Abstract The most common and deadly form of primary brain cancer, glioblastoma (GBM), is characterized by significant intratumoral heterogeneity, high vascularity, and infiltrative growth. Delivering effective and sustained treatments to the invading GBM cells without worsening damage to the adjacent brain is a major challenge. We aim to develop an innovative, local delivery approach that couples chemotherapy-loaded brain penetrating biodegradable nanoparticles with tumor cell-targeting capabilities and convection enhanced delivery (CED). We formulated sub-100 nm sized, close to neutrally charged, poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles with ~5% w/w carmustine (BCNU) payload coated with a fibroblast growth factor-inducible 14 (Fn14) antibody to specifically target Fn14-positive brain-invading tumor cells. We observed that PLGA surface modification using non-adhesive PEG allowed nanoparticles to rapidly move through brain tissue in ex vivo rat brain slices, potentially increasing the distribution of delivered therapeutics. We showed that Fn14-targeted nanoparticles were able to selectively bind to recombinant Fn14 but not to brain extracellular matrix proteins in surface plasmon resonance assays, as well as diffuse within brain tissue in multiple particle tracking assays. In addition, when administered intracranially, Fn14-targeted nanoparticles showed improved brain tumor retention in C57BL/6 mice bearing orthotopic KR158B tumors compared to non-targeted nanoparticles. We propose that targeting treatments to invading cancer cells using non-adhesive nanoparticles will limit non-specific interactions within brain and tumor tissue and thereby allow specific interactions at target structures and increase the BCNU therapeutic index. To test this hypothesis, we plan to determine the therapeutic efficacy of Fn14-targeted and non-targeted, non-adhesive nanoparticles, capable of releasing BCNU over a 3 week period, by intracranial CED injections in C57BL/6 mice bearing orthotopic KR158B invasive tumors. Citation Format: Aniket S. Wadajkar, Jimena G. Dancy, Nina P. Connolly, Jeffrey A. Winkles, Graeme F. Woodworth, Anthony J. Kim. Targeting nanotherapeutics to the invasive glioblastoma margin via the cell surface receptor Fn14 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3107. doi:10.1158/1538-7445.AM2017-3107