Nanotechnology-based cytokine delivery strategies in gastrointestinal cancers.

Gastrointestinal (GI) cancers, including colorectal, gastric, and esophageal malignancies, remain a major global health burden, with high incidence and mortality despite advances in diagnostics and conventional therapies. Cytokine-based immunotherapies have emerged as promising strategies to modulate the tumor microenvironment and enhance antitumor immunity. However, their clinical translation is limited by rapid degradation, systemic toxicity, and poor tumor-specific delivery. Nanotechnology-driven delivery platforms, including liposomes, polymeric nanoparticles, exosomes, hydrogels, and smart nanocarriers, offer innovative solutions by enabling targeted, controlled, and sustained cytokine release. These systems enhance immune cell activation, reprogram the tumor microenvironment, and synergize with immune checkpoint inhibitors, chemotherapy, radiotherapy, and adoptive T cell therapies. Recent preclinical studies demonstrate that engineered nanoparticles can amplify CD8⁺ T and NK cell responses, reduce off-target effects, and improve therapeutic outcomes in GI cancers. Advanced designs,such as layer-by-layer nanoparticles, receptor-targeted liposomes, and multifunctional nanocarriers allow localized cytokine delivery, improved, tumor-specific accumulation, and reduced systemic toxicity. Despite these advances, challenges remain, including biological barriers, cytokine instability, immunogenicity, and manufacturing complexity. Future directions lie in precision nanomedicine and synthetic biology approaches integrating engineered cytokines with multifunctional nanocarriers to achieve safe, effective, and patient-specific immunotherapy. Collectively, nanotechnology-driven cytokine delivery represents a transformative approach with the potential to overcome current limitations and enhance the efficacy of immunotherapy for gastrointestinal malignancies.