Engineered small extracellular vesicles provide low-dose salidroside delivery to attenuate retinal ganglion cell degeneration.

Optic neuropathy is characterized by impaired optic nerve function resulting from various pathological processes, often leading to retinal ganglion cell (RGC) degeneration and irreversible vision loss. Several studies have demonstrated the neuroprotective effects of salidroside (Sal). However, its clinical application has been limited by the high dosage required and the short half-life of Sal. To enhance drug efficacy and prolong therapeutic effects, we developed engineered small extracellular vesicles (sEVs) loaded with Sal (sEVs-Sal) for intravitreal administration in a mouse model of optic nerve crush (ONC). Our findings demonstrate that sEV-mediated low-dose Sal administration significantly enhanced visual functional recovery in ONC mice by mitigating RGC degeneration and inhibiting microglial activation. Proteomic profiling indicated that sEVs-Sal concurrently modulate both the TNF-α/IL-1β inflammatory axis and the Caspase-3/Bcl-2 apoptotic pathway, thereby conferring dual anti-inflammatory and antiapoptotic effects. This study establishes an efficient sEV-based drug delivery platform and highlights the considerable therapeutic potential of sEVs-Sal in the treatment of optic nerve injury. By addressing the pharmacokinetic limitations of free Sal and augmenting neuroprotection, this nanoformulation represents a promising translational strategy for optic neuropathies.