Triphenylphosphonium-functionalized ferric-tannic acid nanometallic framework delivers optic atrophy 1 protein to restore mitochondrial homeostasis in diabetic erectile dysfunction.

Diabetic erectile dysfunction (DMED) is a prevalent complication of diabetes mellitus, with mitochondrial dysfunction playing a central pathogenic role. Current treatments inadequately address these subcellular pathological mechanisms. This study aimed to develop a mitochondria-targeted nanotherapeutic platform for efficient optic atrophy 1 (OPA1) protein delivery to restore mitochondrial homeostasis in cavernous tissue. A triphenylphosphonium (TPP)-functionalized Fe3O4-ferric tannic acid (FeTA) nanocarrier was synthesized and loaded with recombinant human OPA1 to form Fe3O4-FeTA-TPP-OPA1 (OFFT). OFFT nanoparticles exhibited a spherical morphology, a hydrodynamic diameter of 285.00 ± 6.36 nm, and an OPA1 loading content of 0.69%. OFFT showed pH-responsive OPA1 release, with cumulative release reaching 71.27 ± 3.42% at pH 5.5 versus 60.64 ± 0.20% at pH 7.4 within 72 h, and retained intrinsic superoxide dismutase/catalase-like activities. In high glucose-treated mouse Schwann cells, OFFT efficiently targeted mitochondria, restored cell viability from 52.87 ± 1.48% to 87.46 ± 1.60%, reduced apoptosis from 68.73 ± 1.94% to 51.25 ± 0.95%, suppressed reactive oxygen species, increased the JC-1 red/green fluorescence ratio from 25.20 ± 0.96 to 80.09 ± 2.53, and normalized mitochondrial fusion-fission balance. In DMED rats, OFFT treatment (15 mg/kg every 48 h for 8 weeks) increased the intracavernosal pressure/mean arterial pressure (ICP/MAP) ratio from 0.24 ± 0.05 to 0.45 ± 0.05, alleviated cavernosal fibrosis, enhanced local antioxidant capacity, and normalized mitochondrial dynamics-related protein expression. Collectively, the OFFT nanoplatform enables mitochondria-targeted OPA1 delivery, effectively restores mitochondrial homeostasis, and ameliorates DMED. This work presents a promising organelle-targeted protein delivery strategy for treating diabetic complications.