Traumatic optic neuropathies cause the death of retinal ganglion cells (RGCs) and axon degeneration. This is a result of the blockage of neurotrophic factor (NTF) supply from the brain and a vicious cycle of neurotoxicity, possibly mediated by increased levels of retinal Zn . Ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) are two NTFs that are known to support RGC survival and promote axon regeneration. Dipicolylamine (DPA) has a strong affinity to Zn and can selectively chelate this ion. To continuously supply NTFs and reduce elevated retinal Zn , we developed poly(serinol hexamethylene urea)-based sulfonated nanoparticles (S-PSHU NPs), that co-delivers CNTF, BDNF, and DPA. An release study was performed using the NTF-DPA-loaded S-PSHU NPs, demonstrating a sustained release of CNTF and BDNF for up to 8 weeks, while DPA was released for 4 weeks. In a rat optic nerve crush (ONC) model, DPA-loaded S-PSHU NPs exhibited dose-dependent elimination of retinal Zn . Similarly, primary RGC culture demonstrated that the activity of RGCs and axon growth were dependent on the dosage of CNTF and BDNF. In addition, the NTF-DPA-loaded S-PSHU NPs significantly improved RGC survival and axon regeneration following ONC in rats, with the regenerated axons extending to the distal segment of the brain, including the suprachiasmatic nucleus, lateral geniculate nucleus, and superior colliculus.