From Liposomes to Virosomes: Evolution of Phospholipid Nanocarriers in Drug Delivery.

Phospholipid-based nanocarriers are an adaptable and chemically tunable class of drug delivery systems that self-assemble into bilayered vesicles due to the amphiphilic nature of phospholipids. Phospholipid-based nanocarriers can encapsulate both hydrophilic and hydrophobic drugs through non-covalent interactions and modulation of lipid phase behavior. This review explores the molecular and supramolecular principles governing the formation, stability, and function of key phospholipid-derived nanocarriers, including liposomes, transferosomes, ethosomes, invasomes, phytosomes, pharmacosomes, and virosomes. The structural attributes-such as bilayer packing, surface charge, curvature elasticity, and membrane permeability-are critically evaluated for the impact of those structural parameters on optimizing drug loading, drug release, and bioavailability. For example, variations in bilayer packing affect the encapsulation efficiency and drug release profiles, while surface charge modulates cellular uptake and colloidal stability. Curvature elasticity plays a pivotal role in membrane fusion and drug release, and membrane permeability determines the rate at which drugs diffuse from the nanocarrier. Emerging multilamellar systems such as vesosomes and spongosomes are also discussed for their potential in site-specific, controlled drug release. Common fabrication techniques (e.g., thin-film hydration, ethanol injection, freeze-thaw, and microfluidics) and characterization methods (e.g., DLS, DSC, FTIR, and cryo-TEM) are reviewed. The translational landscape is assessed through clinically approved liposomal drugs, patent trends, and ongoing trials involving stimuli-responsive systems. Challenges related to colloidal stability, tumor penetration, immune interactions, and large-scale manufacturing are addressed. This review provides a chemistry-centered framework to guide the rational design and clinical development of phospholipid nanocarriers, particularly in cancer therapeutics.