Oxidative stress destabilizes microRNA homeostasis in retinal pigment epithelium (RPE), driving apoptosis and epithelial-to-mesenchymal transition that contribute to age-related macular degeneration. We investigated whether quantum molecular resonance (QMR®) electrostimulation, alone or combined with Patient Blood-Derived (PBD) secretoma, can reprogram the RPE miRNome and mitigate stress-induced damage. Human ARPE-19 cells were exposed to tert-butyl-hydroperoxide and treated with QMR®, PBD secretome, or their combination. Deep-sequencing of small RNAs at 24 h and 72 h, followed by differential expression and pathway enrichment analyses, delineated treatment-driven miRNA signatures. Oxidative stress deregulated >50 miRNAs, enriching pro-apoptotic, fibrotic, and inflammatory pathways. QMR® restored roughly 40 % of these miRNAs and up-regulated additional cytoprotective species such as miR-590-3p, collectively dampening NF-κB and NLRP3 axes. Secretome treatment preferentially increased anti-inflammatory miR-146a-5p and regenerative miR-204-5p while suppressing pro-fibrotic let-7f-5p. Combined QMR® + secretome triggered the broadest response, normalizing over two-thirds of stress-altered miRNAs and synergistically reinforcing antioxidant, anti-apoptotic, and anti-fibrotic gene networks. These data indicate that QMR® and PBD secretome act through complementary miRNA programs that converge to preserve RPE viability under oxidative insult; their combination offers additive modulation of key survival pathways, supporting development of a non-invasive, cell-free therapeutic strategy for retinal degenerative disorders.