Colorectal cancer (CRC) is the third most common cancer globally. Despite recent treatment improvements, the prognosis of CRC remains poor. Patients with advanced CRC have a 5-year survival of about 10% in the case of unresectable disease. Current first-line treatments for CRC include surgery and chemotherapy. Due to developing resistance of CRC to current chemotherapeutic and targeted agents and limited efficacy and safety concerns for existing targeted therapies and immunotherapies, novel therapeutic regimens with significantly enhanced potency and safety are urgently required to address unmet medical needs. Exosomes are natural membranous vesicles secreted by many types of cells and possess many important and invaluable features for drug development. By exploiting these unique pharmacological properties of exosomes, we propose to develop novel exosome-based therapeutic candidates with increased potency and safety profiles for immunotherapy of CRC. By creatively combining knowledge and technologies from nanotechnology, exosome biology, protein engineering, and cancer immunology, a novel class of engineered exosomes will be rationally designed and synthesized for potently activating the immune system for specific attacking of CRC tumors, which are expected to show excellent safety profiles and enhanced efficacy in animal models. Successful completion of this project will result in novel immunotherapeutic exosomes with excellent pharmacological properties, leading to the development of first-in-class immunotherapeutics for CRC and a paradigm shift in cancer immunotherapy.