Objectives: To present a novel, topical DNAzyme-based therapy for androgenetic alopecia (AGA) that selectively targets the molecular drivers 5α-reductase types 1 and 2 and the androgen receptor. Learning outcomes include understanding the mechanism of action, clinical safety profile, local efficacy on scalp DHT, and the advantages of multi-target follicle-restricted intervention without systemic androgen suppression. Introduction: Androgenetic alopecia affects nearly one billion individuals worldwide and has significant psychosocial impact. Current therapies rely on singular molecular targets, provide limited efficacy, and are associated with systemic side effects or gender restrictions. Dihydrotestosterone (DHT), produced by 5α-reductase and acting through the androgen receptor, is the primary driver of follicular miniaturization, highlighting the need for precise, localized, multi-target treatments. Materials / method: Derma Gene’s patented DNAzyme technology was designed to cleave mRNA of 5α-reductase type 1, type 2, and the androgen receptor. Preclinical studies were conducted in human follicular dermal papilla cells, assessing mRNA and protein suppression. A first-in-human clinical study evaluated scalp DHT levels, 5α-reductase expression, systemic androgen levels, and safety following topical administration. Results: Preclinical studies demonstrated synergistic suppression of key AGA drivers, including approximately 58% reduction of 5α-reductase type 2 protein and 35% reduction of type 1. Clinical results showed statistically significant reductions in scalp 5α-reductase mRNA, protein levels, and local DHT compared to placebo (p < 0.05), with no changes in blood DHT or testosterone. No adverse effects were observed. Conclusion: This DNAzyme-based topical therapy demonstrates a safe and effective multi-target approach for AGA, achieving localized suppression of DHT and its upstream regulators without systemic hormonal effects. The precision, safety profile, and follicle-restricted activity position this technology as a promising next-generation treatment for both male and female patients, addressing major limitations of existing therapies.