Kidney-Targeted Gene Transfer: Therapeutic Advances in Native Kidney Disease and Emerging Ex Vivo Allograft Engineering

Kidney-targeted gene transfer is progressing toward two distinct clinical applications: correcting molecular defects or modifying disease pathways in native kidneys and modifying donor kidneys before allotransplantation to reduce ischemia–reperfusion injury or rejection. These applications share a delivery challenge but differ in their target cells, therapeutic mechanisms, required duration and acceptable systemic exposure. Advances in renal delivery have produced disease benefit in selected animal models, while ex vivo perfusion offers a controlled opportunity to expose and assess a graft before implantation. Neither renal vector detection nor reporter expression alone establishes therapeutic efficacy. This review evaluates the evidence through four linked layers: vector distribution, cell-resolved delivery or expression, therapeutic target engagement and functional benefit. It compares candidate strategies according to indication and duration, distinguishes capsid tropism from promoter-mediated expression bias and separates demonstrated outcomes from mechanistic proposals. For donor-kidney engineering, limited treatment time, uneven intrarenal delivery, perfusion injury and delayed vector release after reperfusion remain central constraints. Translation will require indication-specific dose–response studies, human-relevant delivery assessment and surveillance extending beyond early benefit or transient immune silencing. Progress therefore depends on a coherent therapeutic configuration, rather than a universal kidney vector.