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However, significant challenges remain in maintaining the physiological stability of the mucosal matrix due to the nanoparticle\u2010induced reduction in the matrix diffusivity and promotion of mucin aggregation. Such aggregation also adversely impacts the permeability of the nanoparticles, and thus, diminishes the efficacy of nanoparticle\u2010based formulations. Here, an entirely complementary approach is proposed to the existing nanoparticle functionalization methods to address these challenges by using trehalose, a naturally occurring disaccharide that offers exceptional protein stabilization. Plasmon\u2010enhanced Raman spectroscopy and far\u2010red fluorescence emission of the plasmonic silver nanoparticulate clusters are harnessed to create a unique dual\u2010functional, aggregating, and imaging agent that obviates the need of an additional reporter to investigate mucus\u2013nanoparticle interactions. These spectroscopy\u2010based density mapping tools uncover the mechanism of mucus\u2013nanoparticle interactions and establish the protective role of trehalose microenvironment in minimizing the nanoparticle aggregation. Thus, in contrast to the prevailing belief, these results demonstrate that nonfunctionalized nanoparticles may rapidly penetrate through mucus barriers, and by leveraging the bioprotectant attributes of trehalose, an in vivo milieu for efficient mucosal drug delivery can be generated.<\/jats:p>","DOI":"10.1002\/smll.201901679","type":"journal-article","created":{"date-parts":[[2019,7,3]],"date-time":"2019-07-03T07:55:55Z","timestamp":1562140555000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Shedding Light on the Trehalose\u2010Enabled Mucopermeation of Nanoparticles with Label\u2010Free Raman Spectroscopy"],"prefix":"10.1002","volume":"15","author":[{"given":"Soumik","family":"Siddhanta","sequence":"first","affiliation":[{"name":"Department of Mechanical Engineering Johns Hopkins University  Baltimore MD 21218 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