RNAs are promising therapeutics for the treatment of a variety of genetic and intractable diseases. Short interfering RNAs (siRNAs) were developed in 2001 following the discovery of RNA interference (RNAi) in Caenorhabditis elegans in 1998 [1,2] and were successfully approved by the Food and Drug Administration (FDA) as Onpattro (Alnylam) in 2018 [3]. Furthermore, with the arrival of the coronavirus (COVID-19) pandemic in 2019, mRNA vaccines including Comirnaty (Pfizer/BioNTech) and Spikevax (Moderna) have been rapidly approved following disclosure of the genome sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [4]. These drugs have contributed to a significant decrease in the resultant worldwide mortality rate [5,6]. All of the above RNA therapeutics are lipid nanoparticle (LNP) drugs, and the development of high-performance ionizable lipids based on rational design and high-throughput screening has contributed greatly to their excellent efficacy. In this paper, important discoveries regarding the structural design of ionizable lipids and our own lipid design are highlighted from the viewpoints of efficient RNA delivery, improved safety, biodistribution, and the efficacy of mRNA vaccines.

Cancer immunotherapy has become a standard in cancer drug therapy since approval of the first immune checkpoint inhibitor (ICI) in 2011, which is anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (ipilimumab). When our immune system spontaneously removes transformed (abnormal) cells and the immunotherapies work, credit should be given to the fundamental framework mechanism that is in accordance with the cancer-immunity cycle proposed in 2013 [7]. Recently, the cancer-immunity cycle has been updated with remarkable developments in tumor immunology [8]. The cancer-immunity cycle is mainly depicted as T cell responses to cancer, but emerging data have revealed that natural killer (NK) cells are also deeply involved in the cancer-immunity cycle [9]. Thus, the development of direct delivery system (DDS) technology to control the cancer-immunity cycle and NK cells could contribute to new cancer immunotherapies. The nano DDS technology for controlling the cancer-immunity cycle and NK cell functions is discussed herein based on our recent findings.

Organelle targeting is expected as the next-generation technology and mitochondria is considered a target that is as important as the nucleus. Mitochondria play an essential role in maintaining life, and dysfunction in mitochondrial function can trigger various diseases such as cancer, ischemic disorders, neurodegenerative diseases, metabolic disorders, and mitochondrial genetic diseases. Therefore, the development of a DDS targeted to mitochondria is expected to advance the medical and life sciences fields. In the early 2000s when our research began, there were few reports on mitochondrial DDS. However, the importance of delivery that targets mitochondria is now well established, and the development of mitochondrial DDS is frequently highlighted [10,11]. In this paper, we provide an overview of DDS that targets mitochondria and we introduce our mitochondrial-targeting DDS, which is referred to as the MITO-Porter [12]. Considering the increasing attention on cell transplantation therapy with stem cells in nanomedicines, we specifically focus on mitochondrial activation by mitochondrial delivery of functional cargoes using the MITO-Porter. And last, we introduce mitochondria-activated cells, which are referred to as MITO cells [13,14] and have been in development by medical professionals for more than a decade.