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Purpose: Nanoparticles (NPs) carry important promises for the treatment of neurological diseases, such as glioblastoma multiform (GBM) and Parkinson's disease. Several methods have been developed to achieve higher NP concentrations in the brain, including local infusions using convection enhanced delivery (CED), focused ultrasound, and the use of surface targeting moieties specifically designed to increase the passage across the blood brain barrier (BBB). However, even when sufficient NP amounts are delivered to the targeted region, a better understanding of the interactions between the particles and the brain parenchyma will be necessary to reach clinical efficacy. This is particularly true for polymeric NPs, which behavior can be dramatically influenced by multiple factors such as their size and their surface properties. Here, we investigated the cellular fate of PLA-based nanoparticles of similar size, but bearing different surface modifications, following CED in the healthy brain and the tumor bearing brain. Methods: Four PLA-based NP formulations with different surface modifications (PLA, PLA-PEG, PLA-HPG and PLA-HPG-CHO) and similar size were obtained by emulsion or nanoprecipitation. CED of each formulation was performed in healthy or tumor bearing brain, and comparable volumes of distribution were obtained. 4 h and 24 h after infusion, brains were harvested and processed for flow cytometry analysis and immunohistochemical staining, to quantify particle internalization by neurons, astrocytes, microglia and tumor cells, when applicable. In vitro uptake studies were performed using relevant cell lines for neurons (N27 cells), astrocytes (TNC1), microglia (BV2) and tumors (RG2). Rate of association kinetics of different particles with these cells were derived from an uptake study and then correlated with in vivo internalization results. Finally, to evaluate how different NPs surface modifications and their different internalization patterns can influence survival benefits, the different particles were loaded with epothilone B (EB) and infused into rats bearing RG2 tumors via CED. Results: We observed that in the healthy brain, stealth NPs distributed evenly between neurons, astrocytes and microglia, while exhibiting the highest specificity towards tumor cells in the tumor bearing brain. Overall, the functionalization of PLA NPs with aldehyde groups allowed for an increased uptake by all cell types, in both healthy and tumor bearing brain. These NPs also presented an increased relative uptake by microglia cells in both environments, compared to stealth particles, suggesting the induction of an immune response. Rates of association of NPs in vitro varied significantly between particle types. We were then able to correlate the in vivo uptake of each particle and cell type with in vitro particle association rates with neurons, astrocytes and microglia in culture, demonstrating the possibility of predicting in vivo uptake using in vitro association rates. Finally, comparison of particles in a survival efficacy showed significant differences, highlighting the importance of uptake of NPs. Conclusions: This study demonstrates for the first time that NP surface modifications significantly influence the cellular tropism of NPs in the brain in vivo, and that in vitro association rates can be used to anticipate the different internalization patterns. These differences open the possibility of tuning surface properties to optimize cellular delivery and therapeutic outcome. Acknowledgements: This work is supported by a NIH/NCI R01 grant (#5R01CA149128-04). Citation Format: Eric Song, Alice Gaudin, Amanda R. King, Youngeun Seo, Paul Won, Heewon Suh, Yang Deng, Jiajia Cui, Gregory Tietjen, W Mark Saltzman. Surface chemistry governs cellular tropism of nanoparticles in the brain. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B46.