Testosterone-Modified Liposomes Loaded with the Zn–Polyphenol Complex for Treatment of Male Infertility

In this study, we developed an androgen-mediated, testis-targeted nanodrug delivery system with both antioxidant and anti-inflammatory functions, namely, testosterone-modified epigallocatechin gallate-zinc complex liposomes (EGCG-Zn@T-Lipo), and systematically investigated its biological mechanisms and cellular effects in the treatment of orchitis. EGCG coordinated with Zn2+ to form a stable antioxidant complex, while testosterone modification enabled specific targeting to androgen receptor (AR)-positive tissues. EGCG-Zn@T-Lipo exhibited a uniform particle size, good stability, high encapsulation efficiency, and excellent biocompatibility. In LPS/nigericin-induced inflammation models, it efficiently scavenged reactive oxygen species, inhibited NOD-like receptor protein 3 (NLRP3) inflammasome activation, and reduced inflammatory cytokines, such as IL-1β and IL-18, maintaining redox homeostasis in Sertoli and Leydig cells. In RAW264.7 macrophages, it suppressed inflammatory signaling and promoted M2 polarization through liposome fusion and EGCG-Zn2+ synergistic antioxidation. In vivo, EGCG-Zn@T-Lipo showed strong testicular targeting and therapeutic efficacy, alleviating inflammation, restoring testosterone secretion, and preserving the spermatogenic structure. These results indicate that EGCG-Zn@T-Lipo achieves precise protection against testicular inflammation through testosterone-mediated targeting, the synergistic antioxidative effect of EGCG and Zn2+, and inhibition of the NLRP3 inflammasome, providing a promising nanotherapeutic strategy for testis-related inflammatory diseases.