Nanomedicine (NM)-mediated delivery of RNA faces many extra-and intracellular barriers. Upon endocytosis by target cells, NMs are trafficked toward lysosomes for degradation and conventional endosomal escape strategies fall short. Here, we propose to exploit cationic amphiphilic drugs (CADs) as adjuvants to trigger lysosomal escape of RNA therapeutics and to formulate CADs into lipid nanoparticles for improved siRNA and mRNA delivery.