Delivery platforms for in vivo CAR-T engineering

Ex vivo CAR-T changed cancer care, but its made-to-order manufacturing keeps too many patients waiting. In vivo CAR-T takes a different path: deliver the genetic blueprint to a patient’s own immune cells and let the body build the therapy. In this review, we compare the leading delivery platforms—retargeted lentiviral vectors, engineered AAVs, LNPs (mRNA/circRNA), polymeric nanoparticles, and bioinspired systems—through the lenses of specificity, expression durability, redosing, manufacturability, immunogenicity, safety, and clinical maturity. Early human observations in hematologic malignancies and autoimmune disease show what’s possible; solid-tumor progress is still largely preclinical. Key translational challenges include: off-target transduction and murky biodistribution, liver-skewed exposure for non-viral systems, integration risk for durable vectors, repeat-dose immunity, CMC consistency, and regulatory fit. We outline a practical roadmap—quantitative biodistribution and potency, cargo-tuned persistence, receptor-aware targeting, robust CMC, and indication-specific risk–benefit—to support reproducible and clinically interpretable therapeutic development.