lewis X antibody-conjugated PAMAM dendrimers have shown substantial promise in the capture and inhibition of CRC cell circulation[142]. Another study explored the integration of novel nanomaterials with both diagnostic and therapeutic functions into a single nanoplatform. HCT-8 cells exposed to Au NR@PAMAM-GX1/FAM172A had only 20.45% of viability upon laser irradiation - much lower than that obtained with single-modality treatments single-mode PTT or gene therapy. In animal experiments, these complexes were able to perform tumor thermal imaging and gene therapy after being given intravenously[143]. This research uniquely devises an innovative combined treatment platform based on dendrimer-stabilized gold nanorods, encompassing PTT and gene therapy. This nanoplatform holds great potential in the field of integrated diagnosis and treatment for CRC with its computed tomography and thermal imaging capabilities. Another piece of research looked at 5-FU/PAMAM complexes within four different tumor cell lines and found that the IC₅₀ of 5-FU went down by as much as 30%[144]. The issues regarding the stability of 5-Fu and the fate of the conjugates in organisms require further investigation. In the application of dendrimers combined with immunoadjuvants for enhanced photoimmunotherapy of CRC, hematoporphyrin-modified G5 PAMAM nanomaterials also showed strong photodynamic activity and excellent photothermal conversion efficiency, which allowed them to effectively kill tumor cells and trigger immunogenic cell death[145]. All these examples point to one thing: Dendrimers are especially handy when we need a multifunctional system, especially one that combines imaging and therapy.

Liposomes: Liposomes are spherical vesicles made up of at least one concentric lipid bilayer and possess an aqueous core enclosed by an amphiphilic phospholipid membrane[146,147]. Due to their biodegradability and non-toxicity, they are considered ideal candidates for direct injection into the bloodstream[148]. Their clinical track record also makes them particularly important when talking about real-world translational potential in CRC.

Recently, liposomal systems are suggested to do more than just carry drugs - they can also support metabolic targeting and immunomodulation. One study found that dual-drug loaded liposomes bearing apigenin and 5-Fu improved the inhibition of blood vessel formation and activated apoptotic pathways more effectively. Cell signaling analysis showed that these dual-drug liposomes markedly upregulated phosphorylated AMP-activated kinase and had great effects on downstream targets, suggesting that they are involved in abolishing the Warburg effect[149]. There is further scope for improving the formulation to enhance the stability of the formulation over time. Another formulation, liposomes co-loaded with 2-deoxyglucose and metformin worked well against localized and metastatic CRC through reducing radioresistance while preventing T cell exhaustion[150]. This research provides a viable strategy and important reference for addressing the issue of poor efficacy in fractionated radiotherapy for clinical CRC patients. There was also a liposome-based nano-vaccine (LBP-CD155 L NVs) that carried the CD155 gene; it enhanced dendritic cell uptake and maturation via a TLR4- and monoacylglycerol lipase-mediated mechanism. In a CRC mouse model, this formulation made therapeutic interventions more effective[151]. This nanovaccine may serve as a promising tool for reversing the immunosuppressive TME and enhancing ICB therapy in CRC. Future research can focus on investigating its combination with other emerging immunotherapies in the treatment of CRC and exploring its potential in clinical translation. A series of explorations are conducted on strategies for improving the pharmacokinetic properties and targeting ability of liposome formulations. The pH-responsive and folate-coated liposomes encapsulating irinotecan have significantly better antitumor activity and no evidence of systemic toxicity[152]. Relative to additional organic platforms, liposomes can be particularly attractive since they are flexible and can be translated into drug and immunotherapy delivery.

Polymeric NPs: Of the various polymeric NPs, poly (lactic-co-glycolic acid) (PLGA) represents the biodegradable polymer that has been approved by the United States FDA and widely investigated for biomedical use. Another material, PEG-PLGA, is an amphiphilic polymer with biocompatibility and biodegradability, and it is usually utilized as a nanocarrier[153]. Such materials are popular since they allow controlled drug release, improve formulation stability, and are easily modified for targeted delivery.

