Engineered exosomes for CRISPR/Cas delivery to overcome oncogene-driven drug resistance

Engineered exosomes are emerging as biocompatible nanocarriers for delivering CRISPR/Cas components to resistant tumor cells, enabling targeted disruption of oncogenic drivers and resistance-associated pathways. Engineered exosomes offer several delivery-platform advantages, including biocompatibility, membrane-mediated cargo protection, programmable tumor targeting, and potential tissue penetration. Selection of the CRISPR modality, Cas9 ribonucleoprotein, mRNA, base editor, or prime editor, depends on payload size, stability, editing duration, endosomal escape, and nuclear delivery requirements. Therapeutically, these systems may disrupt oncogenic drivers, inhibit resistance pathways, restore tumor-suppressor activity, and re-sensitize tumors to targeted therapy, chemotherapy, or immunotherapy. Clinical translation will require scalable manufacturing, reproducible cargo loading, standardized characterization, validated potency assays, off-target control, and clearly defined regulatory pathways. The goal of this review is to outline a realistic pathway featuring proof-of-concept research, through discoveries to the creation of manufacturable, safe, and effective exosome/CRISPR therapeutics that can trigger durable therapeutic responses in resistant malignancies.