Bicontinuous nanospheres (BCNs) are polymeric analogs to lipid cubosomes, possessing cubic liquid crystalline phases with high internal surface area, aqueous channels for loading hydrophilic molecules, and high hydrophobic volume for lipophilic payloads. Primarily due to difficulties in scalable and consistent fabrication, neither controlled delivery of payloads via BCNs nor their organ or cellular biodistributions following in vivo administration have been demonstrated or characterized. We have recently validated flash nanoprecipitation as a rapid method of assembling uniform monodisperse 200-300 nm diameter BCNs from poly(ethylene glycol) -b-poly(propylene sulfide) (PEG -b-PPS) co-polymers. Here, we compare these BCNs both in vitro and in vivo to 100 nm PEG -b-PPS polymersomes (PSs), which have been well characterized as nanocarriers for controlled delivery applications. Using a small molecule fluorophore and a fluorescently tagged protein as respective lipophilic and water-soluble model cargos, we demonstrate that BCNs can achieve significantly higher encapsulation efficiencies for both payloads on a per unit mass basis. At time points of 4 and 24 h after intravenous administration to mice, we found significant differences in organ-level uptake between BCNs and PSs, with BCNs showing reduced accumulation in the liver and increased uptake in the spleen. Despite these organ-level differences, BCNs and PSs displayed strikingly similar uptake profiles by immune cell populations in vitro and in the liver, spleen, and blood, as assayed by flow cytometry. In conclusion, we have found PEG -b-PPS BCNs to be well suited for dual loading and delivery of molecular payloads, with a favorable organ biodistribution and high cell uptake by therapeutically relevant immune cell populations.

Magnetic nanostructures (MNS) have a wide range of biological applications due to their biocompatibility, superparamagnetic properties, and customizable composition that includes iron oxide (Fe3O4), Zn2+, and Mn2+. However, several challenges to the biomedical usage of MNS must still be addressed, such as formulation stability, inability to encapsulate therapeutic payloads, and variable clearance rates in vivo. Here, we enhance the utility of MNS during controlled delivery applications via encapsulation within polymeric bicontinuous nanospheres (BCNs) composed of poly­(ethylene glycol)-block-poly­(propylene sulfide) (PEG-b-PPS) copolymers. PEG-b-PPS BCNs have demonstrated versatile encapsulation and delivery capabilities for both hydrophilic and hydrophobic payloads due to their unique and highly organized cubic phase nanoarchitecture. MNS-embedded BCNs (MBCNs) were thus coloaded with physicochemically diverse molecular payloads using the technique of flash nanoprecipitation and characterized in terms of their structure and in vivo biodistribution following intravenous administration. Retention of the internal aqueous channels and cubic architecture of MBCNs were verified using cryogenic transmission electron microscopy and small-angle X-ray scattering, respectively. MBCNs demonstrated improvement in magnetic resonance imaging (MRI) contrast enhancement (r 2 relaxivity) as compared to free MNS, which in combination with scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy evidenced the clustering and continued access to water of MNS following encapsulation. Furthermore, MBCNs were found to be noncytotoxic and able to deliver their hydrophilic and hydrophobic small-molecule payloads both in vitro and in vivo. Finally, the oxidation sensitivity of the hydrophobic PPS block allowed MBCNs to undergo a unique, triggerable transition in morphology into MNS-bearing micellar nanocarriers. In summary, MBCNs are an attractive platform for the delivery of molecular and nanoscale payloads for diverse on-demand and sustained drug delivery applications.

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.

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