Rational design and translational advancement of phospholipid-based nanocarriers for targeted cancer therapy

Phospholipid-derived nanocarriers represent a versatile and chemically customizable class of drug delivery systems that self-assemble into bilayered vesicles due to their intrinsic amphiphilicity. These systems can encapsulate both hydrophilic and hydrophobic drugs through non-covalent interactions and manipulation of lipid phase behavior. This review examines the molecular and supramolecular principles underlying the formation, stability, and functional performance of key phospholipid-based nanocarriers-including liposomes, transferosomes, ethosomes, invasomes, phytosomes, pharmacosomes, and virosomes. We analyze critical structural parameters such as bilayer packing, surface charge, curvature elasticity, and membrane permeability, emphasizing their impact on drug loading efficiency, controlled release, and bioavailability. Advanced multilamellar systems such as vesosomes and spongosomes are also highlighted for their promise in achieving site-specific, sustained drug delivery. Key fabrication methods-including thin-film hydration, ethanol injection, freeze-thaw cycles, and microfluidics-are discussed alongside analytical techniques such as dynamic light scattering (DLS), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and cryo-transmission electron microscopy (cryo-TEM). The review further explores the translational landscape, with a focus on clinically approved liposomal formulations, patent developments, and emerging clinical trials involving stimuli-responsive systems. Persistent challenges such as colloidal stability, tumor penetration, immune system interactions, and scalable manufacturing are critically assessed. Altogether, this review offers a chemistry-focused framework for the rational design and clinical translation of phospholipid nanocarriers in cancer drug delivery.