Beyond Free Diffusion: Enhanced Permeation Promotes Lysosomal Release of Endocytic Drug by Deuterated Liposome and SERS-Raman Technique

Abstract: Understanding the spatiotemporal delivery and release of photosensitizers (PS) is critical to the efffcacy of photodynamic therapy. Herein, we developed a deuterated liposomal nanoplatform (HB4@D-Lip) and investigated its intracellular trafffcking and photo-responsive release. The lipid bilayer was labeled with the stable isotope deuterium, whose C–D stretching vibration at 2165 cm−1 lies in the cell-silent region and serves as an internal isotope tag for the carrier. Liposome encapsulation fundamentally alters subcellular drug routing. HB4@D-Lip nanoassemblies were internalized via endocytosis and preferentially localized in lysosomes. In contrast, free HB4 entered cells through passive diffusion and accumulated in mitochondria. Upon laser irradiation, liposome conffnement promoted reactive oxygen species generation and photothermal effects, thus enhancing lysosomal membrane permeabilization and enabling HB4 to escape from lysosomes and redistribute to mitochondria, whereas the carrier remained trapped in lysosomes. This "roundabout yet effective" strategy circumvents π–π stacking-induced aggregation of free photosensitizers, thereby enhancing Photodynamic Therapy (PDT) efffcacy.