Genetically Unmodified Cells for Drug Delivery and Therapy

Cell-based drug delivery uses living cells’ advantages, including prolonged circulation, tissue tropism, barrier crossing, and immune compatibility, to improve drug biodistribution, prolong exposure, and enhance efficacy with reduced toxicity. Genetic engineering approaches like CAR-T therapy, while transformative, face significant hurdles, such as genomic risks, immune toxicities like cytokine release syndrome, strict regulations, expensive GMP manufacturing, and lengthy production timelines. These issues have spurred interest in nongenetic strategies that maintain native cell functions through intracellular loading methods (endocytosis, hypotonic loading, physical poration, cell–liposome fusion) and membrane modifications (covalent and noncovalent conjugation). This Review examines the mechanisms, trade-offs, and compatibility of these approaches with various carrier cells such as erythrocytes, platelets, macrophages, neutrophils, T cells, and NK cells. It further discusses key translational challenges, including safety, immunogenicity, donor and batch heterogeneity, manufacturing, cryopreservation, regulatory standardization, and progression from preclinical to clinical stages.