Engineering a nano delivery system targets EphA2 for treating colorectal cancer oxaliplatin resistant

• • Development of a novel nano-drug delivery system targeting EphA2. • • Targeting EphA2 increases the sensitivity of colorectal cancer cells to oxaliplatin. • • Nano-drug delivery system enhances the therapeutic effect of anti-PD-L1 in colorectal cancer. As a first-line chemotherapeutic regimen, oxaliplatin resistance is a challenge for colorectal cancer treatment. Eph receptor A2 (EphA2) is highly expressed in colorectal tumors and is an important contributor to the poor prognosis of the patients. Herein, We found that targeting EphA2 can inhibit cell proliferation and alleviated oxaliplatin resistance in colorectal cancer cells. This study aimed to develop a safe and effective nanocarrier system targeting EphA2 and to evaluate its efficacy in treating oxaliplatin-resistant colorectal cancer cells and mouse models. The synthesized nanocarrier system is characterized by carrying the EphA2 inhibitor ALW-II-41–27, which is encapsulated on the surface of colon cancer cell membranes with modifying YSA peptide. This drug delivery system greatly increases drug accumulation in tumor tissues and enhances the therapeutic effect of drugs on tumors by wrapping tumor cell membranes and modifying YSA peptides to the surface of cell membranes using “click chemistry”. In addition, we found that EphA2 is responsible for oxaliplatin resistance, and the nanocarrier system can inhibit colorectal cancer oxaliplatin-resistant cells by precisely targeting EphA2. Nano-drug delivery system increases tumor suppression in combination with immune checkpoint inhibitors. This study provides a new potential therapeutic approach for colorectal tumor resistance.