Engineering tunable GTP/TPi-responsive liposomes through liposomal membrane modulation using a bis-triphenylphosphonium lipid switch

Abstract

Liposomes are effective nanocarriers for targeted therapeutic delivery, yet challenges regarding the extent and specificity of cargo release persist. Many disease conditions result in metabolite concentration dysregulation, increasing the appeal to harness overly abundant metabolite concentrations as triggers for targeted delivery and cargo release. Here, we introduce a novel stimuli-responsive liposomal platform with a tunable response to either guanosine triphosphate (GTP) or tripolyphosphate (TPi) that was achieved through incorporation of a novel bis-phosphonium-based lipid switch (BPLS) and strategic manipulation of liposome composition. This platform enables selective cargo release triggered by GTP, a metabolite upregulated in many fast-growing cancer cells. Fine-tuning of liposome composition also allows for TPi triggered release, a model phosphate compound to illustrate the dual response of this system. Hydrophobic and hydrophilic dye release assays, dynamic light scattering, transmission electron microscopy, and kinetic cargo release studies confirmed metabolite-responsive membrane perturbation driven by BPLS, inciting controlled release of both polar and non-polar cargo. By fine-tuning liposome composition to control metabolite selectivity and release kinetics, this platform offers a versatile framework for addressing complex metabolite profiles in diseased cells, expanding the stimuli-responsive liposome toolbox toward the potential of customized drug delivery.