Delivering therapeutics across the blood-brain barrier (BBB) for treating central nervous system (CNS) diseases is one of the biggest challenges today as the BBB limits the uptake of molecules greater than 500 Da into the CNS. Here we describe a novel trans-nasal mucosal drug delivery as an alternative to the intranasal drug delivery to overcome its limitations and deliver high molecular weight (HMW) therapeutics efficiently to the brain. This approach is based on human endoscopic skull base surgical techniques in which a surgical defect is repaired by engrafting semipermeable nasal mucosa over a skull base defect. Based on endoscopic skull based surgeries, our groups has developed a trans-nasal mucosal rodent model where we have evaluated the permeability of ovalbumin (45 kDa) as a model protein through the implanted mucosal graft for delivering HMW therapeutics to the brain. A thermo sensitive liposome-in-gel (LiG) system was developed for creating a drug depot allowing for a sustained release from the site of delivery to the brain through the implanted nasal graft. We would like to report this as an exploratory pilot study where we are using this novel surgical model to show that the implanted nasal mucosal graft and the LiG delivery system result in an efficient and a sustained brain delivery of HMW proteins. Hence, this study demonstrates that the trans-nasal mucosal engrafting technique could overcome the limitations for intranasal drug delivery and enable the uptake of HMW protein therapeutics into the CNS for the treatment of a wide range of neurodegenerative diseases.