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Risk factor behavior e.g. smoking with/without alcohol or diseases associated with DNA repair deficits e.g. Fanconi anemia (FA) render the entire oral cavity at risk to develop OSCC. While systemically- delivered chemopreventives should conceivably provide oral mucosal field-coverage, bioavailability issues and drug-related toxicities generated disappointing outcomes. In contrast, local delivery formulations can deliver therapeutically-relevant levels without systemic side-effects. This proof of concept study determined whether Janus nanoparticles are a viable field-coverage chemopreventive strategy. Due to IL6's vital role in OSCC de- velopment, tocilizumab was selected as the payload chemopreventive.Methods:1) Formulation of tocilizumab- containing PLGA-chitosan nanoparticles (electrohydrodynamic co-jetting), 2) Determination of keratinocyte [FA- OSCC and E6/E7 transduced (epi) human cell lines] Internalization via confocal microscopy and fluorescent- activated cell sorting (FACS), 3)Assessment of nanoparticle-delivered tocilizumab immunoreactivity (tocilizumab ELISA), 4)Evaluation of fluorescenttagged nanoparticle penetration of oral mucosal explants (fluorescent mi- croscopy). Results:1) JNP were successfully formulated to achieve 65% tocilizumab loading and subsequent re- lease of immuno-reactive tocilizumab (ELISA confirmed)., 2) Qualitative (confocal microscopy) and quantitative (FACS) analyses confirmed human keratinocyte nanoparticle internalization in a time-dependent fashion. Notably, even the shortest co-incubation FACS time point (1 h) revealed appreciable internalization (75% and 73% of epi and FA-OSCC cell populations, respectively)., 3) Fluorescent-tagged nanoparticle studies revealed 85% of the mucosal explants (11/13) demonstrated particle penetration past the stratum corneum while 38% (5/13) contained nanopar- ticles in the basilar third of the epithelium. One of the mechanisms by which nanoparticles penetrate stratified epithelium is energy dependent (transcytosis). It is therefore probable that JNP optimization combined with in vivo analyses in ATP-replete tissues will enhance nanoparticle transport to the targeted, proliferative ep- ithelial cells. Previously, our lab has shown that local injections of tocilizumab significantly reduced OSCC tumori- genesis in vivo. Studies are currently ongoing to determine the OSCC chemoprevention efficacy of locally injected, sustained-release tocilizumab JNP. [ABSTRACT FROM AUTHOR]