(587f) Enhancing Nanocarrier Targeting: Role of Cell Morphology, Mechanics, and Receptor-Ligand Interactions

Despite significant advances in the design of functionalized nanocarriers (NCs), developing efficient targeted delivery systems remains challenging due to insufficient understanding of the biological barriers imposed by the cellular microenvironment. This study advances efforts to overcome these challenges by employing a multiscale computational framework, acknowledging that while systemic factors across multiple scales influence these barriers, critical details at the cellular level play a pivotal role in specific applications.

Cellular targeting involves both the adhesion (avidity) and internalization (uptake) of NCs, which are influenced by the properties of the NCs, the targeted cells, and their microenvironment. Adhesion requires the simultaneous binding of numerous ligands on the NC’s surface to receptors on a cell surface. The outcome of such multivalent adhesion, critical for processes including cell uptake, is determined by the strength of ligand-receptor binding interactions. These interactions are essential in cell biology for cellular response to external stimuli, impacting signaling pathways, gene expression, and interactions with the cellular matrix and other cells, thereby influencing cell fate decisions. They are also key in receptor trafficking, viral entry, and are exploited in targeted therapies and diagnostic imaging for precise drug delivery and diagnostics.

In this context, we examine how cell morphology and mechanics, receptor expression levels, and ligand composition influence the binding of ligand-coated particles to cell membranes with target receptors. We quantify the binding efficacy of these interactions through multivalency, the binding free-energy landscape, and changes in configurational entropies. Our findings indicate that: 1) the binding avidity of NCs is determined by the balance between enthalpic and entropic contributions, 2) cell mechanics and cytoskeletal proteins create unique membrane topographies that affect NC binding and uptake, and 3) changes in receptor levels and ligand composition can modify binding avidity independently of multivalency. Our methods and findings offer significant insights for the design of functionalized carriers and deepen understanding of cell adhesion mechanisms.

This work is supported by NSF Grant CBET-2327899 and Oracle for Research