In one study, according to in vitro cytotoxicity tests using HT-29 CRC cells, 5-FU loaded into FOL-PEG-PLGA NPs had an IC₅₀ roughly four times lower than 5-FU loaded into plain PLGA NPs[154]. NPs made from PLGA and activated with an epithelial cell adhesion molecule aptamer - referred to as (AP-FU-NPs) - proved to be an efficient platform for delivering 5-FU specifically to CRC cells that overexpressed epithelial cell adhesion molecule[155]. Berberine-loaded PEG-PLGA NPs substantially enhanced drug accumulation and prolonged targeted delivery at tumor site, resulting in maximum apoptosis and suppression of cell proliferation[156].

These systems have also been extended to gene-based strategies. To address the drawbacks of free synthetic microRNAs, including easy degradation in biofluids and poor cellular uptake, it is essential to develop innovative delivery systems for microRNAs. PLGA/PLA-PEG-FA loaded with miR-204-5p (FA-NPs-miR-204) were absorbed into HT-29 and HCT-116 cells, suppressing cell proliferation while promoting apoptosis[157]. Sorafenib and PEDF, a potent antiangiogenic gene, were co-encapsulated into PEG-PLGA NPs, resulting in significant tumor growth inhibition[158]. Overall, polymeric NPs are versatile organic carriers in CRC because they can accommodate both small molecules and nucleic acid-based therapeutics while remaining compatible with targeted design strategies.

CHALLENGES AND FUTURE PERSPECTIVES

Challenges

Every opportunity is accompanied by challenges, and NDDSs are no exception. The failure rate reached 52% during phase 2 clinical trials, increasing to a maximum of 86% in phase 3 trials. Of these failures, 71.4% in phase 2 and 100% in phase 3 were primarily attributed to inadequate therapeutic effectiveness[159]. The challenges limiting the success of NDDSs are potential nanocarrier toxicity, cost-effectiveness of the delivery system, cancer heterogeneity, and absence of specific regulatory guidelines[160]. The restricted clinical translation of cancer nanomedicines from animal models to human subjects has been partly linked to two key factors: (1) An insufficient availability of representative models capable of translating pharmacokinetic and biodistribution data on NPs from preclinical animal trials to human applications[161]; and (2) Diminished NP accumulation within tumor tissues[162,163]. The unique anatomical location and microenvironmental characteristics of CRC present special challenges for nanodrug delivery, among which the most prominent issues are the mucus barrier, the interaction with gut microbiota, and tumor heterogeneity.

Safety concerns: As emphasized in this review, the practical application of nanotechnology may encounter several problems. The primary concern lies in the insufficient evaluation or regulation of safety and health issues arising from NPs’ distinctive properties by relevant authorities[164]. It is urgently needed to design nanomaterials showing enhanced biocompatibility and degradability to address those challenges posed by current limitations in industrializing and clinically translating NDDSs.

The toxicity observed with some NPs must not be ignored when evaluating the potential of nanomedicine for widespread clinical practice. Many animal studies investigating the toxicological effects of nanomaterials have been conducted; however, research on toxicity in human subjects remains limited[165]. Recently, NPs have been increasingly combined with natural compounds to address toxicity concerns[166]. Therefore, the incorporation of “green” NPs into DDSs holds potential for reducing the incidence of adverse drug effects.

Cost issues: The cost considerations involved in NDDSs include multiple components such as capital expenditure on equipment and technology, cost of raw materials, expenditure on quality control and testing, and expenses linked to safety assessments[167].

Lack of standardization and scalability: Although many nanocarrier-based anticancer therapies are currently under development, the number approved by the FDA remains low[168]. One major hurdle for nanomedicines in clinical use is that no dedicated regulatory guidelines cover their research and characterization. People keep debating whether current regulatory frameworks and protocols are up to the job, and that has turned more attention to the potential risks of nanotechnology. These concerns include possible toxic effects of NPs, unintended biological consequences from the blood-brain barrier crossing ability, and long-term unknowns after NP administration[169].

