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

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.

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.