Endosomal escape remains the most prominent bottleneck at the intracellular level for non-viral vectors today. Gold nanoparticles (AuNP) can be used to overcome the endosomal membrane barrier upon laser irradiation. Depending on the energy of nanosecond laser pulses, this can be achieved by either endosomal rupture by the mechanical energy from water vapor nanobubbles (VNBs) that emerge around the AuNP, or permeabilization of the endosomal membrane by heat diffusion. Here, we designed a siRNA/AuNP drug delivery system, to address the open question of how both photothermal effects influence cargo release, transfection efficiency, acute cytotoxicity and cell homeostasis. We found that, contrary to heat-mediated endosomal escape, VNB generation produced excellent transfection levels independent of the cell type, without inducing long-term changes in cell homeostasis.