Engineering Smart Hybrid Nanocarriers: Impact of Architecture on Responsive Behavior

Abstract Stimuli-responsive hybrid nanosystems have attracted increasing attention because they enable adaptive behavior through the integration of multiple functional nanobuilding blocks. Herein, we report on the engineering of environment-responsive nanosystems through the development of reproducible and potentially scalable synthetic routes, while providing insight into how nanoarchitecture influences their stimulus-response behavior. We produced multilayer core–shell copolymers colloids composed of three modular components: Au (plasmonic heating module), silica (providing metal stabilization and surface chemistry compatibility), and P(NIPAM-co-AA) (thermo- and pH-responsive domain). To elucidate the impact of the nanoarchitecture on the dual response behavior, we methodically varied the silica shell structure (dense versus mesoporous) and the copolymer architecture (cross-linked network versus brushlike structure), enabling a systematic evaluation of how these structural features govern stimulus-responsive behavior and their capability in loading and controlling molecule release. The resulting nanosystems were monodisperse and colloidally stable, while their thermo- and pH-responsive behavior could be precisely tuned through the silica and polymer nanoarchitecture. The nanosystems were studied as carriers for doxorubicin (DOX), which is a well-known chemotherapeutic drug. We demonstrated that the nanosystems efficiently loaded DOX, particularly when porous domains were present in either the silica or polymer shell. DOX release was controlled by the combined effects of the tumor microenvironment and plasmonic heating. In vitro assays performed on a human melanoma cell line (Mel-J) proved that the DOX release from the nanosystems exhibited cytotoxicity comparable to that of free DOX, reducing the cell viability to approximately 50%. These findings highlight the potential of the developed smart hybrid nanosystems as an alternative strategy for DOX-based chemotherapy.