Pi-Stacking Enhances Stability, Scalability of Formation, Control over Flexibility, and Circulation Time of Polymeric Filamentous Nanocarriers

Self-assembling filomicelles (FMs) are of great interest to nanomedicine due to their structural flexibility, extensive systemic circulation time, and amenability to unique "cylinder-to-sphere" morphological transitions. However, current fabrication techniques for preparing FMs are highly variable and difficult to scale. Herein, it is demonstrated that tetrablock copolymers composed of poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) diblocks linked by a pi-stacking perylene bisimide (PBI) moiety permit rapid, scalable, and facile assembly of FMs via the flash nanoprecipitation (FNP) method. Coassembling the tetrablocks and PEG-b-PPS diblocks at different molar ratios resulted in mixed PBI-containing FMs (mPBI-FM) with tunable length and flexibility. The flexibility of mPBI-FM can be optimized to decrease uptake by macrophages in vivo, leading to increased circulation time versus (-)PBI-FM without PBI tetrablocks after intravenous administration in mice. While PEG-b-PPS diblocks form FM within a narrow range of hydrophilic weight fractions, incorporation of pi-stacking PBI groups expanded this range to increase favorability of FM assembly. Furthermore, the aggregation-dependent fluorescence of PBI shifted during oxidation-induced "cylinder-to-sphere" transitions of mPBI-FM into micelles, resulting in a distinct emission wavelength for filamentous versus spherical nanostructures. Thus, incorporation of pi-stacking allows for rapid, scalable assembly of FMs with tunable flexibility and stability for theranostic and nanomedicine applications.