Advanced Therapies for Diabetic Kidney Disease: A Critical Review of Gene-, RNA-, and Cell-Based Strategies to Address Residual Risk

Background. Diabetic kidney disease (DKD) can progress despite contemporary kidney-protective treatment, motivating the development of additional mechanism-based interventions. This critical narrative review evaluates whether gene-, RNA-, and cell-based strategies are ready to address this residual risk and identifies the evidence required for clinical translation. Methods. A targeted literature verification and update was undertaken for the revision, with emphasis on primary intervention studies, contradictory findings, and the distinction between target validation and product efficacy. Mechanistic and model system background is considered in relation to therapeutic selection. Results. Adeno-associated viral vectors offer potentially durable expression but face species-dependent renal tropism, immunity, and limited control after administration. RNA therapeutics permit time-limited modulation, although productive renal delivery and compartment-specific effects remain unresolved. Mesenchymal stromal cells and extracellular vesicles provide broader paracrine activity, with challenges in potency definition, biodistribution, and manufacturing. Autologous renal cell products have entered clinical testing but require individualized production and invasive delivery. Most gene and RNA evidence is preclinical; cell therapy trials provide feasibility or exploratory efficacy signals rather than definitive kidney protection. Conclusions. Thus, at present, progress toward routine DKD use requires reproducible renal target engagement, validated manufacturing, and confirmation of clinical benefit in randomized trials.