Dual‐Pathway Modulated Biomimetic Conductive Hydrogel Conduit Enables Spatiotemporal Co‐Delivery of Engineered C3‐Exosomes and TT‐10 to Potentiate Optic Nerve Regeneration

Abstract Traumatic optic neuropathy (TON) causes irreversible vision loss due to the limited regenerative capacity of retinal ganglion cell (RGC) axons and the inhibitory glial microenvironment. Promoting RGC axon regeneration while suppressing glial scar formation represents a feasible therapeutic strategy for TON. C3 exoenzyme (C3) can promote axon regeneration by inactivating the RhoA pathway. However, RhoA inactivation concomitantly suppresses YAP, thereby exacerbating glial scar formation and limiting the efficacy of C3 in axonal regeneration. YAP signaling activator TT‐10 has the potential to counteract this glial scar‐promoting effect. Additionally, electrical conductivity is critical for neuronal function, and reduced graphene oxide (rGO) offers superior conductivity with minimal cytotoxicity. Based on these, BMSC exosomes encapsulating C3 (Exo&C3) are prepared, and a customized rGO‐GelMA conduit (Exo&C3‐TT10@rGOHC) co‐loaded with Exo&C3 and TT‐10 is further fabricated via MRI‐guided 3D printing for TON treatment. Exo&C3‐TT10@rGOHC exhibits optimal biocompatibility, mechanical stability, spatiotemporal drug release kinetics, and electrical conductivity, robustly improving neural regenerative microenvironment and promoting axonal regeneration. Mechanistic analyses reveal that this system promotes axonal regeneration via RhoA/ROCK/F‐actin pathway inhibition and suppresses glial scarring through upregulation of YAP/TEAD pathway and downregulation of p38 MAPK pathway. Collectively, Exo&C3‐TT10@rGOHC provides a novel personalized therapeutic strategy for TON with significant clinical translation potential.