Fluorination: A strategy to tune the interactions of molecules and nanoscale systems with biological matter.

Fluorination has become a key molecular engineering strategy in medicinal chemistry and nanomedicine, enabling the fine tuning of the physicochemical and biological properties of therapeutic molecules and drug delivery systems. The unique characteristics of fluorine, including its small steric footprint, high electronegativity, and exceptional strength of the C-F bond, enhance metabolic stability, modulate lipophilicity and acidity, and improve pharmacokinetic profiles. Beyond these well-established effects, fluorination has emerged as a tool for controlling the assembly and biological behavior of nanocarriers. Fluorinated biomolecules, polymers, dendrimers, and lipid-based systems often display improved colloidal stability, reduced nonspecific protein adsorption, enhanced cellular uptake, and efficient endosomal escape, ultimately leading to superior intracellular delivery of nucleic acids, proteins, and other therapeutic cargoes. Here we summarize recent advances in the fluorination of both therapeutic cargoes and delivery carriers, emphasizing how different fluorination strategies, including single fluorine atoms, trifluoromethyl groups, linear perfluoroalkyl chains, and emerging short branched fluorinated motifs, can be exploited to optimize drug delivery performance. Attention is devoted to the relationship between fluorinated molecular architectures, self-assembly, and bio-nano interactions that govern biological activity. Furthermore, the advantages and limitations of current fluorination approaches are discussed. Finally, we highlight the need for a deeper mechanistic understanding of how fluorinated moieties interact with proteins and biological membranes. Advanced physicochemical techniques, including neutron and X-ray scattering and reflectometry, are expected to provide fundamental insights into these processes, enabling the rational design of more effective, safer, and environmentally sustainable fluorinated therapeutics and nanomedicines.