An integrated nano-delivery platform via baicalein-loaded polydopamine-MOF for enhanced neuroprotection against retinal ischemia reperfusion injury.

Retinal ischemia reperfusion injury (RIRI) presents a complex pathological mechanism involving oxidative stress, neuroinflammation, and retinal ganglion cell (RGC) apoptosis, with current therapies limited by their inability to address these multifaceted cascades. To address this challenge, we engineered microenvironment-responsive nanoparticles, pZIF-8@Bai, by encapsulating baicalein (Bai) within a polydopamine-coated zeolitic imidazolate framework (ZIF-8), The pZIF-8@Bai nanoparticles achieved targeted combination therapy through a sustained-release mechanism, resulting in comprehensive retinal protection: attenuating oxidative damage, promoting microglial M2 polarization, and significantly inhibiting RGC apoptosis. Importantly, functional assessments demonstrated substantial recovery of a-wave and b-wave amplitudes in electroretinography (ERG) and enhanced P1-wave amplitudes in flash visual evoked potential (FVEP) recordings. Mechanistically, proteomic analysis revealed suppression of Nogo-A expression, which modulated NF-κB signaling and the intrinsic apoptotic pathway, involving caspase-8 inhibition and BCL-2/BAX balance restoration. These actions preserved retinal structural integrity and restored visual function, as confirmed by electroretinography, with excellent biosafety profiles, offering a promising multi-target therapeutic strategy for neurodegenerative retinal diseases.