Light-Responsive Hybrid Lipid Nanoparticles with Gold Nanorods for Light-Triggered DNA Delivery

Gene therapy is a cutting-edge strategy for treating, preventing, and potentially eradicating a wide range of diseases. Its success is critically dependent on the transfection efficiency of gene delivery systems. In this context, lipid nanoparticles (LNPs) are widely investigated for the delivery of plasmid DNA. However, their performance still lacks precise spatiotemporal control. To address this limitation, we present a novel plasmonic hybrid delivery system composed of gold nanorods (AuNRs) assembled on the LNP surface. This architecture integrates the efficient delivery properties of LNPs with the optical responsiveness of AuNRs, enabling the light-induced release of plasmid DNA upon near-infrared (NIR) laser irradiation. The morphology of AuNRs was specifically tailored to achieve photothermal (PT) heating under NIR laser excitation, thereby enabling PT-assisted regulation of transfection. Thermo-optical, physicochemical, and morphological analyses confirm that LNP/AuNRs display the desired features, including an absorption band centered at 860 nm, a unimodal size distribution, and a positive surface charge. Ultrastructural evaluation by transmission electron microscopy (TEM) reveals cellular internalization of LNP/AuNRs and robust plasmid DNA transfection following NIR laser irradiation. PT heating significantly enhances transfection efficiency in human embryonic kidney 293 (HEK293) cells compared to nonirradiated samples. Biomimetic assays using anionic liposomes revealed that NIR-triggered DNA release is facilitated by nanoparticle-membrane interactions, likely involving structural destabilization of the hybrid system under PT activation. Time-lapse imaging and multichannel confocal microscopy revealed that NIR-induced PT activation modulates the intracellular dynamics of LNP/AuNRs by reducing lysosomal association and promoting a more diffusive behavior, potentially contributing to enhanced cargo availability and transfection efficiency. These findings demonstrate the multifunctional properties of LNP/AuNRs as an efficient, light-responsive platform for PT-triggered plasmid DNA delivery, opening a new avenue for on-demand gene therapy.