Lipid-based nanoparticles (LNP) have shown significant progress in delivering mRNA for therapeutics, particularly with the success of coronavirus disease 2019 (COVID-19) vaccines. However, there are still challenges, such as organ-specific targeting, sustained protein expression, immunogenicity, and storage that need to be addressed. Therefore, there is interest in developing additional nano drug delivery systems (DDS) to complement LNP technology. Some of these include polymer, lipid-polymer hybrid, organic/inorganic hybrid nanostructure, and inorganic nanoparticle. In our opinion, LNP technology may not be suitable for every disease scenario in categories such as infection disease, cancer, pulmonary disease, autoimmune disorders and genetic rare disease (among others). This is because different diseases may require distinct administration routes, doses, and treatment durations, as well as considerations for biological barriers that may lower the efficacy and/or exert safety concern. In this perspective, we will highlight the need and potential for enhancing the diversity of nano delivery platforms for mRNA-based nanotherapeutics.