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Polymeric nanoconstructs will be rationally designed and synthesized for the precise delivery and controlled release of therapeutic (small molecules and RNAs) and imaging agents. Polymeric nanoconstructs will be realized using either bottom-up or top-down fabrication approaches, depending on the geometrical features. Biodegradable, biocompatible and bioactive polymeric materials, synthetic and natural, will be considered. Labeling with agents for optical imaging (Rhodamine B; Cy5.5); magnetic resonance imaging (Gd3+-ions); and nuclear imaging (64Cu and 89Zr) will be routinely performed for quantitative biodistribution studies and precise nanoconstruct localization.

Three different delivery strategies will be quantitatively explored for lodging therapeutic cargos within the central nervous system: systemic delivery (strategy one); local implantation (strategy two); and inhalation (strategy three). For strategy one, the size, shape, surface properties and mechanical stiffness of discoidal polymeric nanoconstructs will be tested for augmenting deposition within the brain microvasculature. Endogenous and exogenous stimuli will be used for favoring localized and transient opening of the blood brain barrier and the triggered release of therapeutic cargos. For strategy two, hierarchically-structured nanoconstructs with different geometrical configurations and material properties will be directly implanted within the diseases region and engineered to release therapeutic cargos over long term periods (weeks to months), while progressively degrading. For strategy three, polymeric nanoconstructs will be deposited within the nasal cavity. The journey of therapeutic molecules from the olfactory bulb, across the neuronal connections, to remote regions of the brain will be assessed in terms of transport efficiency and therapeutic effectiveness.

In vitro 3D multicellular tissue models will be originated for refining the vascular and extra-vascular performance of nanoconstructs. Multi-compartmental microfluidic chips will be realized and integrated with primary cells from patients (somatic cells and induced pluripotent stem cells – iPSCs). This will allow for reproducing the biological and biophysical characteristics of the vascular compartment, blood brain barrier, diseased and healthy tissues. Sophisticated computational models will be developed for predicting the vascular and extravascular behavior of nanoconstructs as well as their interaction with blood proteins and small molecules with the objective of optimizing their vascular targeting, deep tissue permeation and recognition by target and immune cells.