Liposomal Nanoparticulate Drug Delivery Systems: Strategies to Destabilize Biological Membranes at the Target Tissue

Liposomal nanoparticulate drug delivery systems (LNDDSs) are clinically validated nanomedicine platforms seeing regular use in oncology and infectious disease. Their applications have rapidly expanded with several tissue targeting formulations in early-phase clinical trials. Beyond small molecular drugs, LNDDSs are increasingly employed for delivery of nucleic acid therapeutics, such as ribonucleic acid (RNA) based vaccines and immunomodulators. Recent advances in nanomaterials have enabled LNDDSs not only to transport therapeutic agents across systemic biological barriers but also to selectively destabilize plasma and organelle membranes, such as endosomes and mitochondria, addressing a wide range of diseases. This review systematically examines design strategies for LNDDSs that traverse key biological barriers focusing on the blood-tumor barrier, blood-brain barrier, and lymphatic transport barriers. We further explore approaches including fusogenic, pH-, redox- and, enzyme-sensitive and externally (ultrasound and thermal) triggered LNDDSs to facilitate internalization and membrane destabilization for specific organelle-targeting. The mechanisms and representative formulations and of membrane interactions, and clinical progress are discussed. Finally, the translational opportunities and challenges, and future perspectives for rational design of next-generation LNDDSs are addressed.