Engineered extracellular vesicles: pharmacological barriers, engineering strategies, and translational opportunities

Extracellular vesicle (EV) therapeutics are progressing from broad proof-of-concept studies toward product-specific engineering and clinically defined applications. Native EVs offer biological membrane functions and the capacity to transport diverse molecular cargoes, but their therapeutic performance is limited by low cargo stoichiometry, rapid mononuclear phagocyte system clearance, clearance-dominated biodistribution, and inefficient functional cargo release. This Review examines how EV engineering strategies are used to address these barriers. We compare approaches for cargo loading, circulation control, tissue- and cell-selective targeting, and intracellular delivery, while considering the immunogenicity and manufacturing risks introduced by engineering. We also assess recent preclinical and clinical progress, including programs that were paused or discontinued, and discuss the practical constraints of cost, supply chain, and cold-chain distribution. Current evidence suggests that engineered EVs are unlikely to replace established lipid nanoparticles or viral vectors across all applications. Their near-term value is more likely to arise in localized delivery, immune-microenvironment modulation, complex cargo delivery, and defined cell-targeting settings in which biological membrane functions provide a measurable advantage.