PROJECT SUMMARY In the U.S., approximately 2.2 million people suffer from optic neuropathies, accounting for 9 to 12% of all cases of blindness. Of them, 10% of patients that receive proper medical treatment continue to experience vision loss, which obviously needs an alternative treatment strategy. One of current treatments utilizes neurotrophic factors (NTFs) to increase retinal ganglion cell (RGC) survival, responsible for the visual function. While direct administration of NTFs via intravitreal injection has had some success, a susceptibility to denaturation of these NTFs limits its clinical success. Also, the delivery of NTFs alone may result in limited treatment success since optic neuropathies accompany neurodegeneration, caused by the neurotoxic cycles. To resolve these problems, we have engineered polymeric nanoparticles that mimic negatively charged sulfonate groups in natural heparin and deliver multiple therapeutic agents to continuously supply NTFs and inhibit the neurotoxicity. The advantages of our strategy include: 1) sustained delivery of NTFs at target site, mimicking continuous NTF transport, 2) prolonged bioactivity of NTFs encapsulated in the system and 3) sustained delivery of an anti-neurotoxic agent, continuously inhibiting neurodegeneration during the progression of optic neuropathies. We have constructed this application under two specific aims: (1) determine an appropriate nanoparticle formulation for the co-delivery of the multiple therapeutic agents and (2) evaluate RGC axon regeneration in rat optic nerve crush model.