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Evan Scott1 Nicholas Karabin1 Sean Allen1

1, Northwestern University, Evanston, Illinois, United States

Nanocarrier administration has primarily been restricted to intermittent bolus injections with limited available options for sustained delivery in vivo. Here, we demonstrate that the cylinder-to-sphere transitions of self-assembled filomicelle (FM) scaffolds can be employed for sustained delivery of monodisperse micellar nanocarriers with improved bioresorptive capacity, modularity for customization, and biocompatibility. These controllable transitions in nanostructure morphology were achieved using oxidation-sensitive poly(ethylene glycol)-bl-poly(propylene sulfide) block copolymer (BCP), which promoted spherical micelle formation in response to changes in surface tension under mild oxidative conditions. Cylinder-to-sphere transitions were characterized in 2D by cryogenic electron microscopy and in 3D by cryo-electron tomography. Modular assembly of FMs from diverse BCP chemistries allowed customization for in situ gelation into porous hydrogel scaffolds following subcutaneous injection into mice. Upon photo- or physiological oxidation, molecular payloads within FMs transferred to intact micellar vehicles during the morphological transition, which was verified in vivo by flow cytometry. FMs composed of multiple distinct BCP fluorescent conjugates permitted multimodal analysis of the scaffold’s non-inflammatory bioresorption and micellar delivery to immune cell populations for up to three months. Mice receiving in situ crosslinked FM-scaffolds exhibited significantly greater uptake within the draining lymph nodes than those receiving injections of non-crosslinked FM or free form fluorescent dye. Specifically, macrophages and both immature and mature dendritic cells exhibited a discernible increase in micelle fluorescence in comparison to free form FM and dye controls. Differences in cell uptake reflected the distinct release rates observed when comparing the slower crosslinked scaffolds and the more rapidly dispersing free form FMs. These scaffolds provide a highly efficient mechanism of bioresorption wherein all components participate in retention and transport of therapeutics, presenting previously unexplored mechanisms for controlled delivery of immunotheranostic nanocarriers for sustained targeting and imaging of lymph node resident immune cell populations.

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