Low delivery efficiency of NPs: Even though NDDSs help therapeutics build up within tumors via passive or active targeting, the reality is that less than 0.7% of the given chemotherapeutic will reach the tumor[170]. The low delivery efficiency to CRC is a basic barrier to translating NDDSs into clinical practice. Researchers have constructed a deep neural network model for predicting tumor delivery rate, and two key factors turned out to be zeta potential and core material[171,172]. Taking these factors into account, several dimensions are involved in the clinical development of nanomedicines, which requires careful attention to some critical areas: Biological development, manufacturing processes, intellectual property management, biocompatibility and safety assessments, regulatory compliance, and whether the cost is reasonable compared with traditional treatments[173,174]. These factors can become major barriers that keep nanomedicines from reaching the market, no matter how well they work therapeutically.

Mucus barrier: The mucus barrier is the first big obstacle to delivering nanomedicines orally. The colonic mucosal structure is covered with a heavily hydrated, cross-linked gel layer. Goblet cells secrete and form extracellular mucus. Mucins entangle with each other and form a dense fibrous network, thereby restricting the entry of NPs. Meanwhile, intestinal epithelial cells may absorb NPs, leading to transcytosis or degradation of the NPs[175]. That dramatically cuts down the bioavailability of nanomedicines given through oral administration.

Microbiota interaction: Interactions of gut microorganisms also make it challenging to use nanomedicines in clinical practice. The gut microbiota is closely associated with the occurrence and development of CRC. On one hand, specific pathogenic bacteria such as Fn can secrete virulence factors, activate carcinogenic signaling pathways, and reshape the immune microenvironment. On the other hand, the gut microbiota may also affect the metabolism and stability of nanomedicines, and may lead to dysbiosis after being non-specifically taken up by nanocarriers[176].

Tumor heterogeneity: CRC is a highly heterogeneous malignant tumor, which is manifested at multiple levels, including differences in gene mutation profiles, TMEs, and spatiotemporal heterogeneity (differences between primary and metastatic lesions). This heterogeneity renders nanomedicines targeting a single target ineffective for all patients and all tumor regions, and it is also a core reason for limited clinical translation.

Future perspectives

Although nanotechnology is advancing rapidly and multifunctional nanomedicines are being developed, the corresponding research remains at the beginning stage. These delivery systems were mostly developed and evaluated in small animal models, demonstrating promising therapeutic outcomes. However, it is challenging to translate such results in effective clinical applications[85]. To accelerate the clinical application of research findings, many critical issues must be resolved.

To enhance drug accumulation within tumor tissues, an effective strategy involves increasing nanocarrier permeability and retention through developing step-by-step targeted NDDSs. These systems are capable of selectively increasing vascular permeability, promoting drug-loaded NPs infiltration in tumor sites, and accurately targeting tumor cells as well as subcellular organelles. Pharmacological and physical combination therapies are utilized to modulate the TME[177]. Nano-interventions can be integrated with chemotherapy, gene therapy, and photodynamic therapy, to elicit synergistic effects in CRC[178]. To improve colon-specific drug delivery by controlled drug release, NPs with enteric coatings demonstrate significant potential in enhancing the efficacy of anticancer drugs like 5-FU, due to improved delayed, prolonged, and sustained drug release profile within colonic tissues[77]. Future advances in NDDSs for CRC therapy should emphasize pH-responsive drug release mechanisms and incorporation of certain targeted abilities directed at CRC cells. These strategies may be particularly relevant in CRC because local delivery must overcome mucus barriers, variable luminal conditions, and marked intertumoral heterogeneity.

In response to the mucus barrier, researchers have developed a variety of penetration strategies. Surface PEGylated NPs can significantly enhance their diffusion ability in mucus[179]. In addition, co-delivering mucolytics with nanomedicines can reduce the viscosity of mucus. Moreover, robotic NPs can be used to penetrate the mucus barrier[180].

