Nucleus-Targeted Delivery of Anticancer Drug Using Alpha-Synuclein(Y136C)-Gold Nanoparticle Conjugates

The nucleus plays a central role in eukaryotic cell survival by regulating essential processes. This makes it a strategic target for disrupting tumor growth in cancer therapy. Conventional nucleus-directed anticancer agents, including doxorubicin (Dox), have demonstrated effectiveness in treatment but face challenges related to poor cellular uptake and nuclear localization. To overcome these limitations, nanoparticle-based systems have been explored. In this study, α-synuclein-gold nanoparticle conjugates (αS-AuNPs) were employed as an intracellular drug delivery system for nuclear-targeted cancer therapy. αS, an intrinsically disordered protein, facilitates cellular uptake and nuclear accumulation. Dox was linked to αS-(Y136C)-AuNP via a heat-labile cross-linker, enabling controlled drug release upon near-infrared (NIR) irradiation. The photothermal effect of AuNPs induced localized hyperthermia, cleaving the linker. This facilitated the release of Dox directly into the nucleus, thereby enhancing its anticancer efficacy. This study demonstrates that Dox-αS-AuNP represents a promising nucleus-targeted drug delivery system for controlled and efficient cancer therapy.