High-Efficiency Ocular Delivery of Brain-Derived Neurotrophic Factor and Oligomycin for Neuroprotection in Glaucoma.

Glaucoma is a retinal neurodegenerative disease characterized by progressive apoptosis of retinal ganglion cells (RGCs) and irreversible visual impairment. Current therapies rarely offer direct protection for RGCs, highlighting the need for new neuroprotective approaches. Although viral delivery of brain-derived neurotrophic factor (BDNF) has shown potential, concerns about retinal inflammation and limited applicability persist. Meanwhile, non-viral vectors remain inefficient for in vivo ocular gene delivery. Here, a highly biocompatible nanoplatform-PBAE-PLGA-Oligomycin-pBDNF nanoparticles (PPOB NPs) is reported-that co-delivers oligomycin (an ATP inhibitor) and a BDNF plasmid to Müller cells in vivo. This nanoplatform attains an unprecedented transfection efficiency of 64.26% in Müller cells, thereby overcoming the limitations of monotherapeutic neurotrophic approaches that fail to inhibit ATP overproduction and attendant inflammatory responses. In a chronic ocular hypertension rat model, oligomycin effectively mitigated RGC damage by suppressing Müller cell hyperactivation and excessive ATP production under elevated intraocular pressure. Concurrently, it synergistically enhanced BDNF expression in Müller cells, achieving robust protection of RGCs and preservation of optic nerve function. These findings underscore the promise of PPOB NPs as a dual-functional platform, featuring high biocompatibility and efficient gene delivery, for multifaceted therapies against glaucoma and other ocular diseases.