EGFR-targeted therapies based on antibody engineering and nanotechnology for colorectal cancer.

Epidermal Growth Factor Receptor (EGFR) is crucial for cell proliferation and survival, and has emerged as a promising therapeutic target for colorectal cancer (CRC). Anti-EGFR monoclonal antibodies (mAbs) have demonstrated success in various clinical practice in CRC patients. However, they are only effective in patients with RAS wild-type, and more importantly, most patients eventually develop resistance to anti-EGFR therapy due to the mutations of the effector molecules in EGFR downstream signaling pathways or/and the activation of compensatory feedback loop signaling, which limits the long-term efficacy of anti-EGFR mAbs. Advances in antibody engineering and nanotechnology have brought new hope for cancer treatment, particularly through bi-/tri-specific antibodies, antibody-drug conjugates(ADCs), and antibody-functionalized nanoparticles(AFNPs), which can simultaneously inhibit the activation of EGFR and its compensatory pathways-or even directly eradicate cancer cells bypassing EGFR-mediated signaling-these innovations hold promise for addressing drug resistance and leading to better response rates of EGFR-targeted therapy in CRC. In this review, we provide an overview of the design strategy of EGFR-targeted therapies based on antibody engineering and nanotechnology for CRC using a mechanistic framework, focusing on analyzing the optimization strategies for representative drugs or studies and their potential in overcoming heterogeneous drug resistance in CRC, in order to provide useful information for researchers developing EGFR-targeted drugs for CRC.