Next-generation nanocarriers for colorectal cancer: passive, active, and stimuli-responsive strategies for precision therapy

Colorectal cancer (CRC) remains a major global health burden, necessitating more effective and selective therapeutic approaches. Nanocarrier-based drug delivery systems offer significant advantages by enhancing drug accumulation in tumors, reducing off-target toxicity, and overcoming resistance mechanisms. This review provides a comprehensive overview of recent advancements in nanocarriers for CRC therapy, including passive targeting via the enhanced permeability and retention (EPR) effect, and active targeting strategies that exploit specific tumor markers using ligands such as antibodies, peptides, and aptamers. Additionally, various stimuli-responsive systems are explored, which leverage tumor-specific cues—such as pH, redox, enzymes, light, heat, and magnetic fields—for controlled and localized drug release. Multifunctional and hybrid platforms combining multiple targeting mechanisms and therapeutic functionalities are also discussed for their potential in theranostics and personalized medicine. Unlike prior reviews, this article emphasizes emerging ligand-engineered nanosystems, multi-stimuli-responsive designs, and translational challenges, providing a forward-looking perspective on next-generation CRC nanomedicine. While preclinical studies demonstrate encouraging outcomes, clinical translation remains limited due to challenges in scalability, biocompatibility, and tumor heterogeneity. Future research should focus on the rational design of safe, smart, and modular nanocarriers, integration of machine learning tools, and personalized approaches to maximize efficacy. Overall, the evolving landscape of nanotechnology presents promising avenues for improving CRC treatment and patient prognosis.