Self‐Sealing Microneedles Improve Precision and Reduce Reflux in Subretinal Cell Transplantation

ABSTRACT Subretinal delivery of cell and gene therapies faces significant constraints due to retinotomy‐associated reflux and tissue disruption, which limit surgical precision and therapeutic retention. This study introduces an ultrafine microneedle‐based delivery strategy for minimally invasive subretinal transplantation, optimizing microscale flow dynamics and needle–tissue interactions. Human primary and induced pluripotent stem cell‐derived retinal pigment epithelial (iPSC‐RPE) cells pass through microneedles with luminal diameters as small as 30 µm, successfully maintaining high viability, standard morphology, cytoskeletal integrity, and normal vascular endothelial growth factor secretion in vitro. Furthermore, ex vivo porcine models demonstrate reliable subretinal delivery without needle obstruction and reveal a progressive reduction in reflux with decreasing needle diameter, achieving no detectable reflux with the finest microneedles. In vivo rabbit studies establish that microneedle delivery minimizes full‐thickness retinotomy formation, accelerates neurosensory detachment resolution, and produces highly uniform subretinal bleb expansion compared to conventional cannulas. By significantly reducing the reflux burden and inner retinal apposition, this ultrafine microneedle platform provides a clinically translatable approach to enhance the precision, safety, and cellular retention of microscale intraocular therapies.