With the FDA's emergency use/authorization of two lipid nanoparticles (LNPs) based mRNA vaccines for COVID-19 pandemic prevention, i.e. Pfizer-BioNTech and Moderna mRNA vaccines, the research on the use of mRNA vaccines for preventive and therapeutic applications against emerging diseases has significantly increased [1,2]. Currently, there are >70 ongoing mRNA-based clinical trials [3]. Apart from the research for preventing infectious diseases, most of the mRNA vaccines are studied for cancer vaccination [4]. As a matter of fact, mRNA-based cancer vaccines have been investigated in small trials for a decade, and researchers used the experiences from developing cancer vaccines to develop COVID-19 vaccines. The research advantages in mRNA vaccine design and delivery in turn accelerate the research and clinical application of cancer mRNA vaccines [5,6].

Cancer vaccines are designed to strengthen the body's natural defenses to eliminate cancerous cells by stimulating anti-tumor immune responses [7]. Until now, only two prophylactic and one therapeutic cancer vaccines have been approved for clinical use. Both the prophylactic ones are vaccines against virus caused tumors, one is against human papillomavirus (HPV) induced cervical cancer, and the other is for Hepatitis B virus caused liver cancer [8]. The therapeutic cancer vaccine Sipuleucel-T is a dendritic cell based vaccine for prostate cancer [9]. The limited success of the cancer vaccines despite decades of research is partly due to the sub-optimal antigen targeting and weak immune stimulation potency of the available vaccines [10].

mRNA based vaccines represent an attractive platform to improve the immune stimulation and therapeutic efficacy of cancer vaccines. As compared to protein or peptide-based vaccine strategies, mRNA vaccines have multiple advantages. First, mRNA vaccines can encode full length tumor antigens, thereby can stimulate a broader T cell response [11]. Besides, mRNA vaccines allow delivery of multiple antigens at the same time, enabling stimulation of both cellular and humoral immune responses [12]. Secondly, potent CD8+ T cell responses are crucial for the elimination of cancerous cells [13]. Successful transfection of mRNA will lead to endogenous expression of the antigen, which can induce more efficient CD8+ T cell responses than that occur via cross-presentation [14]. Finally, the production of mRNA can be easily enlarged, which is more rapid, cheap and conducive to large-scale deployment [15]. The produced mRNA vaccines are free of protein or virus-derived contaminations, thereby possess better safety [16]. On the other hand, as compared to DNA based vaccines, mRNA vaccine is safer as the mRNA antigen does not integrate into the genome sequence, causing no gene toxicity [17].

Despite the advantages of mRNA-based vaccines, the poor stability and low transfection efficiency of mRNA vaccines are the obstacles lying in front of their successful translation. Naked mRNA is unstable, and can be quickly degraded by extracellular RNases [18]. Additionally, the mRNA needs to pass through the cellular membrane before they can enter into the cytoplasm to express the encoded protein, while the cellular uptake efficiency of naked mRNA is extremely low [19]. To overcome these challenges, non-viral gene transfer strategies including lipoplexes, polyplexes and electroporation have been developed [20]. The success of LNPs for mRNA vaccine delivery further brings researcher's attention to nano-vector based mRNA delivery systems. In order to overcome the constrains of currently available mRNA carriers and to conquer the specific hurdles for immune activation in tumor environmental settings, emerging new nano-vector based delivery systems have been developed with the aim of improving the transfection and immune stimulation capacity of mRNA vaccines for anti-tumor use [[21], [22], [23]].

In the current review, we focused on the use of nano-vectors for enhancing the delivery efficiency of mRNA based cancer vaccines. We reviewed the working mechanism and research progress of different nano-vectors in the past decade, especially in the past 5 years, with focuses on LNPs, lipid enveloped hybrid nanoparticles and polymeric nanoparticles. Several strategies that have been reported for improving the immune stimulation capacity of the mRNA nano-vaccines, including fabricating mRNA based nano-vaccines for co-delivering adjuvants, combination of mRNA nano-vaccines with immune checkpoint inhibitors and tunation of injection routes for enhancing immune responses, have been discussed. We also provide the overview of research progress of different nanoplatforms in clinical studies, and discussed the prospects of mRNA nanovaccines for cancer vaccination.