(464h) Engineering Nano-Bio Interface to Overcome Biological Barriers for Precision Nanomedicine

Nanoparticles have played important roles in advancing biological sciences and medicine. These nanomaterials have demonstrated tremendous potential for various nanomedicine and theranostic applications, including biomedical imaging, drug delivery, and disease diagnostics [1-4]. Nevertheless, there have been increasing studies reporting the failures of nanoparticles in realizing their intended objectives due to a single or combination of factors [5-7], notably the existence of biological barriers throughout the body, such as cell membrane and phagocytic barriers [8-9]. These biological barriers present significant obstacles for the trafficking and target localization of nanoparticles and ultimately, challenge the merit of nanoparticles for nanomedicine and theranostic applications. Numerous attempts have been made to overcome biological barriers by controlling the biological behaviors of nanoparticles, which is primarily achieved through manipulating nanoparticle properties. However, many of these attempts still fail to adequately address the issue of biological barriers, which may be due to a lack of fundamental understanding of the interfacial interactions between nanoparticles and biological barriers. Furthermore, a majority of the reported works have focused on the biological effects, either at the molecular, cellular, or organ levels, elicited by nanoparticles by tuning only one or two of their properties. Crucially, the interdependency of several physicochemical properties of nanoparticles in determining their biological effects across multiple scales remain unclear.

Herein, using polymeric nanoparticles as model nanomaterials, I will describe our effort in interrogating their nano-bio interactions with various biological entities, such as blood plasma proteins, endothelial cells, macrophages, and zebrafish larvae, and how the acquired information could be used to inform the rational engineering of nanoparticles with improved theranostic efficacy [10]. First, a series of polymeric nanoparticles comprising biocompatible polymeric nanoshells (i.e., polystyrene, poly(lactic-co-glycolic acid) (PLGA), and polyethylene glycol (PEG)) wrapping organic fluorophores was formulated. After the preparation of nanoparticles, we evaluated their physicochemical characteristics, such as surface morphology, size distribution, zeta potential, lipophilicity, optical absorbance, and fluorescence. Subsequently, based on different experimental characterization and molecular simulation, we comprehensively assessed the interdependent effect of nanoparticle lipophilicity, zeta potential, and size on the recruitment of plasma proteins around the nanoparticles as well as the in vitro cellular internalization and in vivo biodistribution of nanoparticles in zebrafish larvae.

Nanoparticle lipophilicity was noted to influence the recruitment of plasma proteins, where non-specific protein adsorption could be decreased by reducing nanoparticle lipophilicity. For a particular lipophilicity, the nanoparticle size had a more pronounced role in dictating protein adsorption than the nanoparticle surface charge. However, irrespective of size, the surface charge of nanoparticles affected their endothelium and macrophage uptake as well as circulation lifetime. Specifically, the negatively charged nanoparticles could be preferentially internalized by endothelial cells without requiring active targeting ligands. In addition, these nanoparticles were minimally taken up by macrophages and displayed a much longer circulation lifetime. In light of our experimental results, we proposed a two-step framework to rationally design a single polymeric nanoparticle system capable of overcoming various biological barriers, including non-specific biomolecule adsorption, endothelial cell membrane barrier, and phagocytic clearance. We anticipate that this work will provide a strong basis for the design of more effective theranostic nanoparticles and further aid the engineering of nano-bio interface to overcome biological barriers for precision nanomedicine.

References

[1] Elsabahy et al., Chemical Reviews 115 (2015), 10967-11011.

[2] Ulbrich et al., Chemical Reviews 116 (2016), 5338-5431.

[3] Kenry et al., Accounts of Chemical Research 52 (2019), 3051-3063.

[4] Wong et al., ACS Nano 14 (2020), 2585-2627.

[5] Wilhelm et al., Nature Review Materials 1 (2016), 16014.

[6] Rosenblum et al., Nature Communications 9 (2018), 1410.

[7] Nature Nanotechnology 14 (2019), 1083.

[8] Blanco et al., Nature Biotechnology 33 (2015), 941-951.

[9] Meng et al., Biomaterials 174 (2018), 41-53.

[10] Kenry et al., ACS Nano 14 (2020), 4509-4522.