Transdermal Delivery of Icariin via Microneedle Patches Attenuates Phthalate‐Induced Testicular Injury

ABSTRACT Di‐(2‐ethylhexyl) phthalate (DEHP) is a prevalent plasticizer that has been demonstrated to induce male reproductive toxicity through the disruption of spermatogenesis. Icariin (ICA), a bioactive compound derived from the traditional Chinese medicine Epimedium, holds significant potential in the treatment of male infertility. However, its clinical utilization is constrained by low absorption and fast metabolism upon oral administration. Herein, we first developed ICA‐loaded chondroitin sulfate (CS) and polyvinylpyrrolidone K30 (PVP K30) microneedle (MN) patches (ICA MNs) for treating DEHP‐induced testicular dysfunction. The results found that ICA MNs significantly reduced DEHP‐induced oxidative stress and apoptosis in GC‐1 cells by modulating the Keap1/Nrf2/HO‐1 pathway. In addition, ICA MNs mitigated DEHP‐induced testicular damage, sperm irregularities, and blood‐testis barrier impairment in rats, surpassing the efficacy of oral ICA treatment. Proteomic analysis indicated a restoration of the testicular proteome toward normal levels after ICA MN treatment. Comprehensive safety assessments revealed no adverse systemic effects, highlighting the biocompatibility of ICA MNs. These findings suggest ICA MNs as a promising therapeutic approach for male infertility associated with DEHP exposure, offering targeted and efficient transdermal delivery.