Alpha-Synuclein-Stabilized Nanocarriers for Intracellular Delivery of Drugs and Their Controlled Release with Light

α-synuclein-stabilized nanocarriers (α-Syn NCs) have been developed as a functional drug delivery platform exhibiting a facilitated intracellular delivery of drugs and their light-triggered induced release via heat generation, which could exert both chemical and physical therapeutic effects on cancer cells. To achieve this, a eutectic phase-changing material (PCM) composed of lauric and myristic acids was used as the core to encapsulate both chemical drug and near-infrared (NIR) absorbing dye by employing an oil-in-water emulsification procedure. α-Syn, an intrinsically disordered protein with self-assembly properties, served as a stabilizer at the oil-water interface by forming a structurally stable shell around the PCM core. The resulting α-Syn NCs exhibited physicochemical stability under various conditions including changes in pH, ionic strength, and mechanical stress. Notably, the α-helix induced on the surface of α-Syn NC facilitated membrane penetration of the nanocarrier, which would contribute to an efficient intracellular drug delivery. Upon NIR laser irradiation, the photothermal effect of the NIR-absorbing dye allowed the PCM core to melt, enabling controlled drug release. Simultaneously, the localized heat also caused the death of cancer cells, and the combined action of thermal damage and chemotherapeutic drug release demonstrated a potential of α-Syn NCs to be utilized for combinatorial therapy. This integrated system, therefore, offers a distinctive therapeutic strategy toward cancer by exerting both chemical and physical therapeutic effects with the α-Syn-stabilized nanocarrier capable of facilitating membrane translocation and an externally triggered drug release.