Proceedings of the National Academy of Sciences of the United States of AmericaJul 16, 2026

Fast production of personalized cancer vaccines using lab-made RNA that makes proteins without cell-based methods

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Updated Jul 17, 2026

Abstract

Personalized mRNA neoantigen vaccines can now be produced rapidly using a novel RNA oligonucleotide method.

Current mRNA vaccine production typically takes over three months, risking the loss of therapeutic opportunities for patients.
Chemically synthesized RNA oligonucleotides can be produced without the need for DNA templates or complex fermentation processes.
A new 39 nucleotide cap-independent translation enhancer (CITE) element, BBV, can facilitate RNA translation.
Protein-Encoding RNA Oligonucleotides (PEOs) were developed to encode proteins efficiently in mammalian cells through a circularization process.
PEOs showed undetectable levels of proinflammatory double-stranded RNAs and minimal immunogenicity compared to traditional mRNA vaccines.
In animal models, PEO vaccines demonstrated significant tumor growth inhibition and therapeutic benefits alongside checkpoint blockade therapy.

Simplified

Personalized mRNA neoantigen vaccines demonstrate great potential in cancer therapy, but their customization typically requires more than three months, risking the loss of the optimal therapeutic window for patients. This delay is primarily due to the reliance of current mRNA vaccine production on plasmid fermentation and in vitro transcription (IVT), which involve multiple complex steps. Chemically synthesized RNA oligonucleotides, such as antisense oligonucleotides (ASOs), are produced sparing DNA templates or IVT, thus enabling rapid manufacturing. However, ASOs are limited in length, which precludes their ability to encode proteins. Here, we introduced a 39 nucleotides cap-independent translation enhancer (CITE) element termed BBV that can drive RNA translation. Furthermore, BBV was compatible with efficient rolling circle translation (RCT). We chemically synthesized RNA oligonucleotides containing BBV and gene of interest (GOI) with characteristic 5'-OH and 3'-P termini, which could undergo circularization by endogenous RtcB RNA ligases and efficiently encode proteins through RCT in mammalian cells. We designated these RNA oligonucleotides as Protein-Encoding RNA Oligonucleotides (PEOs). Notably, compared with IVT-produced RNAs, PEOs contained undetectable levels of proinflammatory double-stranded RNAs and exhibited minimal immunogenicity. We further demonstrated that PEO-OVA (encoding OVA antigens) significantly inhibited tumor growth comparable to mRNA vaccine. In an orthotopic glioma model, PEO vaccine also exhibited therapeutic benefits with checkpoint blockade therapy. This study establishes an IVT-free RNA vaccine platform that enables rapid, safe, and highly druggable manufacturing of personalized cancer vaccines, offering substantial potential for clinical application.

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Competing interests

Competing interests statement:L.Q. is the founder of JianJie BioTech. The other authors declare no competing interests. Patents related to the data presented in this manuscript have been filed.

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Fast production of personalized cancer vaccines using lab-made RNA that makes proteins without cell-based methods

Abstract

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Funding

Competing interests

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