Lineage-selective suicide gene system enables post-engraftment editing of cell therapy composition

Human pluripotent stem cell (hPSC)-derived therapies are advancing rapidly toward clinical application, yet heterogeneity of transplanted cell populations remains a major barrier to safety, predictability and scalability. Existing strategies to mitigate this risk either incompletely eliminate proliferative cells or ablate the entire graft, thereby compromising therapeutic benefit. Here we present NeuroGuard, a lineage-selective suicide gene platform that decouples safety from efficacy by preserving functional neurons while enabling inducible elimination of all other cell types after transplantation. NeuroGuard integrates an inducible caspase-9 system with NEUROD1-driven Cre recombination, protecting post-mitotic neurons from apoptosis while rendering non-neuronal and proliferative populations susceptible to ablation. In vitro, activation of the system enriched neuronal content to >90% and increased dopaminergic neuron proportion >3-fold. Following transplantation of ventral midbrain progenitors, timed activation eliminated proliferative and glial populations, resulting in compact, neuron-enriched grafts without loss of dopaminergic neuron number, target innervation or behavioural recovery in Parkinsonian rodents. Single-cell transcriptomics confirmed selective removal of non-neuronal lineages while preserving neuronal identity and maturation programs. This work establishes a generalizable framework for post-engraftment editing of cell therapy composition, providing a versatile strategy to enhance the safety and functional predictability of regenerative therapies.