Fn is present within CRC, and this is a significant cause of drug resistance. To overcome this obstacle, a multifunctional nanoplatform capable of both inhibiting pathogenic bacteria and killing tumor cells can be constructed. For instance, a nano-catalytic DDS can be utilized to disrupt the symbiotic relationship between CRC cells and Fn, achieving synergistic antibacterial and antitumor therapy[176]. Meanwhile, probiotics and chemotherapeutic drugs can be co-delivered through nanocapsulation technology, which restores the gut microbiota balance and enhances antitumor immune response[181].

Personalized therapy is another important future direction. In the face of tumor-specific challenges, nanocarriers with tumor-site-specific intelligent response and dynamic regulation are prepared for precisely releasing drugs into the TME. Personalized nanodrug combinations must be tailored according to the molecular subtypes of CRC and the traits of the gut microbiota to achieve precise treatment[182]. DNA/RNA-based anticancer approaches exhibit considerable promise in enabling more precise and safer treatment modalities. Consequently, the engineering of nanocarriers that can deliver DNA/RNA for selectively targeting and eradicating cancer cells constitutes a compelling direction for ongoing and future research[183]. We assert that promoting interdisciplinary collaboration among experts in drug delivery, molecular biology, and clinical oncology is indispensable for driving successful implementation of personalized therapeutic strategies[184].

A major area for future development is improvement of preclinical modeling. The enhanced permeability and retention effect displays substantial heterogeneity among mouse tumor models with differing vascular pathophysiological profiles, as well as notable variation among patients attributable to individual physiological and genetic factors[185]. So, to get past these challenges, we need new tools, better technologies, and smart strategies. One approach that has been developed is physiologically based pharmacokinetic (PBPK) modeling, which can forecast how different NP formulations distribute in the body - in both preclinical rodent models and humans[186]. Applying engineered microfluidic tumor-on-a-chip platforms along with 3D in vitro systems is an excellent example. These are designed to mimic key features of the tumor TME and vascular structure, which helps us better understand how NPs infiltrate tumor tissues in real clinical settings[187]. Although 2D cell culture platforms are simpler and useful for initial screening, 3D models allow for more rigorous testing of NP safety and effectiveness[188].

Artificial intelligence demonstrates is playing a growing role here. It holds great promise for making hierarchical targeting strategies more precise, and for enhancing the safety and efficacy of NDDSs[171,189]. An artificial intelligence-driven PBPK model offers a robust, animal-free screening tool that can quickly predict how efficiently NPs will be delivered according to the physicochemical traits[190]. These tools could help researchers figure out which nanoplatforms are worth taking forward before committing to expensive in vivo studies and clinical trials. Recent progress in microfluidic tumor-on-chip models and PBPK modeling has made it possible to simulate the CRC TME more accurately, which in turn allows for better assessment of nanocarrier delivery and immune interactions. In functional studies that use a microfluidic tumor chip platform, GAD1 upregulation is related to greater metastatic potential in CRC[191]. A PBPK model has been developed to evaluate drug-drug interactions and optimization in capecitabine and irinotecan combination regimen[192]. In the developed PBPK model, the influence of different tumor burden levels was explored to achieve the prospective prediction of aldehyde oxidase substrates in the CRC liver metastasis population[193].

The future of NDDSs in CRC will not just depend on developing fancier NPs, but on constructing stronger pathways from bench to bedside. The systems that are most likely to succeed will be those that integrate biological precision, safety, ease of manufacturing, and real-world clinical practicality.

CONCLUSION

Using nanotechnology in DDSs is the promising approach for improving CRC therapy, but there is still a long road ahead. Major challenges remain before this approach can be widely used in the clinic. Stronger collaboration across different disciplines and between research teams will be essential for moving NDDSs forward in CRC treatment. This review hopes to shed novel lights on how nanodrug delivery technology can be used to treat CRC.

ACKNOWLEDGEMENTS

We would like to thank all the authors and reviewers for their contribution to this special issue.