Design, Synthesis, and Physicochemical Characterization of Boronic Acid-Linked Cationic Lipids: Aggregation, Diol Recognition, Membrane Perturbation, and DNA Complexation.

Boronic acids are attractive functional groups because they form reversible covalent bonds with cis-diols, enabling selective recognition of saccharides, glycoproteins, and related biomolecules. Although widely exploited in sensing and glycobiology, their incorporation into lipid-based systems remains relatively unexplored. Integrating boronic-acid-mediated molecular recognition into amphiphilic frameworks while preserving controlled self-assembly and biomolecular interactions continues to be a significant challenge. Here, we report the design, synthesis, and characterization of a new series of cationic amphiphiles incorporating aromatic boronic acids of differing acidity. Phenylboronic acid (pKa ∼ 9.3) and pyridylboronic acid (pKa ∼ 5.3) were conjugated either to α-tocopherol or to a linear C16 alkyl chain, yielding four lipids, TPhBA, TPyBA, C16PhBA, and C16PyBA, that provide a systematic platform to probe the influence of headgroup pKa and hydrophobic architecture. Physicochemical analysis showed that pyridyl derivatives exhibited higher critical aggregation concentrations and zwitterionic character at neutral pH, while phenyl derivatives formed aggregates at lower concentrations with high surface charge values. Small-angle X-ray diffraction, TEM, and AFM confirmed variations in bilayer packing geometry and aggregate morphology. Preferential carbohydrate interactive behavior was demonstrated through alizarin red S assays, where both phenyl and pyridinyl boronic acid derivatives showed stronger diol binding. 1,2-dipalmitoylphosphatidylcholine (DPPC) membrane studies showed that tocopherol-based lipids markedly disrupted the gel-to-liquid crystalline transition, whereas C16 derivatives caused only modest perturbations. DNA-binding assays further revealed that pyridyl derivatives formed more stable lipoplexes, while phenyl analogues facilitated easier DNA release. Collectively, these findings demonstrate that boronic acid headgroup acidity and hydrophobic architecture govern aggregation, diol recognition, membrane interactions, and DNA complexation, highlighting their potential as responsive materials for membrane engineering and delivery applications.