Amphiphilic Lipid–Polymer Triblock Architectures as Nanocarriers for Therapeutic Delivery

Abstract

This study investigates the formation and characterization of nanocarriers derived from the self-assembly of amphiphilic lipid-polymer hybrids (LPHs) engineered with a symmetric ABA block copolymer architecture. In this design, the terminal A-blocks comprise branched hydrophobic fatty acid (FA) moieties, while the central B-block consists of a hydrophilic polymer segment, either polyethylene glycol (PEG) or a polypeptide-based glycine–lysine (GK) construct. By systematically varying the degree of branching within the hydrophobic blocks and the chemical identity of the hydrophilic segments, this work elucidates how architectural and compositional features govern the physicochemical behavior of the resulting nanoparticles (NPs). Comprehensive characterization, including 1D and 2D NMR spectroscopy, differential scanning calorimetry (DSC), dynamic light scattering (DLS), transmission electron microscopy (TEM), and in vitro cellular assays, revealed that both the morphology and mechanical properties of the NPs could be finely tuned through precise molecular design. Results indicate that NPs within the therapeutic size window (<200 nm) and with near-neutral surface charges meet key criteria for systemic delivery. Encapsulation efficiencies (EE%) for small-molecule therapeutics (doxorubicin and curcumin) ranged from 11–33%. Notably, modulation of hydrophilic block identity produced distinct NP surface chemistries that appear to influence cellular uptake behavior, while variations in hydrophobic block branching affected particle size distributions and nanostructural integrity. Substitution of inert PEG with the cationic, biofunctional GK polypeptide was associated with increased cellular uptake and enhanced doxorubicin delivery efficacy in breast cancer cell models. Additionally, increasing hydrophobic branching density (4FA versus 2FA) was correlated with improved colloidal stability and the formation of larger internal hydrophobic domains, supporting higher drug loading capacity. Collectively, these results provide an initial in vitro proof of concept and begin to establish structure–property–function relationships that expand the design space of amphiphilic LPH nanocarriers. While promising as an exploratory study, the work lays the groundwork for future studies needed to evaluate biological performance, safety, and translational potential.